Satellite Cells and The Muscle Stem Cell PDF

Physiol Rev 93: 23 67, 2013 doi:10.1152/physrev.00043.
2011
SATELLITE CELLS AND THE MUSCLE STEM CELL NICHE

Hang Yin, Feodor Price, and Michael A. Rudnicki
Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
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Yin H, Price F, Rudnicki MA. Satellite Cells and the Muscle Stem Cell Niche. Physiol Rev 93: 23 67, 2013; doi:10.1152/physrev.00043.2011.Adult skeletal muscle in mammals is a stable tissue under normal circumstances but has remarkable ability to repair after injury. Skeletal muscle regeneration is a highly orchestrated process involving the activation of various cellular and molecular responses. As skeletal muscle stem cells, satellite cells play an indispensible role in this process. The self-renewing proliferation of satellite cells not only maintains the stem cell population but also provides numerous myogenic cells, which proliferate, differentiate, fuse, and lead to new myober formation and reconstitution of a functional contractile apparatus. The complex behavior of satellite cells during skeletal muscle regeneration is tightly regulated through the dynamic interplay between intrinsic factors within satellite cells and extrinsic factors constituting the muscle stem cell niche/microenvironment. For the last half century, the advance of molecular biology, cell biology, and genetics has greatly improved our understanding of skeletal muscle biology. Here, we review some recent advances, with focuses on functions of satellite cells and their niche during the process of skeletal muscle regeneration.
INTRODUCTION: SATELLITE CELLS AS... FUNCTIONS OF SATELLITE CELLS IN... ANATOMIC AND FUNCTIONAL... CONCLUDING REMARKS AND... 23 30 41 53
I. INTRODUCTION: SATELLITE CELLS AS ADULT STEM CELLS IN MUSCLE

Skeletal muscle is a form of striated muscle tissue, accounting for 40% of adult human body weight. Skeletal muscle is composed of multinucleated contractile muscle cells (also called myobers). During development, myobers are formed by fusion of mesoderm progenitors called myoblasts. In neonatal/juvenile stages, the number of myobers remains constant, but each myober grows in size by fusion of satellite cells, a population of postnatal muscle stem cells. Adult mammalian skeletal muscle is stable under normal conditions, with only sporadic fusion of satellite cells to compensate for muscle turnover caused by daily wear and tear. However, skeletal muscle has a remarkable ability to regenerate after injury. Responding to injury, skeletal muscle undergoes a highly orchestrated degeneration and regenerative process that takes place at the tissue, cellular, and molecular levels. This results in the reformation of innervated, vascularized contractile muscle apparatuses. This regeneration process greatly relies on the dynamic interplay between satellite cells and their environment (stem cell niche). During the last half century, advances in molecular biology, cell biology, and genetics has greatly improved our understanding of skeletal muscle regeneration. In particular, extensive research on satellite cells and their niche has
elucidated many cellular and molecular mechanisms that underlie skeletal muscle regeneration. These studies have contributed to the development of therapeutic strategies. These strategies serve to alleviate the physiological and pathological conditions associated with poor muscle regeneration observed in sarcopenia and muscular dystrophy. Here, we concentrate on the functions of satellite cells and the regulation of their niche during the process of skeletal muscle regeneration. We rst describe the current understanding of satellite cells with respect to their characteristics, heterogeneity, and embryonic origin. We then provide an integrated view of the roles played by satellite cells during muscle regeneration and normal postnatal muscle growth. We also discuss the contribution of several nonsatellite cell populations in muscle regeneration and their lineage relationships with satellite cells. Next, we focus on the satellite cell niche with emphasis on the regulatory mechanisms associated with each niche component. We further review the links between malfunction of satellite cells and their niche factors during aging. This review focuses on satellite cells and their niche in mammalian models, paying limited attention to the studies of satellite cell biology in other model organisms.
A. A Brief History of Satellite Cells

Half a century ago, Alexander Mauro observed a group of mononucleated cells at the periphery of adult skeletal muscle myobers by electron microscopy (329). These cells were named satellite cells due to their sublaminar location
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YIN, PRICE, AND RUDNICKI and intimate association with the plasma membrane of myobers. The direct juxtaposition of satellite cells and myobers immediately raised a hypothesis that these cells may be involved in skeletal muscle growth and regeneration (329). Indeed, experiments by [3H]thymidine labeling and electron microscopy demonstrated that satellite cells undergo mitosis, assume a cytoplasm-enriched morphology, and contribute to myober nuclei (355, 437). Later on, [3H]thymidine tracing experiments indicated that satellite cells are mitotically quiescent in adult muscle but can quickly enter the cell cycle following muscle injury (499). The same study also demonstrated that satellite cells give rise to proliferating myoblasts (myogenic progenitors cells), which were previously shown to form multinucleated myotubes in vitro (276, 499, 574). More denitive evidence came from in vitro cultures of individually dissected myobers, whereby the behaviors of single myobers and their resident satellite cells during regeneration can be tracked by phase-contrast microscopy (51, 277). It was observed that myober necrosis is accompanied by satellite cell outgrowth, clonal expansion, and later fusion to form functional regenerated myotubes. These experiments support the notion that it is the satellite cell, rather than the myonuclei, that contribute to postnatal muscle growth and repair. The pivotal function of the satellite cell in muscle regeneration stimulated research to determine their regulatory mechanisms. This started with the nding that quiescent satellite cells on single myobers were activated to enter the cell cycle by a mitogen originating from crushed skeletal muscles (53). In search of this mitogen, it was found that the proliferation and differentiation of satellite cell-derived myoblasts cultured in vitro respond to various growth factors in a dose-dependent manner (10, 11). Numerous studies further revealed that the proliferation and differentiation of satellite cells during muscle regeneration is profoundly inuenced by innervation, the vasculature, hormones, nutrition, and the extent of tissue injury (121, 224, 250, 332, 360, 410). Interestingly, satellite cells in contact with the plasma membrane of intact myobers were found to have reduced sensitivity to mitogen stimulation (50). All of these ndings led to an intriguing notion that satellite cells reside in a special microenvironment in vivo, which profoundly affects their behavior. By denition, stem cells found in adult tissues can both replicate themselves (self-renew) and give rise to functional progeny (differentiate). Although the ability of satellite cells to differentiate into myobers was clearly proven, their ability to self-renew was once questioned. The rst evidence of satellite cell self-renewal came from a single myober transplantation assay. It was found that as few as seven satellite cells, when transplanted into irradiated regeneration-insufcient mice along with their resident single myober, can give rise to hundreds of satellite cells and thousands of myonuclei. Most importantly, transplanted satellite cells on a single myober were able to support subsequent rounds of muscle regeneration (105). These observations demonstrate that satellite cells are bona de muscle stem cells. Asymmetric division is a common manner of stem cell selfrenewal. Close examination of satellite cell divisions on single myobers revealed that satellite cells can undergo both asymmetric division and symmetric division (280). The fashion of symmetric versus asymmetric division largely depends on the relative position of the daughter cells in relation to the myober. This nding strongly argues that satellite cell self-renewal is governed by the structure and signaling present in their immediate niche (280). Further investigation has revealed an important role for noncanonical Wnt signaling in the regulation of satellite cell self-renewal (293). The aforementioned observations, together with those from other studies, formed the basis of our current view of satellite cells as muscle stem cells whose functions are dictated by their surrounding niche.
B. Identication and Isolation of Satellite Cells

Classically, satellite cells were identied based on a unique anatomical location: beneath the surrounding basal lamina and outside the myober plasma membrane. This anatomical location gives satellite cells a wedged appearance when viewd by electrictron microscropy (329). This technique also revealed other morphological characteristics of satellite cells: large nuclear-to-cytoplasmic ratio, few organelles, small nucleus, and condensed interphase chromatin. This morphology is in harmony with the notion that most satellite cells, in healthy unstressed muscles, are mitotically quiescent (in G0 phase) and transcriptionally inactive (472). In addition to electron microscopy, satellite cells can be identied by phase-contrast microscopy on single myober explants (53). Based on the same principle, the behaviors of satellite cells on single myober explants can be recorded by utilizing live cell imaging techniques (490). The identication of satellite cells by uorescence microscopy relies on specic biomarkers (FIGURE 1). In adult skeletal muscle, all or most of satellite cells express the paired domain transcription factors Pax7 (478) and Pax3 (72), myogenic regulatory factor Myf5 (116), homeobox transcription factor Barx2 (336), cell adhesion protein M-cadherin (244), tyrosine receptor kinase c-Met (13), cell surface attachment receptor 7-intergin (73, 192), cluster of differentiation protein CD34 (37), transmembrane heparan sulfate proteoglycans syndecan-3 and syndecan-4 (113), chemokine receptor CXCR4 (429), caveolae-forming protein caveolin-1 (192, 552), calcitonin receptor (177), and nuclear en-
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Physiol Rev VOL 93 JANUARY 2013 www.prv.org
A
Itga7 Itgb1 Ncam1 Cav1 cMet Vcam1 CalcR Synd3/4 CD34 CXCR4 Fzd7 Notch Satellite cell markers Transcription factors MyoD Myf5 Pax7 Pax3
Membrane proteins cMet Cav1 Notch Ncam1 Vcam1 CalcR Itga7 Itgb1 Synd3/4 CD34 CXCR4 Fzd7 Mcad Lamin A/C Emerin
MyoD Pax7 Pax3
Emerin
Myf5
Lamin A/C
Mcad
B
Symmetric division
Satellite Stem Cell Asymmetric division Basal lamina Myonuclei
Sarcoplasm
Sarcolemma Symmetric division Symmetric division Satellite Myogenic Cell FIGURE 1. Characteristics of the satellite cell. A: numerous proteins are expressed in satellite cells and have been used as markers to distinguish between surrounding cell types within skeletal muscle. Due to heterogeneity in satellite cell populations, it is unlikely that all of these markers are expressed in a given satellite cell at a specic time. Nevertheless, this panel summarizes the cellular location of markers used to identify satellite cells. B: the satellite cell population is heterogeneous and can be classied in a hierarchical manner based on function and gene expression. Evidence from lineage tracing experiments identied a subpopulation of satellite cells having never expressed the myogenic transcription factor Myf5 (satellite stem cells) are placed hierarchically above satellite cells that have expressed Myf5 at some point during development (satellite myogenic cells). Satellite stem cells, upon asymmetric division (typically in a apical-basal orientation), will give rise to two daughter cells, only one of which has activated Myf5. Functional differences in regenerative potential exist between satellite stem cells and satellite myogenic cells. Following transplantation, satellite stem cells preferentially repopulate the satellite cell niche and contribute to long-term muscle regeneration. In contrast, satellite myogenic cells preferentially differentiate upon transplantation in vivo.
velope proteins lamin A/C and emerin (192). Of these, Pax7 is the canonical biomarker for satellite cells as it is specically expressed in all quiescent and proliferating satellite cells (478) across multiple species, including human (334),
monkey (334), mouse (478), pig (402), chick (216), salamander (353), frog (96), and zebrash (219). Of note, some of the aforementioned satellite cell markers (e.g., 7-intergin, CD34) are also expressed on other cell types within
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YIN, PRICE, AND RUDNICKI skeletal muscle, and thus should not be utilized alone to unequivocally identify satellite cells. Satellite cells can be identied by uorescence microscopy via combined immunouorescence labeling of laminin and M-cadherin, which respectively label the basal lamina and plasma membrane of satellite cells contacting the myobers (517). In vivo, satellite cell populations can be visualized with the aid of newly developed bioluminescence imaging techniques (454, 558). Multiple methodologies have been developed to isolate satellite cells from skeletal muscle. The choice of methods largely depends on the isolation scale and the subsequent experiment. In small scale, limited amounts of satellite cells can be released from single myober explants by physical trituration (446) or enzymatic digestion (107). In large scale, satellite cells can be isolated from skeletal muscles by uorescent-activated cell sorting (FACS). In the latter method, single cells are released from muscle tissue chunks by enzymatic digestion, followed by immunouorescence labeling of satellite cell-specic cell surface markers (positive selection) and denitive cell surface markers for nonsatellite cell populations (negative selection). As Pax7 is specically expressed in satellite cells within skeletal muscle, satellite cells, in both quiescent and proliferating stages, can be FACS-sorted by uorescent protein expression in tamoxifen-injected animals carrying both a Pax7CreER allele and a uorescence Cre reporter allele (e.g., R26R-EYFP). In addition, two transgenic mouse strains, which carry uorescence proteins driven by Nestin- or Pax7-regulatory elements, are also useful for isolating satellite cells by FACS (63, 127). Protocols have been developed to isolate satellite cells in bulk utilizing their characteristic proliferation and adhesion characteristics under dened culturing conditions (144, 364, 425). It is noteworthy that the satellite cell progeny cultured on regular collagen-coated plastic dishes and under activation conditions, also called satellite cell-derived primary myoblasts, are molecularly and functionally distinct from the satellite cells freshly isolated from muscles (160, 177, 350). In addition, the gene expression prole of these cultured primary myoblasts differs from that of activated satellite cells in vivo (398). These essential differences are possibly due to the lack of a satellite cell niche in in vitro culturing conditions. One challenge in future studies is to understand the components and role of the satellite cell niche to better control and manipulate their quiescence, activation, proliferation, and differentiation. stemness, and lineage potential to assume nonmyogenic fates. With regard to gene expression, it was rst observed that only a subset of satellite cells expresses Pax3, a close paralog to Pax7 (350, 431). Although Pax3 satellite cells tend to be associated with skeletal muscle of certain anatomical locations (e.g., diaphragm and truck muscles), the difference of Pax3 expression does not seem to correlate with their embryonic origins, metabolic ber types, or types of innervating motor neurons. Examination of the expression of satellite cell markers CD34, M-cadherin, and Myf5 by immunouorescence staining revealed that a subpopulation of satellite cells do not express these markers (37). Similarly, human satellite cells also manifest heterogeneity in their Pax7, neuronal cell adhesion molecule (NCAM), c-Met, and Dlk1 expression (311). By RT-qPCR, two recent studies showed that satellite cells from head or body muscles are distinct in their molecular signatures (225, 456). Notably, the heterogeneity of gene expression in single satellite cells was investigated in a recent study, wherein the expression of Pax7, Pax3, Myf5, and MyoD was interrogated by RTqPCR for 40 individually FACS-isolated muscle stem cells (CD45/CD11b/CD31/Sca-1/7-intergin/CD34) (454). All of these muscle stem cells express Pax7, indicating they are satellite cells. In addition to the varied expression of Pax3, it was also found that 25% of investigated satellite cells also express MyoD, a basic helix-loop-helix transcription factor critical for myogenic commitment and differentiation. A recent study discovered a small subpopulation of satellite cells, characterized by their surface markers Sca-1/ABCG2 (as compared with Sca-1/ABCG2 for most satellite cells), is able to exclude Hoechst 33342 dye and thus belongs to the skeletal muscle side population (satellite-SP cells) (518). After transplantation into damaged muscle, satellite-SP cells can both fuse to regenerating myobers and return to quiescence in the satellite cell niche. However, by lineage tracing, ABCG2 cells (including satellite-SP cells) seem to only have minor contribution to myober regeneration (146). Satellite cells are also heterogenic in their differentiation potential. Satellite cells on single myobers isolated from various skeletal muscle sources were transplanted into irradiated muscles of mdx/nude mice, which underwent repeated regeneration and were depleted of endogenous satellite cells (105). It was observed that the number of regenerated myobers contributed by tibialis anterior (TA) originated grafts was signicantly less than that derived from either extensor digitorum longus (EDL) or soleus muscle. Although the potential contribution from donor myobers cannot be precisely evaluated, this observation strongly suggests inherent differences in proliferation/differentiation potential of satellite cells and/or composition of satellite cell subpopulations from various muscles. In line with this view, continuous BrdU labeling of satellite cells in
C. Heterogeneity of Satellite Cell Population

Satellite cells were considered to be a homogeneous population of committed muscle progenitors (52). However, recent evidence demonstrated that the satellite cell population is heterogeneous and that satellite cells differ in their gene expression signatures, myogenic differentiation propensity,
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SATELLITE CELLS AND THE MUSCLE STEM CELL NICHE vivo revealed two satellite cell populations that are distinct in terms of their mitotic rates (471). It was found that the majority (80%) of satellite cells readily enter the cell cycle (responsive population), whereas the remaining 20% of satellite cells (reserve population) do this in a much slower manner. It has been proposed that the reserve population maintains in the quiescent state at the beginning of muscle growth/regeneration and only moves into this proliferative state in response to the need for extensive muscle growth/ regeneration (471). In line with this view, a recent study traced satellite cell divisions by a uorescent dye PKH26, which revealed the minority of PKH26high slow-dividing satellite cells retained long-term self-renewal ability (388). Notably, a recent study thoroughly compared the gene expression proles and proliferation/differentiation potential of satellite cells isolated from limb and facial muscles of adult and aged mice (387). This study revealed broad satellite cell heterogeneity at both the population and single-cell levels. Despite their heterogeneous gene expression proles, satellite cells isolated from limb (EDL) and facial (masseter) muscles are comparable in their ability to repair a limb (TA) muscle injury after transplantation. This nding suggests that although satellite cells from various muscles have distinct gene expression and behaviors in vitro, their regeneration potential in vivo might be largely determined by host stem cell niche and microenvironment. Most importantly, recent studies revealed satellite cell heterogeneity in terms of their stemness and indicate that only a small percentage of satellite cells are true stem cells (109, 280, 489). By immunouorescence staining of freshly isolated single myobers from Myf5-nLacZ mice, our group demonstrated that 13% of quiescent satellite cells on EDL muscles are LacZ, making them distinct from the LacZ satellite cells (280). As Myf5 is a myogenic regulatory factor, the absence of Myf5 expression suggests a less committed cell fate for those LacZ satellite cells. Moreover, by the Cre-LoxP based lineage tracing technique, our group further discovered that 10% of satellite cells in Myf5Cre;R26R-YFP mice do not express YFP (Pax7/YFP satellite cells), indicating that this small percent of satellite cells have never expressed Myf5 as did the majority of satellite cells (Pax7/YFP). Remarkably, these two distinct satellite cell subpopulations also differ in terms of their regenerative potential: the Pax7/YFP satellite cells were able to reconstitute the stem cell niche and repaired muscles in a sustainable manner, whereas the Pax7/YFP satellite cells directly underwent myogenic differentiation when transplanted in regenerating muscles of Pax7/ mice. We further demonstrated that only Pax7/YFP satellite cells could undergo asymmetric cell divisions, giving rise to a Pax7/YFP satellite stem cell and a Pax7/YFP satellite committed progenitor cell. These ndings indicate that a hierarchical lineage progression from the Pax7/YFP (satellite stem cell) to the Pax7/ YFP (satellite committed progenitors) exists within the total satellite cell population. Consistent with this notion, multiple studies reported that only a subset of satellite cells undergo asymmetric division in vivo or in vitro (108, 109, 489). For example, Numb, an inhibitor of Notch signaling and a cellfate determinant, was found to asymmetrically distribute in some but not all satellite cell divisions (108, 489). By pulse labeling or tandem pulse labeling of growing/regenerating muscles with halogenated thymidine analogs, it was further discovered that all older chromosomes (the template chromosome during DNA replication during S phase) cosegregate into the more stemlike daughter cell, whereas younger chromosomes are inherited by the more differentiated daughter cell during asymmetric divisions of satellite cells both in vivo and in vitro (109, 489). According to the immortal DNA strand hypothesis (75), this preferential retention of older chromosomes protects stem cells against the accumulation of mutations introduced during DNA replications (109, 489). Alternatively, it has been also proposed that the nonrandom segregation of sister chromatids, and hence their different epigenetic states, is essential to the gene expression patterns and cellular fates of satellite stem cells and satellite progenitor cells (289). In summary, the aforementioned ndings support satellite cell heterogeneity whereby the existence of a hierarchy delineates a small population of true stem cells (satellite stem cells) from a more committed myogenic progenitor population of satellite cells. The satellite stem cells are less committed to the myogenic lineage and tend to retain older template DNA during division. Through asymmetric division, satellite stem cells self-renew to replenish the stem cell pool and produce more committed myogenic progenitors that participate in skeletal muscle growth and regeneration. Satellite cells also exhibit heterogeneity in respect to their cell fate potential. Our group rst revealed that satellite cells have an intrinsic potential to differentiate into multiple mesenchymal lineages (23). When cultured on solubilized basement membrane matrix (matrigel), satellite cells from single myobers spontaneously differentiate into myocytes, adipocytes, and osteocytes. This nding indicates that satellite cells functionally resemble bone marrow-derived mesenchymal stem cells. This notion is substantiated by another study wherein satellite cells were found to assume the adipocyte lineage, which can be enhanced upon oxygen-rich culture conditions (120). By clonal analysis, it was found that myogenic and adipogenic satellite cells are two separate populations in the satellite cell compartment, although both populations express the myogenic marker Pax7 as well as the adipogenic markers peroxisome proliferator-activated receptors (PPAR) and CCAAT/enhancer binding proteins (C/EBPs) (485). This similar molecular signature may reect a common developmental origin of satellite cells and adipogenic progenitors in embryonic somites (discussed in sect. IIE). Satellite cell heterogeneity with regard to myogenic and nonmyogenic potential was thoroughly investigated by in vitro differentiation and in vivo transplant assays (486). In this study, myober-associated satellite cells were isolated from undamaged skeletal muscle by a two-step enzymatic digestion and sorted by FACS based on
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YIN, PRICE, AND RUDNICKI their differential expression of cell surface markers, CD45 and Sca-1. It was found that the vast majority of myogenic satellite cells are within the CD45/Sca-1 population and exhibited no in vitro differentiation potential into broblasts or adipocytes. In contrast, the minor population of CD45/Sca-1 satellite cells can differentiate into both broblasts and adipocytes in culture, a similarity that is shared with CD45/ Sca-1 mesenchymal stem cells found in multiple tissues (316, 401, 417, 441, 509, 519). Despite the plasticity of satellite cells in vitro, it is important to note that myogenesis is the predominant fate of satellite cells in vivo as brosis or adipose inltration is not normally observed in young healthy muscle. Furthermore, recent studies indicate that intramuscular adipocytes and broblasts can also arise from brocyte/adipocyte progenitors (FAPs), which reside in the muscle interstitium (252, 541; and discussed in sect. IIIB1). Indeed, lineage tracing experiments indicate that adipocytes derived from myobers isolated from MyoDiCre;R26R-EYFP mice have never transcribed MyoD (507). As the vast majority of adult satellite cells were permanently labeled with EYFP in this experiment, this nding argues that most satellite cells from myober cultures do not spontaneously differentiate into adipocytes. Further investigation with more denitive lineage tracing (e.g., Pax7CreER;R26R-EYFP) methods would clarify the exact contribution of satellite cells to other nonmyogenic lineages both in vitro and in vivo. As discussed here, multiple lines of evidence demonstrate that satellite cells represent a heterogeneous population. However, our understanding of this heterogeneity is far from complete. First, although several markers can separate the total satellite cell population into functional subpopulations, it is still unknown whether these subpopulations are homogeneous in their function and gene expression. Further studies to identify additional satellite markers will potentially help distinguish the various satellite cell lineages. Moreover, future investigations should attempt to identify the intrinsic differences between satellite cell subpopulations at the molecular and functional levels during muscle regeneration. Such ndings would elucidate regulatory mechanisms governing the transition between different satellite cell subpopulations and potentially distinct roles of satellite cell subpopulations during muscle regeneration. In addition, it would be of great importance to understand the dynamics of satellite cell heterogeneity in response to various environmental cues with regard to research in muscle regeneration and disease. satellite cells in soleus muscle is generally two- to fourfold higher than that in tibialis anterior muscle or EDL muscle (190, 466, 500). Within the same muscle, the number of satellite cells found on slow muscle myobers (type I) is generally higher than those on fast myobers (type IIa and type IIb) (190, 324, 383). The biological meaning and the potential regulatory mechanisms underlying these phenomena are poorly understood. However, it is conceivable that these variances may reect intrinsic heterogeneity of satellite cells on different myobers and implicate a potential role of myobers as a niche factor in regulating the homeostasis of their resident satellite cells. Along a myober, the distribution of satellite cells is not random. It has been reported that the density of satellite cells is higher at the ends of the myobers, where the longitudinal growth of skeletal muscles happens (14). A higher incidence of satellite cells has been observed at perisynaptic regions compared with that at extrasynaptic regions (190, 269, 567). Moreover, satellite cells have been observed in close proximity to capillaries (100, 466). In fact, 88% of satellite cells in adult human muscles were observed to be located within a 21-m distance of a capillary (100). This tight association with capillaries seemed to be compromised by denervation (130). These observations indicate that homing of satellite cells is inuenced by their niche, both by local motor neurons and blood vessels (discussed in sect. IIIB). It is noteworthy that some reported variation in satellite cell numbers may be partially due to techniques or statistical analysis employed in satellite cell counting. For example, satellite cell counting based on immunouorescence labeling of satellite cell specic markers relies on the comparable expression levels of these markers on all satellite cells under investigation. As such, special caution should be taken into account when interpreting data between independent experiments.
E. Origins of Adult Satellite Cells

1. Embryonic origins By classic techniques of developmental biology, it has long been established that skeletal muscles within both the adult trunk and limbs develop from embryonic somites (462). However, the exact origin of adult satellite cells was obscure until recently. Early experiments using a quail-chick chimera technique suggested a somitic origin of satellite cells in amniotes (18). Embryonic somites are segments of paraxial mesoderm formed on both sides of the body axis. In this experiment, somites from donor quail embryos were transplanted into host chick embryos. After embryonic development, the contribution of quail cells to the chick satellite cell compart-
D. Variance of Satellite Cells Number and Location

In addition to the heterogeneity of satellite cells, the quantity of satellite cells differs between muscles, myober types, developmental stages, and species. In general, satellite cells account for 30 35% of the sublaminal nuclei on myobers in early postnatal murine muscles, and this number declines to 27% in adult muscles (9, 227, 450, 469). In adults, the percentage of
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SATELLITE CELLS AND THE MUSCLE STEM CELL NICHE ment was determined using Feulgen staining, which distinguishes quail-specic interphase nuclei from those of chick. It was found that donor cells from quail somites integrated into the chick limb and contributed to both terminally differentiated muscle bers and satellite cells. This nding indicated a common somitic origin for all myogenic cell lineages, including satellite cells. However, the progenitor cell types at the origin and the developmental route remain unknown. Advances in mouse genetics, particularly the generation of Pax3 and Pax7 knock-in reporter alleles, allows precise tracing of Pax3/Pax7-expressing myogenic progenitor cells during muscle development in a temporal and spatial manner (265, 326, 350, 432, 433). These reporters together with labeling of cells by electroporation (40, 203), retrovirus (464), Cre-LoxP based lineage tracing (263, 300, 464), and traditional quail-chick transplantation (203, 464), jointly shed light on the embryonic origins of adult satellite cells. Accumulating evidence indicates that adult satellite cells originate from the dermomyotome (203, 265, 434, 464), an epithelial structure formed on the dorsal part of the somite. The dermomyotome contains multipotent progenitor cells, which eventually give rise to multiple adult tissues/cell types including dermal broblasts, endothelial cells, vascular smooth muscle, brown fat tissue, and all skeletal muscles of the trunk and limbs (71). The cell fate decisions largely depend on the relative position of these multipotent progenitor cells with respect to adjacent tissues such as the notochord, neural tube, dorsal ectoderm, and myotome (71). Embryonic muscle development takes place in two successive stages. During the rst stage, a group of postmitotic mononucleated myocytes, expressing Myf5 and Mrf4, migrate out from the border regions of the dermomyotome and form primitive muscles beneath the dermomyotome (204, 261). These primitive muscles constitute the primary myotome and are the source of fetal and adult trunk muscles. During the second stage of muscle growth, the central portion of the dermomyotome undergoes an epithelial-tomesenchymal transition (EMT). During EMT, tightly packed epithelial cells tease apart and turn in a loose mesenchymal state prior to assuming different developmental fates: cells in the medial dermomyotome will develop into brown fat, dermis, and trunk muscle, while cells in the lateral dermomyotome will give rise to endothelia and limb muscles. The different cell fates assumed by the same group of progenitor cells are proposed to be due to asymmetric cell division (40, 101). EMT is accompanied by the extensive cell migration (203, 265, 434, 464). With the breakdown of dermomyotome, a group of proliferating progenitor cells, expressing both Pax3 and Pax7, migrate from the central region of the dermomyotome into the previously formed primary myotome. Upon arrival, some progenitor cells continue to proliferate and replenish the progenitor pool. These cells, which were absent from the primary myotome at earlier stages, count for the majority of all proliferating cells in embryonic/fetal trunk muscles (203, 434). Some of the proliferating Pax3/Pax7 progenitor cells persist into late fetal development stages and are enveloped beneath the basal lamina of developing myobers (203, 434). These cells, which reside in the satellite cell compartment, are presumed to subsequently become the postnatal satellite cells in trunk muscles. Besides proliferation, progenitor cells also exit the cell cycle and begin differentiating into embryonic/fetal truck muscles. Cell cycle withdrawal is concomitant with the expression of the myogenic regulatory factors MyoD and Myf5 (453). During EMT, another group of proliferating progenitor cells, expressing Pax3 (but not Pax7 in mouse), delaminate from the ventral-lateral border of the dermomyotome and migrate to the limb bud mesenchyme (265, 392, 464). These progenitor cells still maintain their multipotency as they give rise to the limb vascular, lymphatic endothelia, and limb muscles (226, 264). At E11.5 of mouse embryo development, some progenitor cells start to express Pax7 in the anterior limb buds (433). The expression of Pax7 species these cells to the myogenic lineage (242). Similar to the myotome-located progenitors, these Pax3/Pax7 progenitor cells in limb buds undergo proliferation/differentiation while a portion withdraw from cell cycle and become satellite cells. All together, these observations indicate that Pax3/Pax7 embryonic progenitor cells are the major source of adult satellite cells in truck and limb muscles; it is, however, noteworthy that the aforementioned observations from lineage tracing and immunouorescence labeling experiments cannot exclude the possibility that some adult satellite cells may originate from other sources during fetal and postnatal muscle development. For example, embryonic dorsal aorta explants, when cultured and disaggregated in vitro, can efciently give rise to myogenic precursors (129). These myogenic precursors are similar to satellite cells in their gross morphology and expression of molecular markers. Given that adult satellite cells also express endothelial markers, it was proposed that some adult satellite cells originated from the embryonic dorsal aorta (129). However, recent studies revealed that both skeletal muscles and smooth muscles found in dorsal aorta are derived from the same Pax3 cell population in the paraxial mesoderm (155). Thus it is also possible that the observed similarities are merely reminiscent of a common embryonic origin before myogenic specication. Distinct from trunk and limb muscles, head muscles have multiple embryonic origins. The majority of head muscles, including branchiomeric muscles and most extraocular muscles, arise from the cranial paraxial mesoderm (CPM) (225, 540). Posterior neck muscles and tongue develop
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YIN, PRICE, AND RUDNICKI from occipital somites. Similar to progenitor cells migrating to limb buds, the progenitor cells for tongue delaminate from the ventral-lateral border of occipital somites. A small fraction of extraocular muscles also arise from the prechordal mesoderm (PM). On the basis of observations from lineage tracing experiments, it has been found that adult satellite cells of the various head muscles originate from their corresponding embryonic muscles and express distinct combinations of signature genes (225). Unlike trunk and limb progenitors, most progenitor cells for head muscles (except for tongue) express MesP1 rather than Pax3. 2. Alternative origins of adult satellite cells Accumulating evidence indicates that some adult satellite cells may have alternative origins other than dermomyotome-derived Pax3/Pax7 progenitor cells. First, multiple studies have demonstrated that several types of nonsatellite cells can reconstitute the satellite cell niche and turn into bona de satellite cells (Pax7-expressing myogenic cells) after transplantation into regenerating skeletal muscles (for details, see sect. IID). It remains, however, largely unknown to what extent these cells contribute to the adult satellite cell pool and muscle development under physiological conditions. Notably, a recent study utilizing TN-APCreERT2 and VE-cadherinCreERT2 alleles showed that alkaline phosphatase (ALPL) expressing pericytes, but not VE-cadherin-expressing endothelial cells, can develop into postnatal satellite cells and participate in normal development of limb muscles (135). It is noteworthy that some adult satellite cells in mammals may be derived from dedifferentiation of fetal/adult myobers. It has long been established that the dedifferentiation of terminally differentiated multinucleated myobers occurs in injured skeletal muscle of urodele amphibians, such as the newt (69). Nevertheless, it remains controversial as to whether mammalian myotubes in vitro or myobers in vivo can undergo a similar dedifferentiation process. Studies utilizing immortalized murine myoblast cell lines (e.g., C2C12 or pmi28 cells) have shown that some myotubes formed by these cells can dedifferentiate into mononucleated myogenic cells in the presence of protein extract from regenerating newt muscles (331), bioactive compounds like myoseverin or its derivatives (149, 443), ciliary neurotrophic factor (CNTF) (95), or by genetic manipulations such as overexpression of Msx1 (379), Twist1 (232), Barx2 (335), or knockdown of Rb1 in conjunction with a deciency for Cdkn2a (p16Ink4a) (395). By a novel fusion-dependent lineage tracing technique, two recent studies reported that differentiated myotubes formed by satellite cell-derived primary myoblasts (397) or muscle-derived cells (MDCs) (359) can dedifferentiate into Pax7-expressing mononucleated myogenic cells in vitro in response to an inhibitor cocktail (a tyrosine phosphatase inhibitor plus an apoptosis Skeletal muscles consist of myobers, neurons, vasculature networks, and connective tissues, of which the structural and functional element of skeletal muscle is the myober. Each myober is surrounded by the endomysium (also called the basement membrane or basal lamina). Bundles of myobers are surrounded by the perimysium, while the entire muscle is contained within the epimysium. Each myober is anchored at its extremities to tendons or tendon-like fascia at the myotendinous junctions (MTJs) (531). Myobers are composed of actin and myosin myobrils repeated as a sarcomere, which is the basic functional unit of skeletal muscle. Responding to the signals from motor neurons, myobers depolarize and release calcium from the sarcoplasmic reticulum (SR). This drives the movement of actin and myosin laments relative to one another and leads to sarcomere shortening and muscle contraction. Based on their physiological properties, skeletal muscle bers can be grouped into a slow-contracting/fatigue-resistant type and a fast-contracting/fatigue-susceptible type. Myobers also vary in terms of their myosin heavy chain (MyHC) isoforms (fast or slow) and metabolism types (oxidative or glycolytic). The choice of myosin gene expression is under the dynamic regulation of thyroid hormone and work load (reviewed in Ref. 28). Recent studies demonstrated that the specication of myosin expression is also regulated by intronic microRNAs within MyHC genes (545, 546). Mammalian skeletal muscle during adulthood is a stable postmitotic tissue with infrequent turnover of myonuclei (467). Minor lesions inicted by day-to-day wear and tear can be repaired without causing cell death, inammatory responses, or histological changes. For instance, local plasma membrane damage caused by spontaneous eccentric muscle contractions can be efciently repaired by recruiting intracellular vesicles to patch the damaged membrane (30, 508). This repair process involves dysferlin and caveolin-3 (30, 181), and mutations of these genes cause limb girdle muscular dystrophy 2B (LGMD2B) (36, 314) and 1C (LGMD-1C) (344), respectively. In contrast, severe muscle injuries due to either traumatic lesions (e.g., extensive physical activity such as resistance training, or exposure to myotoxin) or genetic defects (e.g., muscular dystrophies) are accompanied by myober necrosis, inammainhibitor) or within regenerating muscle in vivo. Although still not experimentally tested on myobers formed during development, these intriguing observations jointly suggest that some adult satellite cells may be recycled from multinucleated myobers in vivo during postnatal muscle growth or regeneration. Future studies may employ the fusion-dependent lineage tracing technique in chimeric mice to investigate the physiological relevance of this alternative source of satellite cells.
II. FUNCTIONS OF SATELLITE CELLS IN MUSCLE REGENERATION
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SATELLITE CELLS AND THE MUSCLE STEM CELL NICHE tory responses, activation of satellite cells, proliferation, and differentiation of satellite cell-derived myoblasts (FIGURE 2). This process, starting from myober necrosis and ending with new myober formation, is called muscle regeneration. It should be stressed that satellite cells play a pivotal role during muscle regeneration under either physiological conditions (e.g., extensive exercise) (400, 457) or pathological conditions (e.g., myotoxin induced injury) (301, 361, 457). This notion is clearly supported by the ndings that ablation of the total satellite cell pool (all Pax7 cells) in adulthood completely abolished muscle regeneration (301, 361, 457). It has been reported that several types of nonsatellite cells can undergo myogenic differentiation and contribute to muscle regeneration after transplantation into regenerating muscle (24, 210, 287, 345, 413). Nevertheless, the contribution of these cells to adult muscle regeneration seems to be negligible compared with satellite cells, implying the physiological relevance of nonsatellite cell-based myogenesis might depend on Pax7 expression and/or the existence of considerable numbers of satellite cells. In this section, we examine the extensive cellular and molecular dynamics during muscle regeneration, with emphasis on satellite cell. We also review the potential of nonsatellite cell lineages on muscle regeneration. At the end of this section, we briey describe the function of satellite cells in normal postnatal muscle development, and compare and contrast this with muscle regeneration in adulthood.
A. An Introduction to Muscle Regeneration

Muscle regeneration occurs in three sequential but overlapping stages: 1) the inammatory response; 2) the activation, differentiation, and fusion of satellite cells; and 3) the maturation and remodeling of newly formed myobers. Muscle degeneration begins with necrosis of damaged muscle bers. This event is initiated by dissolution of the myober sarcolemma, which leads to increased myober permeability. Disruption of myober integrity is reected by
Differentiation
Return to quiescence
Return to quiescence
Activation
Activation
Basal lamina Quiescence Pax7+ / Myf5 / MyoD / MyoG Pax7+ / Myf5+ / MyoD / MyoG Proliferation Pax7+ / Myf5 / MyoD / MyoG Pax7+ / Myf5 / MyoD+ / MyoG Pax7+ / Myf5+ / MyoD+ / MyoG Pax7+ / Myf5+ / MyoD / MyoG Differentiation Pax7 / Myf5+ / MyoD+ / MyoG+ Pax7 / Myf5 / MyoD+ / MyoG+ Pax7 / Myf5+ / MyoD / MyoG+ Pax7 / Myf5 / MyoD / MyoG+ Pax7 / Myf5 / MyoD / MyoG FIGURE 2. Satellite cell activation, differentiation, and fusion. The myogenic program is orchestrated by key transcription factors that dictate the progression from quiescence, activation, proliferation, and differentiation/self-renewal of satellite cells. This results in the transformation of individual satellite cells into a syncytial contractile myober. Initially satellite cells are mitotically quiescent (G0 phase) and reside in a sublaminar niche. Quiescent satellite cells are characterized by their expression of Pax7 and Myf5 but not MyoD or Myogenin. Damage to the environment surrounding satellite cells results in the deterioration of the basal lamina and their exit from the quiescent state (satellite cell activation). Proliferating satellite cells and their progeny are often referred to as myogenic precursor cells (MPC) or adult myoblasts. Adult myoblasts express the myogenic transcription factors MyoD and Myf5. Following proliferation, adult myoblasts begin differentiation by downregulating Pax7. The initiation of terminal differentiation and fusion begins with the expression of Myogenin, which in concert with MyoD will activate muscle specic structural and contractile genes. During regeneration, activated satellite cells have the capability to return to quiescence to maintain the satellite cell pool. This ability is critical for long-term muscle integrity.
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YIN, PRICE, AND RUDNICKI increased plasma levels of muscle proteins and microRNAs, such as creatine kinase (17) and miR-133a (292), which are usually restricted to the myober cytosol. Similarly, the compromised sarcolemmal integrity also allows the uptake of low-molecular-weight dyes, such as Evans blue or procion orange, by the damaged myober, which is a reliable indication of sarcolemmal damage associated with extensive exercise and muscle degenerative diseases (218, 328, 396). Moreover, myober necrosis is accompanied by increased calcium inux or calcium release from the SR, which in turn activates calcium-dependent proteolysis and drives tissue degeneration (reviewed in Refs. 7, 19, 39). In this process, calpain, a calcium-activated protease, has been shown to cleave myobrillar and other cytoskeletal proteins (reviewed in Ref. 145). Myober necrosis also activates the complement cascade and induces inammatory responses (389). Subsequent to inammatory responses, chemotactic recruitment of circulating leukocytes occurs at local sites of damage (reviewed in Ref. 530). Neutrophils are the rst inammatory cells to inltrate the damaged muscle, with a signicant increase in their number being observed as early as 1 6 h after myotoxin- or exercise-induced muscle damage (168). Following neutrophil inltration, two distinct subpopulations of macrophages sequentially invade the injured muscle and become the predominant inammatory cells (91). The early invading macrophages, characterized by the surface markers CD68/CD163, reach their highest concentration in damaged muscle at 24 h after the onset of injury and thereafter rapidly decline. These CD68/ CD163 macrophages secrete proinammatory cytokines, such as tumor necrosis factor- (TNF-) and interleukin (IL)-1, and are responsible for the phagocytosis of cellular debris. A second population of macrophages, characterized by the surface markers CD68/CD163, reach their peak at 2 4 days after injury. These macrophages secrete antiinammatory cytokines, such as IL-10, and persist in damaged muscle until the termination of inammation. Notably, the CD68/CD163 macrophages also reportedly facilitate the proliferation and differentiation of satellite cells (80, 81, 303, 341, 503). A highly orchestrated regeneration process follows muscle degeneration. A hallmark of this stage is extensive cell proliferation. Blocking cell proliferation by colchicine treatment (411) or irradiation (423) drastically reduced muscle regenerative capacity. Experiments by [3H]thymidine labeling have clearly demonstrated that the proliferation of satellite cells and their progeny provide a sufcient source of new myonuclei for muscle repair (498, 499, 554; reviewed in Ref. 79 and discussed in sect. IIB). It is commonly agreed that following proliferation, myogenic cells differentiate and fuse to existing damaged bers or fuse with one another to form myobers de novo. This process, in many but not all respects, recapitulates embryonic myogenesis. Muscle regeneration can be characterized by a series of morphological characteristics based on histological and immunouorescence staining. On muscle cross-sections, newly formed myobers can be readily distinguished by their small caliber and centrally located myonuclei. These myobers are often basophilic in the beginning of regeneration due to protein synthesis and the expression of embryonic/developmental forms of MyHC (217, 562). On muscle longitudinal sections and on isolated single myobers, the centrally localized myonuclei were observed in discrete segments of regenerating myobers or along the entire new myober, which suggests that cell fusion during regeneration happens in a focal, rather than diffuse, manner (58). Occasionally, concentrated regenerative processes may appear as local protrusions (also called budding) on myobers. Muscle regeneration can often lead to architectural changes of the regenerated myobers, which are presumably due to incomplete fusion of regenerating bers within the same basal lamina (57, 58, 64, 465). Newly formed myotubes may not fuse to each other, resulting in clusters of small caliber myobers within the same basal lamina. Alternatively, they may fuse only at one end, leading to the formation of forked (also called branching or splitting) myobers. Myober branching was commonly observed in muscles from patients suffering neuromuscular diseases, in hypertrophied muscles, and in aging muscles, suggesting this phenotype may relate to abnormal muscle regenerative capacity (59, 90). Small regenerating myobers may also form outside the basal lamina in the interstitium, due to migration of satellite cells or other types of myogenic cells. Finally, the reconstitution of myober integrity may be prevented by scar tissue that separates the two regenerative sites, leading to the formation of a new myotendinous junction. At the end of muscle regeneration, newly formed myobers increase in size, and myonuclei move to the periphery of the muscle ber. Under normal conditions, the regenerated muscles are morphologically and functionally indistinguishable from undamaged muscles.
B. Satellite Cell Activation and Differentiation

In intact muscle, satellite cells are sublaminal and mitotically quiescent (G0 phase). Quiescent satellite cells are characterized by their expression of Pax7 but not MyoD or Myogenin (116). Examination of -galactosidase activity in Myf5-LacZ mice indicated that the Myf5 locus is active in 90% of quiescent satellite cells, which suggests most satellite cells are committed to the myogenic lineage (37). Upon exposure to signals from a damaged environment, satellite cells exit their quiescent state and start to proliferate (satellite cell activation). Proliferating satellite cells and their progeny are often referred to as myogenic precursor
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SATELLITE CELLS AND THE MUSCLE STEM CELL NICHE cells (MPC) or adult myoblasts. Satellite cell activation is governed by multiple niche factors and signaling pathways (discussed in detail in sect. IIIA). Satellite cell activation is not only restricted to the site of muscle damage. In fact, localized damage at one end of a muscle ber leads to the activation of all satellite cells along the same myober and migration of these satellite cells to the regeneration site (473). Satellite cell activation is also accompanied by extensive cell mobility/migration. It has been observed that satellite cells can migrate between myobers and even muscles across barriers of basal lamina and connective tissues during muscle development, growth, and regeneration (241, 251, 557). Recently, sialomucin CD34, whose expression is high on quiescent satellite cells but dramatically reduced during satellite cell activation, was demonstrated to act as an antiadhesive molecule to facilitate migration and promote the proliferation of satellite cells at very early stages of muscle regeneration (8). In addition, dynamic regulation of Eph receptors and ephrin ligands in activated satellite cells and regenerating myobers have been shown to direct satellite cell migration (506). Unlike quiescent satellite cells, myogenic precursor cells are characterized by the rapid expression of myogenic transcription factors MyoD (111, 114, 116, 175, 207, 497, 572, 585) and Myf5 (111, 116). Of note, the presence of MyoD, desmin, and Myogenin in satellite cells was observed as early as 12 h after injury, which is before any noticeable sign of satellite cell proliferation (426, 497). This early expression of MyoD is proposed to be associated with a subpopulation of committed satellite cells, which are poised to differentiate without proliferation (426). In contrast, the majority of satellite cells express either MyoD or Myf5 by 24 h following injury (111, 116, 585) and subsequently coexpress both factors by 48 h (111, 116). The ability of satellite cells to upregulate either MyoD or Myf5 suggests these two transcription factors may have different functions in adult myogenesis. First, MyoD/ mutant mice display markedly reduced muscle mass (338). This atrophy phenotype is reportedly due to delayed myogenic differentiation (564, 573). Similarly, muscle regeneration is also impaired in MyoD/ mice, resulting in an increased number of myoblasts within the damaged area (338). These MyoD/ myoblasts persist for extended periods of time, fail to differentiate, and do not fuse into myotubes. This is consistent with the notion that MyoD/ myoblasts, when cultured in myogenic differentiation conditions, continue to proliferate and eventually give rise to a decreased number of differentiated mononucleated myocytes (114, 452, 573). Intriguingly, transplanted MyoD/ myoblasts have been reported to survive and engraft into MyoD/ regenerating muscles with improved efcacy (compared with wild-type myoblasts). This phenotype is reportedly due to their increased stem cell characteristics and repressed apoptotic potential (22, 231). After regeneration, these transplanted MyoD/ myoblasts not only give rise to myonuclei but also contribute to the satellite cell pool (22). On the other hand, ectopic expression of MyoD in NIH-3T3 and C3H10T1/2 broblasts is sufcient to activate the complete myogenic program in these cells (234). Taken together, these observations indicate that expression of MyoD is an important determinant of myogenic differentiation, and in the absence of MyoD, activated myoblasts have a propensity for proliferation and self-renewal (452). In contrast to the MyoD/ mice, Myf5/ mutant mice show a myober hypertrophy phenotype (187), and the proliferation of Myf5/ myoblasts is compromised (187, 542). Together, these results implicate a distinct role for Myf5 in adult myoblast proliferation, while MyoD is essential for differentiation. Notably, the disparate functions of Myf5 and MyoD in adult muscle regeneration parallel the proposed roles for these transcription factors throughout the development of distinct myogenic lineages during embryogenesis (188, 213, 256 259; reviewed in Ref. 260). Together, the aforementioned observations suggest a hypothesis that satellite cells enter different myogenic programs depending on whether Myf5 or MyoD expression predominates (450). Predominance of MyoD expression would drive the program toward early differentiation, as exemplied by the behavior of Myf5/ myoblasts (349). In contrast, predominance of Myf5 expression would direct the program into enhanced proliferation and delayed differentiation, as shown by the behavior of MyoD/ myoblasts (452). Finally, myoblasts coexpressing both Myf5 and MyoD would exhibit the intermediate growth and differentiation propensities as shown by most of satellite cell-derived myoblasts. This hypothesis is consistent with the observation that MyoD and Myf5 have different expression proles throughout the cell cycle. MyoD expression peaks in mid G1, whereas Myf5 expression is maximal at the G0 and G2 phases of the cell cycle (273). Therefore, disruptions to the MyoD/Myf5 ratio may determine the choice of myogenic programs. This hypothesis also explains the spectrum of proliferation and differentiation potential observed in different primary myoblast clones cultured in vitro. Several studies have revealed that MyoD expression in proliferating myoblasts is positively regulated by serum response factor (SRF), which binds to the serum response element (SRE) within the MyoD regulatory region (186, 285). In proliferating myoblasts, SRF only drives low levels of MyoD expression (286), whose activity is inhibited by cyclin D1 induced cyclin dependent kinase 4 (Cdk4) (587). However, the induction of MEF2 expression prior to differentiation enables MEF2 to out-compete SRF for the SRE binding site and leads to high levels of MyoD expression and initiation of differentiation (286). This function of MEF2 is further regulated by a member of the myocardin family of transcription factors, MASTR, whose expression is upregulated in response to muscle injury (348).
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YIN, PRICE, AND RUDNICKI Notably, our group recently revealed a pro-proliferation function of MyoD in myoblasts (191). We found that the isoform of p38 kinase (p38) phosphorylates MyoD, which negates the transcriptional activation potential of MyoD and leads to a repressive MyoD complex occupying the Myogenin promoter (191). This positive effect of p38 on myoblast proliferation is also supported by the observation that Myogenin is prematurely expressed in p38-decient muscle, which displays markedly reduced myoblast proliferation (191). These results also support the notion that the functional state of MyoD depends on cofactors present in the MyoD transcriptional complex. Moreover, multiple studies demonstrated that MyoD expression does not always warrant myogenic commitment. Monitoring satellite cell lineage progression revealed that some Pax7/MyoD proliferating myoblasts could retract back to a Pax7/MyoD state and eventually return to quiescence (127, 216, 584; discussed in sect. IIC). In addition, the reciprocal inhibition of Pax7 with MRFs (MyoD and Myogenin) has been revealed in C3H10T1/2 broblasts and MM14 myoblasts in vitro (385). It was found that Pax7 decreases MyoD transcription activity and stability, whereas Myogenin represses Pax7 transcription likely via the HMGB1-RAGE axis (385, 438). Based on these observations, it was proposed that the ratio of Pax7 and MyoD activities are critical for satellite cell fate determination (385). A high ratio of Pax7 to MyoD (as seen in quiescent satellite cells) keeps satellite cells in their quiescent state. An intermediate ratio of Pax7 to MyoD allows satellite cells to proliferate, but not differentiate. Satellite cells with a low Pax7-to-MyoD ratio begin to differentiate, and further reduction in Pax7 levels are observed following activation of Myogenin. After limited rounds of proliferation, the majority of satellite cells enter the myogenic differentiation program and begin to fuse to damaged myobers or fuse to each other to form new myobers. The initiation of terminal differentiation starts with the expression of Myogenin and Myf6 (also called Mrf4) (114, 116, 207, 497, 572). The induction of Myogenin expression primarily depends on MyoD and is proposed to enhance expression of a subset of genes previously initiated by MyoD (83). Target genes of MyoD and Myogenin have been revealed by candidate approaches (405), ChIP-on-chip experiments (44, 56, 83), and more recently by ChIP-Seq analysis (84). These investigations jointly reveal a convoluted hierarchical gene expression circuitry centered on MyoD and its immediate downstream targets: Myogenin and Mef2 transcription factors (Mef2s). Based on the temporal expression pattern of MyoD, Myogenin and Mef2s, a feed-forward regulatory circuit is proposed. In this hypothesis, myogenic differentiation is an irreversible procedure and is driven by the sequential expression of key transcription factors (master regulators), which are destined to transduce gene expression signals to their target genes (45, 405). A large portion of target genes induced by MyoD, Myogenin, and Mef2s are muscle-specic structural and contractile genes, such as those encoding actins, myosins, and troponins. The expression of these genes is essential for the proper formation, morphology, and function of skeletal muscle and thus they are regulated by multiple mechanisms (41). First, the transcriptional activities of MyoD, Myogenin, and Mef2s are regulated by posttranscriptional modications (reviewed in Ref. 420). The and isoforms of p38 kinase (p38-/) have an important role in the expression of muscle-specic genes (405) and in muscle terminal differentiation (571). The function of p38-/ is at least partially responsible for the phosphorylation of Mef2s as inhibition of p38-/ disrupts the transcriptional activities of Mef2s. In contrast, the expression of constitutively active forms of p38-/ promotes myogenesis (117, 221, 390, 420, 571, 589). p38-/ activity stimulates the binding of MyoD and Mef2s to the promoters of muscle-specic genes, leading to the recruitment of chromatin remodeling complexes, and ultimately the RNA polymerase II holoenzyme (405, 424, 491). Similarly, the transcriptional activity of Myogenin is regulated by protein kinase A (PKA) (308) and protein kinase C (PKC)(309). Protein inhibitors of MRFs also control myogenic gene expression. The transcriptional activity of MRFs relies on heterodimerization with E proteins (ITF1, ITF2, E12, E47) (291, 362, 363). This heterodimerization is negatively regulated by a group of inhibition of DNA binding proteins (Ids: Id1, Id2, Id3, and Id4), which are also helix-loop-helix proteins but lack the basic DNA-binding domain (42, 43). Id proteins heterodimerize with E proteins and prevent their association with MRFs, thus abrogating myogenic gene expression (43). Similar results occur when Mist1 directly interacts with MyoD and prevents MyoD from binding E-boxes (298). MyoD activity can be further inhibited by the sequestration of E proteins, by Twist (504). Finally, the transcriptional activity of MyoD is also determined by specic cofactors present on the promoters of myogenic genes (reviewed in Ref. 450). In vitro, MyoD associates with histone acetyltransferases (HATs) p300 and p300/CBP (CREB-binding protein)-associated factor (PCAF) on E-box motifs of its target genes (419). This association is presumed to induce histone acetylation and transcriptional activation (45). MyoD also interacts with histone deactylases (HDACs), which negatively regulate the transcriptional activity of MyoD either directly (325) or in a Mef2-dependent manner (319). Besides MRFs and their regulators, other factors have been shown to be involved in myogenic differentiation. MicroRNAs are 20 22nt noncoding small RNAs, which function to repress translation and reduce the stability of their target mRNAs. Recent studies demonstrated that MRFs, such as Myf5, MyoD, and Myogenin, activate the expression of a collection of myogenic microRNAs (e.g., miR-1, miR-133,
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SATELLITE CELLS AND THE MUSCLE STEM CELL NICHE miR-206 together called MyomiRs). These myogenic microRNAs, in conjunction with other microRNAs, modulate the expression levels of key myogenic transcription factors and regulators, such as Pax3 (119, 196, 231), Pax7 (94, 139), SRF (93), c-Met (526, 577), and Dek (98) during satellite cell activation/proliferation and differentiation (also reviewed in Refs. 374, 565). Furthermore, recent studies have demonstrated the requirement for caspase-3 and its activation of CAD (caspase-activated DNase) in initiating myoblasts differentiation in vitro (164, 290). Activation of CAD by caspase-3 induces double-stranded DNA breaks (DSBs) in the genome and the association of CAD with various target promoters. One such promoter is the cyclindependent kinase (CDK) inhibitor p21(Waf1/Cip1) which following binding by CAD is activated (290). MyoD also induces the expression of p21(Waf1/Cip1) (209, 215) and subsequent permanent cell cycle arrest. p21 is known to dephosphorylate the retinoblastoma protein (Rb) and cause the inactivation of the Rb-associated E2F family of transcription factors known to activate S-phase genes (reviewed in Ref. 559). Thus, through this pathway, MyoD induces permanent cell cycle withdrawal in myoblasts. Consistently, myoblasts in p21/ mice are defective in cell cycle arrest and myotube formation, leading to increased apoptosis (555, 588). Similarly, Rb-decient myoblasts cannot complete cell cycle withdrawal and arrest during both S and G2 phases of the cell cycle (378). After exiting the cell cycle, myogenic cells undergo cell-tocell fusion to repair damaged myobers or form nascent multinucleated myobers. The cellular events in this complex process have been extensively studied (274, 312, 418, 428, 553). Akin to embryonic myogenesis, de novo formation of myobers during muscle regeneration happens in two stages. In the rst stage, individual differentiated myoblasts fuse to one another and generate nascent myotubes with few nuclei. In the second phase, additional myoblasts incorporate into the nascent myotubes, forming a mature myober with increased size and expression of contractile proteins. In recent years, studies in myoblast fusion in vitro have identied a cadre of cell surface, extracellular, and intracellular molecules, which are important for these two stages of myogenic cell fusion (reviewed in Ref. 238). For example, cell membrane proteins 1-integrin (474), VLA-4 integrin (445), integrin receptor V-CAM (445), caveolin-3 (180), and transcription factor FKHR (Forkhead in human rhabdomyosarcoma, also called FOXO1a) have been shown to act in myoblast-to-myoblast fusion. Whereas the cytokine IL-4 (238) and calcium and calmodulin activated NFATC2 (nuclear factor of activated T cell isoforms C2) pathway (237) is critical for the fusion of myoblasts with nascent myotubes. As discussed here, activation of satellite cells following muscle injury results in the expansion of the myogenic cell pool and leads to the initiation of the myogenic program. This program, orchestrated by key transcription factors, dictates the balance between proliferation and differentiation and drives the functional transformation from individual proliferating myogenic cells to a syncytial contractile myober. Although numerous studies have shed light on this complex process, there are still many interesting questions that remain to be answered. For example, what are the intrinsic and extrinsic mechanisms that determine the scale of satellite cell proliferation in vivo, which essentially generate sufcient but not excessive numbers of myogenic cells for muscle regeneration? Similarly, what mechanisms regulate the magnitude of muscle regeneration in response to variable levels of damage and eventually prevent muscle atrophy or hypertrophy? With the recent advances in high-throughput sequencing and system biology, is it possible to elucidate a core regulatory network of myogenic gene expression and employ such knowledge on directing myogenic determination and differentiation from multipotent cells? The answers to these questions will improve our understanding of muscle regeneration and facilitate future development of therapeutic approaches to cure muscle diseases.
C. Satellite Cell Self-Renewal

A hallmark of stem cells is the ability to self-renew. Stem cells can divide and self-renew in two fashions: asymmetric cell division and symmetric cell division. In asymmetric cell division, one parental stem cell gives rise to two functionally different daughter cells: one daughter stem cell and another daughter cell destined for differentiation. In symmetric cell division, one parental stem cell divides into two daughter stem cells of equal stemness. In either fashion, the number of stem cells is maintained at a constant level. Stem cell self-renewal by asymmetric cell division is exemplied by neuronal stem cells (590). Stem cell self-renewal by symmetric cell division is frequently observed in hematopoietic stem cells and mammalian male germline stem cells (spermatogonia) (570). The self-renewing capability of satellite cells is clearly demonstrated by their remarkable ability to sustain the capacity of muscle to regenerate. For example, in a single myober transplantation experiment (105), 722 satellite cells together with their intact myobers were transplanted into irradiated muscles of immunodecient dystrophic (scidmdx) mice. It was found that one grafted myober can give rise to over 100 new myobers, which contain 25,000 30,000 differentiated myonuclei. In addition, the grafted satellite cells can undergo a 10-fold expansion via self-renewal. The expanded satellite cells are functional as they can be activated and support further rounds of muscle regeneration (105). Similarly, the self-renewing capability of satellite cells was further proven by single satellite cell transplantation experiments (454). In this study, single Lin/7integrin/CD34 cells freshly isolated by FACS were transplanted into irradiated muscles of scid-mdx mice. It was
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YIN, PRICE, AND RUDNICKI observed that progeny from these single cells not only generated myobers, but also migrated to the satellite cell niche and persisted in host muscles (454). An intriguing question is how satellite cells renew themselves. By using the Cre-LoxP based permanent lineage tracing technique (Myf5Cre;R26R-loxP-stop-loxP-YFP), our group rst demonstrated that satellite cells can undergo both asymmetric and symmetric divisions within their natural niche environment in mildly damaged EDL muscle (280). The choice of asymmetric versus symmetric division is largely correlated to the mitotic spindle orientation relative to the longitude axis of the myober. Asymmetric divisions are only observed for Pax7/Myf5 satellite cells, which give rise to one satellite stem cell (Pax7/Myf5) and one satellite myogenic (Pax7/Myf5) cell. Asymmetric division predominantly happens when the mitotic spindle is perpendicular to the myober axis (apical-basal division) with the satellite stem cell (Pax7/Myf5) in close contact with the basal lamina (basal) and the Pax7/Myf5 satellite myogenic cell adjacent to the myober plasma membrane (apical). Occasionally, it was observed that Pax7 expression is dampened in the apical satellite cell, suggesting a progression towards terminal differentiation. Furthermore, the asymmetric nature of this kind of division is also underscored by the observation that the apical Pax7/Myf5 cells express higher levels of the Notch ligand Delta-1, whereas the basal Pax7/Myf5 satellite cells express higher levels of the Notch-3 receptor. Symmetric divisions were observed for both Pax7/Myf5 satellite cells and Pax7/Myf5 satellite cells and in either case the mitotic spindle was frequently parallel to the myober axis (planar division) and both daughter cells were in contact with the myober plasma membrane and the basal lamina. When both satellite stem cells and satellite myogenic cells are freshly sorted and transplanted into Pax7/ muscles lacking any functional endogenous satellite cell, both cell types can colonize the host muscle. However, only Pax7/ Myf5 satellite cells can efciently reconstitute the satellite cell compartment (7-fold more efcient than Pax7/ Myf5). These observations indicate that Pax7/Myf5 satellite cells represent a bona de stem cell population, which can undergo self-renewal by both asymmetric division and symmetric division (280). Although asymmetric self-renewal may be sufcient under physiological conditions, satellite stem cells may favor symmetric self-renewal divisions to replenish and expand their population in response to acute need for a large number of satellite cells after injury or disease state (354). Indeed, it was observed that Pax7/Myf5 satellite stem cells represent 10% of total satellite cells in intact muscles, whereas this percentage increases to 30% at 3 wk after injury (280). In search of intrinsic and extrinsic cues regulating Pax7/Myf5 satellite stem cell self-renewal, our group further revealed that symmetric self-renewal is promoted by a niche factor, Wnt7a, during muscle regeneration (293; discussed in sect. IIIA1A). Therefore, the mode of satellite cell self-renewal is governed by the satellite cell niche. With regards to activated satellite cells returning to quiescence, observations on the dynamic expression of Pax7, MyoD, and Myogenin in ex vivo cultured single myobers suggest it is possible (127, 216, 584). After myober isolation (the isolation procedure per se is a form of injury to initiate muscle regeneration), satellite cells are activated and rapidly start to express MyoD (572, 584). It has been observed that almost all myoblasts express MyoD after 24 h of in vitro culture (584). While most of these proliferating Pax7/MyoD myoblasts differentiate into Pax7/MyoD/Myogenin cells after 72 h of culture, some Pax7/MyoD myoblasts (also called reserve cells) nonetheless have been observed to repress MyoD expression and maintain Pax7 expression and eventually withdraw from the cell cycle (216, 584). These Pax7/MyoD satellite cells acquired the quiescence marker Nestin, albeit at a much later (3 4 wk in culture) stage (127). These observations suggest that quiescent satellite cells renew by lineage regression from committed myogenic cells at least in vitro, and this renewal may be promoted by Pax7 (584). In addition, the capability of activated satellite cells to generate reserve cells may be an important mechanism to maintain the size of the satellite cell pool, as reduction of such capability was suggested to lead to decreased numbers of satellite cells with age (128). Intriguingly, this lineage regression has also been recently observed in vivo (482). Sprouty-1, a negative regulator of receptor tyrosine kinase (RTK) signaling, plays a critical role in satellite cell renewal (482). Sprouty-1 is expressed in quiescent but not proliferating satellite cells (177, 482). Upon injury, released broblast growth factor (FGF) and hepatocyte growth factor (HGF) act through the RTK/ ERK pathway to stimulate satellite cell proliferation (482). Most satellite cells entered the cell cycle during regeneration as indicated by BrdU labeling. It was conrmed that some satellite cell-derived myogenic progenitors withdrew from the cell cycle, returned to the satellite cell compartment, and regained Sprouty-1 expression, indicative of satellite cell renewal in vivo. In the absence of Sprouty-1, it was observed that satellite cell-derived myogenic progenitors proliferate and differentiate normally, but markedly reduced numbers of satellite cells exist after regeneration. Further investigations revealed that Sprouty-1 is required only for a distinct subset of myogenic progenitors to return to their quiescence state (482). These results indicate that Sprouty-1 is essential for some satellite cells to regain quiescence following regeneration. The function of Sprouty-1 in this process is most likely due to its inhibitory effect on the ERK pathway and subsequent enhanced cell cycle withdrawal. It should be stressed that this renewal of satellite cells at a population level and the aforementioned self-renewal of satellite cells at a single-cell level are not mutually exclu-
36
SATELLITE CELLS AND THE MUSCLE STEM CELL NICHE sive but rather represent two different perspectives of the same regeneration process. Future studies are needed to identify the essential differences between Sprouty-1-dependent and Sprouty-1-independent populations and understand whether these differences reect any other functional distinction. In addition, it would be interesting to investigate the regulatory mechanisms governing Sprouty-1 expression, for example, whether the reappearance of Sprouty-1 is regulated by Pax7 or Wnt signaling. signaling and chemokine receptor 2 (CCR2) have been implicated in guiding bone marrow cells towards muscle injury sites (429, 510). However, it has also been reported that SDF-1/CXCR4 signaling is dispensable for the homing of CD45 hematopoietic lineage cells to injured muscle, which are instead responsive to HGF/c-Met signaling (447). Overall, it is noteworthy that bone marrow transplantation has not been reported to robustly or therapeutically ameliorate any muscle disease. Future studies are required to dene the subpopulation(s) of bone marrow cells, which have long-term myogenic potential in vivo especially in the context of muscle diseases. Also, it would be interesting to investigate whether bone marrow-derived cells are involved in postnatal muscle growth since satellite cells with similar markers have been identied in adult muscles. 2. Muscle side population cells The myogenic potential of bone marrow cells was demonstrated by either intravenous injection of bone marrow cells into subjects following muscle injury or directly via intramuscular injection of whole bone marrow into injured muscles. Both of these methods led to the incorporation of bone marrow-derived cells into newly formed myobers within regenerating muscles (54, 166, 210). Because of the extremely low efcacy of incorporation, doubts persist regarding the ability of bone marrow-derived cells to reconstitute the satellite cell niche (210). Nevertheless, lineage tracing experiments demonstrated that bone marrow cells, when systematically injected into irradiated mice, were able to reconstitute the satellite cell niche and expressed satellite cell markers, such as Myf5, c-Met, and 7-integrin (287). These bone marrow-derived satellite cells can undergo myogenic differentiation in vitro and give rise to myobers when injected into damaged muscles (287). Adult bone marrow contains hematopoietic stem cells (HSC) and stromal cells (also called mesenchymal stem cells). Due to a lack of a standardized denition, conicting results exist regarding the exact bone marrow-derived progenitor cell type(s) that contribute to muscle regeneration. Bone marrow-residing hematopoietic stem cells, isolated by cell surface markers c-Kit/Sca-1 or CD45/Sca-1, or CD45/c-Kit/ Sca-1 are able to incorporate into newly forming myobers (1, 78, 112, 581), although it was unclear whether the progeny of these cells were able to occupy the satellite cell niche. It was also demonstrated that Mac-1low bone marrow SP cells, particularly those c-Kit/CD11b immature cells, were able to generate myobers (147, 382). On the other hand, mesenchymal stem cells were able to incorporate into myobers in injured muscles (140, 488) and gave rise to Pax7 satellite cells, which can support multiple rounds of muscle regeneration (140). Interestingly, the high myober turnover rate induced by muscle stress and injury seems to facilitate bone marrow cell engraftment into regenerating muscles (1, 68, 287, 460, 487). These results further emphasize the importance of the microenvironment on satellite cell specication. In accordance with this, stromal cellderived factor-1 (SDF-1)/chemokine receptor 4 (CXCR4) Similar to bone marrow, skeletal muscle contains a unique cell population termed muscle side population (SP) cells, which can be isolated based on their ability to efux Hoechst 33342 dye (210, 245). The majority of muscle SP cells are characterized by CD45/c-Kit/Sca-1/ABCG2/ Pax7/Myf5/Desmin and reside in the skeletal muscle interstitium juxtaposed to blood vessels, which make them distinct from satellite cells and bone marrow-derived SP cells (24, 146, 210, 439, 464). Multiple lines of evidence indicate that muscle SP cells are heterogenic (24, 464). Initially, a minor population of CD45 muscle SP cells was identied (24, 464, 478). These CD45 muscle SP cells persist in Pax7/ germline null mice and can efciently differentiate into hematopoietic cells in culture (24, 478). In addition, CD45 muscle SP cells also have myogenic potential when isolated from both wild-type and Pax7/ mice. They can be induced to differentiate into myogenic cells following coculture with primary myoblasts or through the forced expression of Pax7 or MyoD (24, 477). In addition, lineage tracing experiments have revealed that only the main population of CD45 muscle SP cells arise from embryonic Pax3 hypaxial somitic cells, suggesting the minor CD45 SP cells might have distinct origins, possibly from endothelial, hematopoietic stem, or bone marrow cells (464). This is consistent with results from transcriptome analysis of muscle SP cells in resting and regenerating muscles, which indicate the increased expression of c-Kit and CD45 in the muscle SP population 5 days after injury (337). Furthermore, it was also demonstrated that somite-derived CD45 SP cells have more myogenic potential than CD45 SP cells when cultured in vitro, suggesting that the developmental origin of SP cells affect their intrinsic myogenic capacity (464). Lastly, a recent study revealed that a subpopulation of satellite cells also have an SP phenotype (518). These SP cells that reside in the satellite cell compartment, termed satellite-SP cells, are characterized by CD45/Sca1/ABCG2/Pax7/Syndecan-4, which makes them distinct from the majority of CD45 SP cells in muscle. Following direct injection into regenerating muscles, the grafted
D. Contributions and Therapeutic Potential of Nonsatellite Cells in Trauma-Induced Muscle Regeneration

1. Bone marrow stem cells
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YIN, PRICE, AND RUDNICKI muscle SP cells were found in myobers and the satellite cell niche, which suggests that these cells can contribute to longterm muscle regeneration (24). Importantly, when introduced intravenously into mdx mice, muscle SP cells from wild-type mice incorporate into host myobers and restore their dystrophin expression (27, 210), suggesting these cells are able to migrate to regenerating muscles through the bloodstream. Indeed, compared with satellite cells and their derivatives, muscle SP cells are much more efcient at engrafting into mdx hosts after systemic delivery (368). Interestingly, the systemic delivery of wild-type SP cells into mdx mice can also repopulate the bone marrow of an irradiated host, although at lower efcacy compared with bone marrow-derived SP cells (210). Muscle SP cells constitute a distinct cell population based on their unique properties. However, it is still unclear whether the SP phenotype per se is of any importance to the muscle regeneration process. Although muscle SP cells outperform the main population in muscle regeneration, future studies are needed to carefully compare muscle SP cells with other dened myogenic precursors, such as non-SP satellite cells, based on their myogenic potential. 3. PW1 interstitial cells It has been reported that some interstitial cells, characterized by their expression of PW1 (also called peg3), might be involved in perinatal skeletal muscle growth (345). Intriguingly, a recent study from the same group reported that adult stem cells/progenitors residing in multiple tissues/organs can be directly identied and isolated from PW1-reporter mice (46). PW1 is encoded by a 8.5 kb long, intronless transcript, which is strongly transcribed in skeletal muscle in both embryonic and postnatal stages (435). Within skeletal muscle, PW1 expression was detected in both satellite cells and a group of Sca-1/CD34/Pax7 interstitial cells (PIC) (351, 376, 476). In transgenic mice with a dominant negative form of PW1 (PW1) driven by a Myogenin promoter, embryonic and fetal muscle development is normal but postnatal muscle growth is severely impaired with a profound phenotype, to some extent, reminiscent to that of Pax7/ germline mutant mice (376, 478). Compared with wild-type mice, the number of quiescent satellite cells is markedly reduced in postnatal muscle of PW1 mice (376). In contrast, the number of Pax7/PW1 interstitial cells (PIC) is signicantly increased within postnatal muscles from Pax7/ mice (345), which is accompanied by progressive loss of Pax7 satellite cells (345, 380, 478). Interestingly, PICs have myogenic potential when cultured in vitro (345). This myogenic potential is enhanced by coculture with satellite cells and is compromised in PICs isolated from Pax7/ mice (345). Importantly, when transplanted into injured muscles, FACS isolated Sca-1/CD34/CD45 PICs give rise to both interstitial cells and Pax7 satellite cells, whereas Sca-1/CD34/CD45 cells (enriched for satellite cells) only derive into Pax7 satellite cells (345). Although not directly assessed by lineage tracing, these observations together support a hypothesis that PICs may contribute to the satellite cell population during postnatal muscle growth and during adult muscle regeneration (345). In addition, Pax7 expression is presumably essential for the myogenic specication of PICs as PICs isolated from Pax7/ mice cannot give rise to myogenic cells in vitro (345). Of note, Pax3 lineage tracing experiments further indicated that PICs do not arise from embryonic Pax3 myogenic progenitor cells, indicating PICs and satellite cells are derived from distinct lineages (345). These intriguing observations also raised several issues regarding the identity and lineage progression of the Sca-1/ CD34/CD45/(50% PW1) interstitial cells. A recent study indicated that FAPs isolated from adult muscle are characterized by similar markers Sca-1/CD34/CD45 (also CD31) but only give rise to adipogenic and brogenic lineages in vitro (252 and discussed in sect. IIIB1A). Coculture with myogenic cells cannot promote the myogenic potential of FAPs (252). Accordingly, FAPs also do not assume the myogenic lineage in vivo when transplanted into either uninjured or injured muscles. These discrepant observations on PICs and FAPs lead to two possibilities: 1) FAPs are depleted of CD31 cells and thus the myogenic potential resides in these CD31 cells; or more likely 2) PICs and FAPs represent the same cell population but in young and adult stages, respectively. Notably, muscle SP cells (Sca-1/ABCG2) are also CD34 and thus could be originating from the same lineage as FAPs and PICs (226). Future studies may provide direct answers in terms of the lineage origin and hierarchy of these cell types. Future investigations should also focus on the mechanisms that regulate the myogenic potential of these interstitial cells. 4. Muscle-derived stem cells A series of studies have demonstrated that a distinct cell population, termed muscle-derived stem cells (MDSCs), can be isolated from skeletal muscles based on their weak adhesion characteristics and long-term proliferation behaviors in culture (247, 294, 421, 422). Further characterization of MDSCs indicated that these cells are CD45/MCadherin/CD34/Flk-1/Sca-1/Desmin, which makes them distinct from satellite cells and hematopoietic cells but more similar to muscle SP cells (294, 421). MDSCs and satellite cell-derived myoblasts in culture appear to represent two distinct populations as evidenced by the nding that MDSCs can be isolated from Pax7/ germline null mice (318). Like muscle SP cells, the myogenic differentiation of MDSCs depends on Pax7 (318). A unique characteristic of MDSCs is their multipotency (294, 421, 536). It has been reported that MDSCs can differentiate into myogenic, adipogenic, osteogenic, chondrogenic, and hematopoietic lineages (reviewed in Ref. 404). After intra-arterial transplantation, MDSCs contribute to regenerated myobers, incorporate into the satellite cell niche, and also give
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SATELLITE CELLS AND THE MUSCLE STEM CELL NICHE rise to endothelial and neural cells (421). Interestingly, like muscle SP cells, MDSCs can also repopulate the hematopoietic lineage in irradiated murine hosts, and the reconstituted bone marrow can in turn contribute to muscle regeneration (82). In addition, MDSCs are more efcient than myoblasts at forming dystrophin myobers when directly transplanted into mdx mice (243). Due to the prolonged isolation procedure of MDSCs and the accompanied dynamics of gene expression, it is difcult to trace the origin of MDSCs in vivo based on cell surface markers. Future investigation by candidate lineage tracing and clonal analysis may help to elucidate the lineage relationship between MDSC and other myogenic cells. 5. Mesoangioblasts Mesoangioblasts arise from the embryonic dorsal aorta and are characterized by CD34/c-Kit/Flk-1/NKX2.5/ Myf5/Oct4 expression (129, 343). Mesoangioblasts are highly proliferative when cultured in vitro, and long-term cultured mesoangioblasts are multipotent, being able to give rise to multiple mesodermal lineages, such as bone, cartilage, smooth, cardiac, and skeletal muscle following transplantation (343). Although the contribution of mesoangioblasts to normal muscle development is controversial, multiple studies have demonstrated that mesoangioblasts can be employed to facilitate muscle regeneration, particularly for dystrophic muscles. First, it was found that -sarcoglycan/ mesoangioblasts can be transduced in vitro with -sarcoglycan expressing lentiviral vector and robustly generate -sarcoglycan myobers following transplantation into -sarcoglycan/ mice (a model for limb girdle muscular dystrophy) via intra-artery injection (458). The high efciency of normal myober reconstitution observed in this study suggests that intrinsic properties of mesoangioblasts may help them travel to regenerating muscles via the bloodstream. In addition, mesoangioblasts can release immunosuppressive and tolerogenic molecules, which supposedly help mesoangioblasts incorporate into allogeneic dystrophic hosts (211). The myogenic potential of mesoangioblasts isolated from human patient biopsies suffering from dermatomyositis (DM), polymyositis (PM) and inclusion-body myositis (IBM) were compared (352). It was observed that mesoangioblasts from the IBM patients could not differentiate into myobers when cultured in vitro or xenotransplanted into injured mouse muscles. Interestingly, this defect can be rescued by either transient overexpressing of MyoD or knockdown of a MyoD inhibitor protein, bHLH-B3, which suggests that the myogenic program of mesoangioblasts is MyoD-dependent (352). Several investigations demonstrated that factors involved in normal muscle regeneration also facilitate mesoangioblastbased muscle regeneration. For example, HMGB1, SDF-1, CXCR4, and 4-integrin have been shown to enhance the migration of mesoangioblasts from blood vessels toward injured muscles (182, 399). Similarly, pretreatment of mesoangioblasts with nitric oxide before transplantation also stimulated -sarcoglycan expression in mesoangioblast-derived myobers (475). Taken together, investigations on mesoangioblasts have revealed great therapeutic potential for the amelioration of human dystrophic diseases. Future studies may focus on identifying the adult counterparts of these cells and characterizing their myogenic potentials. 6. Pericytes Pericytes (also called Rouget cells or Mural cells) are contractile connective tissue cells residing beneath the microvascular basement membrane. Pericytes originate from the embryonic sclerotome and are believed to regulate the blood ow in capillaries (415, 284, 406). As a multipotent stem cell population, pericytes can differentiate into adipocytes (161), chondrocytes (161), and osteoblasts (142) in vitro. Two recent studies indicated that pericytes, which do not express Pax7, Myf5, or MyoD, can differentiate into skeletal muscles both in vitro and in vivo (135, 136), suggesting pericyte-mediated myogenesis may follow a myogenic differentiation program distinct from that of satellite cells. FACS sorted human pericytes display the following cell surface marker combination: CD45/CD34/CD56/ CD144/CD146/PDGFR-1/NG2 proteoglycan, which makes them distinct from embryonic mesoangioblasts, hematopoietic cells, or satellite cells (136). Intriguingly, cells carrying the same surface marks can be isolated from various tissues, including pancreas, adipose, and placenta and differentiate into skeletal muscle cells when cultured in vitro, irrespective of their origins (118). The fact that pericytes also display cell surface markers characteristic of mesenchymal stem cells (CD10/CD13/ CD44/CD73/CD90) raised the hypothesis that pericytes may represent a signicant portion of mesenchymal stem cells in the adult (85, 118, 163). Xenographic transplantation of human pericytes into combined immune decient-X-linked, mouse muscular dystrophy (scid-mdx) mice through the femoral artery gave rise to numerous myobers expressing human dystrophin (136). Interestingly, a small portion (35%) of transplanted pericytes incorporated beneath the basal lamina of myobers, indicating that pericytes are able to occupy the satellite cell niche in dystrophic muscle. Importantly, pericyte transplantation signicantly improved the physiological performance of treated dystrophic muscles, indicating that pericyte-derived myobers are functional. Similar promising results were achieved in a prototype experiment, wherein pericytes isolated from Duchenne patients were transduced in vitro with a human mini-dystrophin expressing lentiviral vector and transplanted into scid-mdx mice (136). The myogenic potential, together with their abilities to be cultured in vitro and penetrate the blood vessel wall, makes pericytes a promising candidate for future cell-based therapies to treat muscular dystrophy. Future research may investigate whether transplanted pericytes possess sufcient long-term myogenic capability in dystrophic muscles.
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YIN, PRICE, AND RUDNICKI 7. CD133 cells Recent studies demonstrated that a fraction of CD133 (also called AC133) mononucleated cells in adult peripheral blood have myogenic potential (535). Freshly isolated human CD133 cells can undergo myogenic differentiation when cocultured with myogenic cells or exposed to Wntproducing cells in vitro (535). Importantly, when xenotransplanted via intra-arterial or intramuscular injection, these CD133 cells can fuse with regenerating muscles in scid-mdx mice and improve the force generation of treated muscles. Moreover, donor human CD133 cells, expressing satellite cell markers M-Cadherin and Myf5, were detected in the satellite cell compartment after transplantation, indicating they can reconstitute the satellite cell niche (535). A small subpopulation of CD133/ CD34 double positive cells can be identied in the blood and skeletal muscle interstitium (233). Similar to blood-derived CD133 cells, human muscle-derived CD133 cells manifested remarkable myogenic differentiation capacity in regenerating muscle (372). As CD133 cells can be readily isolated from the blood, manipulated in vitro and delivered through the circulation, a couple of studies have explored their application to treating Duchenne muscular dystrophy (DMD). In one of these studies, CD133 cells isolated from human dystrophic muscles were genetically engineered ex vivo to restore dystrophin expression and subsequently delivered into scid-mdx mice (41). Treated dystrophic muscles were improved in terms of muscle morphology, function, and dystrophin expression, although the long-term effect of this treatment has not been documented so far. The safety of this CD133 cell therapy (without dystrophin correction) was later conrmed in human DMD patients by autologous transplantation (534). Taken together, CD133 cells are one of the most promising candidates for cell-based therapy of DMD. Future studies should focus on whether these cells can survive long term and support repeated bouts of regeneration in DMD patients. 8. Embryonic stem cells and induced pluripotent stem cells Embryonic stem (ES) cells are pluripotent stem cells, which can differentiate into all three germ layers and hence have been extensively studied for cell-based therapies. In an early study, mouse ES cells cocultured with muscle cells were transplanted into irradiated mdx mice by intramuscular injection (47). Donor-derived myobers were occasionally found on the surface of the host muscles. The low efcacy of engraftment in this study suggested that selective markers might be necessary to enrich myogenic precursors from ES cell cultures. In a later study, a subpopulation of CD73/ N-CAM human ES cells, which are enriched for mesenchymal precursors, were injected into regenerating muscle of scid mice (31). It was observed that human donor cells gave rise to myoblasts and established prolonged engraftment; however, the overall efciency was not compared with other myogenic cells, such as satellite cells. Recently, several strategies have been established to achieve persistent engraftment and avoid teratoma formation. In one study, Pax3 was transiently expressed to induce paraxial mesoderm formation during embryoid body differentiation, and PDGFR-, a paraxial mesoderm marker, was subsequently used to isolate a homogeneous population of proliferating myogenic progenitors (124). The transplantation of this population into mdx mice resulted in improved muscle function, and teratoma formation was prevented. In another study, PDGFR- cells were directly isolated from ES cells in an earlier stage without Pax3 induction (455). It was found that these early paraxial mesodermal cells, when transplanted into injured muscles, could give rise to bona de satellite cells that can further differentiate into functional myobers. Similarly, transient expression of Pax7 seems to facilitate the myogenic specication of ES cells (125). Recently, it was shown that SM/C-2.6 cells isolated from cultured embryoid bodies can differentiate into skeletal muscle myobers both in vitro and in vivo (88). When transplanted into injured muscles, these cells can incorporate into the satellite cell compartment and express satellite cell markers, such as Pax7 and M-cadherin. Importantly, these ES-derived satellite cells undergo extensive self-renewal during subsequent muscle injury and can be further transplanted with high engraftment efciency (88). Over the last ve years, various types of differentiated somatic cells have been successfully induced into pluripotent stem cells (iPS cells) via a process involving transcription factor based reprogramming (371, 384, 515, 516, 582). Given their adult somatic origin and pluripotent nature, iPS cells hold tremendous potential for cell-based therapy. In an attempt to apply iPS cells to muscle regeneration, a recent study demonstrated that SM/C-2.6 cells isolated from mouse iPS cells have comparable regenerative potential to those from mES cells (346). In addition, conditional expression of Pax7 in human iPS cells was successful in inducing large quantities of myogenic progenitors, which were able to efciently engraft and produce abundant human-derived dystrophin myobers in dystrophic mouse muscle (123). Notably, a new strategy of iPS cell-based therapy to treat DMD was reported recently (267). In this study, iPS cells were derived from mdx mice or a human DMD patient, and the genetic deciency of dystrophin in these cells was corrected by transferring a human articial chromosome (HAC) containing a complete genomic dystrophin sequence via microcell-mediated chromosome transfer (MMCT). These genetically corrected iPS cells can differentiate into muscle-like tissues and can be used to generate chimeric mice, wherein tissue-specic expression of dystrophin was observed (267). These inspiring results warrant future investigations on regulatory mechanisms governing the myogenic specication of ES and iPS cells.
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E. Satellite Cells in Perinatal/Juvenile Muscle Growth

In neonatal mouse muscle, satellite cells account for 30 35% of the sublaminal nuclei on myobers (9, 227, 471). This proportion of satellite cells decreases while the number of myonuclei increases over postnatal growth (150). Experiments by [3H]thymidine labeling indicate that satellite cells are proliferative in growing muscle, give rise to myonuclei, and continue to fuse with myobers (355, 470, 481). The cell cycle time of juvenile satellite cells in growing rat muscles was determined to be 32 h, with 14 h within the S phase (471). This high proliferation rate of juvenile satellite cells is likely due to a large requirement for muscle growth at this stage. Like their adult counterparts, juvenile satellite cells are also likely heterogeneous. By continuous BrdU labeling and tandem BrdU/[3H]thymidine labeling, two subpopulations of satellite cells in growing muscle have been identied (471). A fast-cycling satellite cell population, accounting for 80% of the cells, was readily labeled over the rst 5 days of continuous BrdU infusion. In contrast, slowdividing satellite cells incorporated BrdU at a much slower rate, and some of them were not labeled with BrdU even after an additional 9 days. Moreover, only a small portion of the satellite cells labeled with BrdU during the rst 5 days could be labeled with [3H]thymidine during a second 5-day continuous infusion. This observation suggests that 1) the majority of fast-cycling satellite cells only undergo a limited number of mitotic divisions prior to fusion, and 2) the number of fast-cycling satellite cells in growing muscle are maintained by the slow-cycling satellite cells through asymmetric divisions (471). Interestingly, the functional difference and lineage relationship between these two satellite cell populations during postnatal muscle growth largely resemble that of satellite cells and myoblasts during adult muscle regeneration. This analogy may reect a common scheme of myogenesis in both postnatal muscle growth and adult muscle regeneration. Despite their similarities, studies have revealed distinct genetic requirements for both juvenile and adult satellite cell populations. Pax7 is required for the maintenance of a functional myogenic cell population in the perinatal/juvenile stage, as muscle growth and regeneration are severely impaired in Pax7 germline null mutants during this period (279, 393, 478). In contrast, Pax7 seems to be dispensable for adult muscle regeneration in Pax7 conditional knockout mutants, wherein Pax7 expression is ablated only in the adult stage (299). In conditional Pax7 knockout mice, satellite cells, expressing M-cadherin but not Pax7, were observed in the satellite cell compartment in adult muscle after one round of regeneration, and these cells can support a second round of regeneration (299). The regenerative capacity of Pax7 satellite cells was not due to a compensatory mechanism by Pax3, as muscle regeneration is not impaired by simultaneous deletion of both Pax7 and Pax3 in adulthood. It is well known that both juvenile and adult
satellite cells express Pax7 (478). The apparent distinct requirement for Pax7 in juvenile but not adult muscle regeneration may suggest that Pax7 is only necessary for the initial establishment of perinatal satellite cells and/or de novo myogenic specication of other nonsatellite cell lineages, which presumably contribute to the total satellite cell pool during postnatal growth. In contrast, the maintenance of satellite cell establishment might be Pax7 independent and the rare occasion of de novo myogenic specication from other nonsatellite cell lineages may be negligible in adulthood. In this sense, the sustained expression of Pax7 in adult satellite cells may be due to sustained interactions with their niche, rather than a necessity for Pax7 function. In support of this hypothesis, genetically marked hematopoietic stem cells (bone marrow derived CD45/c-Kit/Sca1/Lin cells) have been shown to express Pax7 once they are present in the satellite cell niche (148, 581).
III. ANATOMIC AND FUNCTIONAL DIMENSIONS OF THE SATELLITE CELL NICHE

Based on the stem cell niche concept, behaviors of tissuespecic stem cells are determined by structural and biochemical cues emanating from the surrounding microenvironment (380). In recent years, adult stem cells and their corresponding niches were identied in numerous tissues including bone marrow (566), brain (322), testis (240), liver (528), intestine (55), heart (302), white fat (441, 519), and skin (174). Similar to these adult stem cells, satellite cells are also present in a highly specied niche, which consists of the extracellular matrix (ECM), vascular and neural networks, different types of surrounding cells, and various diffusible molecules (FIGURE 3). Furthermore, satellite cells, as one of the niche components, also inuence each other by means of cell-cell interaction and autocrine or paracrine signals. The dynamic interactions between satellite cells and their niche specically regulate satellite cell quiescence, self-renewal, proliferation, and differentiation. In this fashion, muscle atrophy or excessive growth is prevented, and the satellite cell pool is maintained during regeneration. Understanding the interactions between satellite cells and their niche is of paramount importance for the development of therapies to treat both age-related skeletal muscle atrophy (sarcopenia) and skeletal muscle diseases. In the following section, we will dene the scope of the satellite cell niche and discuss how these niche factors affect satellite cells during muscle regeneration.
A. The Immediate Niche

1. Satellite cell: regulatory signaling pathways
A) WNT SIGNALING.
Wnt signaling controls diverse biological processes, such as cell proliferation, cell fate determination,
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YIN, PRICE, AND RUDNICKI
Signaling within the Immediate Niche Satellite cell Fibronectin bFGF Decorin Proteoglycans Basal lamina SDF-1 Myotube Sarcolemma Wnt7a
Laminin Entactin Collagen HGF Perlecan Signaling within the Local Milieu EGF
IGF
Glycoproteins
Fibroblast
Pericytes
Motor neurons (axons)
Perimysium
Connective tissue Capillaries Adipocytes
Muscle fascicle Signaling within the Systemic Milieu Immune cells Monocytes Macrophages Neutrophils Tibia Androgens
IL-6 Myofibers fi ib _Neutrophils Satellite cells Nitric Oxide Epithelial cells Endothelial cells Fibroblasts Macrophages Myofibers
Fibula
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SATELLITE CELLS AND THE MUSCLE STEM CELL NICHE cell adhesion, cell polarity, and morphology. Wnt signaling is activated by binding of extracellular Wnt family glycoproteins with Frizzled receptors and low-density lipoprotein receptor-related protein (LRP5, LRP6) pairs. The Frizzled receptor can initiate two distinct signaling pathways: the Wnt/-catenin and Wnt/PCP pathways. Wnt/-catenin pathway is characterized by the regulation of -catenin stabilization and its entry into the nucleus. The Wnt/PCP pathway is involved in planar cell polarization (PCP) and establishment of polarized cellular structures (183). In the Wnt/-catenin pathway, the level and subcellular localization of -catenin determine the ultimate output. Normal levels of -catenin dimerize and associate with both transmembrane cadherins and cytoskeleton-bound -catenin, which promotes cell adhesion and controls cell shape. The normal levels of cytoplasmic -catenin are maintained by constitutive degradation of excess -catenin by GSK3-. In the cytoplasm, GSK3- and -catenin complex with Axin and adenomatous polyposis coli (APC), leading to -catenin phosphorylation by GSK3-. Phosphorylated -catenin is bound by the -TrCP component of the ubiquitin ligase complex and degraded by the proteosome. GSK3- is constitutively active but can be inhibited by Dishevelled (Dvl), which is activated by Wnts binding to a Frizzled and LRP receptor pair. Thus, when Wnt signaling is active, elevated levels of cytoplasmic -catenin enter the nucleus and interact with Tcf/Lef transcription factors to regulate gene expression (373). Accumulating evidence indicates that Wnt/-catenin signaling is involved in satellite cell function during muscle regeneration, although its dened roles remain controversial. First, Brack et al. (65) suggested that Wnt signaling promotes myogenic commitment and terminal differentiation in adult myogenesis. By examining the effects of exogenous Wnt3a and sFRP3 as activator and inhibitor of Wnt signaling, respectively, it was found that regenerating muscles in vivo and myoblasts derived from cultured single myobers are responsive to Wnt signaling only at a late stage of differentiation. Activation of Wnt/-catenin signaling increased both Desmin expression in myogenic cells in vitro and the size of newly formed myobers in vivo, whereas inhibition of Wnt signaling caused the opposite effects. Interestingly, Notch signaling seems to antagonize the effects of Wnt signaling at early stages of myoblast proliferation. This counteracting effect is reected by the levels of the active form of GSK3-, which are high in the early Notch activating stage and low in later Wnt activating stage. It was proposed that low activity of Wnt signaling in early proliferation allows the expansion of enough myoblasts by Notch signaling for later differentiation (65). Notably, although this study reported that the mRNA levels of Wnt ligands and Frizzled receptors within isolated myobers increase in late culture, it is still possible that Wnt ligands may originate from other sources in vivo, such as the ECM, and may function through preexisting Frizzled receptors on satellite cells. Perez-Ruiz et al. (407) proposed that -catenin promotes self-renewal of satellite cells and prevents them from immediate myogenic differentiation. By retrovirus-based overexpression and RNAi knockdown of proliferating Pax7/ MyoD satellite cells on single myobers, it was found that constitutive expression of stabilized -catenin, or inhibition of degradation by GSK3 leads to downregulation of MyoD and Myogenin expression. In contrast, when -catenin was downregulated by RNAi or when its target genes were repressed by the dominant-negative -cateninERD, fewer Pax7/MyoD myoblasts were observed. As -catenin levels determined the observed cellular changes, it was proposed that the Wnt/-catenin pathway is involved (407). It should be stressed that although MyoD expression can be regulated by directly changing -catenin levels, the physiological relevance of this phenomenon still largely depends on the availability of Wnt ligands and expression of Frizzled receptors on satellite cells. In addition, a recent study revealed that -catenin directly interacts with MyoD to enhance MyoD binding to E-box elements to initiate the myogenic program (271). However, in vivo studies are required to further conrm and elaborate on the mechanism whereby -catenin interacts with MyoD. Otto et al. (391) proposed that Wnt ligands are important regulators of proliferation for satellite cells during adult muscle regeneration. mRNAs for Wnt ligands (Wnt1, Wnt3a, Wnt5a, Wnt11) were expressed in single myobers (together with satellite cells) upon 2 days of culture in vitro. These data along with reporter assays indicated that Wnt signaling is active at this point. It was found that exogenous
FIGURE 3. The satellite cell niche. A: satellite cells reside between the basal lamina and the sarcolemma of adult skeletal myobers and as such are inuenced by structural and biochemical cues emanating from this microenvironment. A complex set of diffusible molecules (e.g., Wnt, IGF, and FGF) are exchanged between the satellite cell and the myober to maintain quiescence or promote activation. In addition, numerous extracellular matrix components and cellular receptors are present either on the surface of the sarcolemma, satellite cell, or contained within the basal lamina. These components comprise the immediate niche of the satellite cell and dictate rapid changes in the satellite cell state. B: the muscle fascicle denes the extremities of the local milieu an environment that is more diverse compared with the immediate niche due to the heterogeneity of cell types and signaling factors. The local milieu surrounding the satellite cell is made up of other myobers in addition to interstitial cells, capillaries, and neuromuscular junctions. Each of these cell types inuences the surrounding environment and thereby affects the state of the satellite cell. C: the systemic milieu contains the greatest diversity with which the satellite cell is inuenced. Exposure of satellite cells to the hosts immune system, and circulating hormones along with the skeleton and surrounding skeletal muscles present the broadest environment for the satellite cell. Changes that occur in the systemic milieu affect the satellite cell gradually. Prolonged exposure of signals from the systemic milieu plays an important role in the ability of satellite cells to participate in multiple rounds of regeneration.
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YIN, PRICE, AND RUDNICKI Wnt1, Wnt3a, and Wnt5a induced satellite cell proliferation, whereas exogenous Wnt4 and Wnt6, whose expression is absent from regenerating muscle, inhibited the proliferation. This is consistent with the inhibitory effect of ECGC, a potent Wnt signaling inhibitor, on satellite cell proliferation (391). Importantly, the expression and subcellular location of the active form of -catenin (Act--Cat) was carefully examined by immunouorescence staining in this study. Nuclear Act--Cat was observed only after MyoD expression and was absent in Myogenin cells, which suggests Wnt signaling is inactive either before satellite cell activation or after differentiation determination. This temporal progression of Wnt signaling was further conrmed in mouse regenerating muscles and human dystrophic muscle biopsies. Thus Otto et al. (391) concluded that activating Wnt ligands function to promote satellite cell proliferation during muscle regeneration, whereas inhibitory Wnt ligands antagonize the proliferation by secluding -catenin to the cell membrane in quiescent satellite cells. Perplexingly, the pro-proliferation function of Wnt3a signaling revealed by this study seems to oppose the prodifferentiation function reported by Brack et al. (65). This might be due to different sources of Wnt ligands, either from cultured Wnt-expressing cells or from recombinant protein, which in turn affect Wnt concentration and effective time. In addition to -catenin-dependent gene activation, recent studies indicate that the binding of Wnt ligands with Frizzled/ LRP receptors can also lead to a transduction cascade to establish PCP, which is referred to as the Wnt/PCP pathway (reviewed in Ref. 492). In this signaling pathway, signaling from Wnt ligand/receptor binding activates Rho/Rac small GTPase and Jun NH2-terminal kinase (JNK) via Dishevelled. Dishevelled activates Rac, which further activates JNK to assist in the subsequent regulation of cytoskeleton organization and gene expression. The Wnt/PCP signaling pathway plays an important role in the development of anterior-posterior extension of the neural tube and the establishment of the aligned cellular structure in epithelium. Emerging evidence reveals that satellite cells are under the regulation of Wnt/PCP signaling pathway. Our group demonstrated that quiescent satellite cells can be separated into two functional subpopulations based on their Myf5 expression: Pax7/Myf5 satellite stem cells and Pax7/Myf5 satellite progenitor cells (280). Of interest, we determined that mRNAs of the Frizzled7 receptor are preferentially present in Pax7/Myf5 quiescent satellite stem cells (293). However, upon injury, Frizzled7 is ubiquitously expressed in all satellite cells and their proliferating progeny. In a frozen injury model, Wnt1, Wnt2, Wnt5b, Wnt8b, Wnt10a, Wnt16a, Frizzled receptors, and sFRP inhibitors were increased in muscles 3 days postinjury (acute phase of regeneration). In contrast, an increase of Wnt7a and Wnt10a was detected in muscles 6 days postinjury, when satellite cells returned to the sublaminar position. It was determined that Wnt7a acts through the Frizzled7 receptor to specically activate the Wnt/PCP pathway and induce cell polarity both ex vivo and in vitro. Activation of the Wnt/PCP pathway by recombinant Wnt7a simulated the symmetrical division of satellite cells and hence expanded the satellite stem cell population on single myober explants. Knockdown of Wnt/PCP downstream component, Vangl2, by RNAi caused the opposite effects, conrming the involvement of Wnt/PCP pathway in this process. In vivo, Wnt7a injection into regenerating muscles remarkably improved muscle regeneration as evidenced by increased muscle mass and myober size. We postulated that the activation of Wnt/PCP pathway promotes the planar alignment of two daughter cells along the myober during satellite cell division. This alignment and the induced cell polarity may facilitate the attachment of both daughter cells to the basal lamina and hence maintain their stem cell fate (293). Although it is still unknown, one possible source of endogenous Wnt7a is the regenerative myober, given its close proximity to satellite cells and perfect alignment to the basal lamina (65, 413). Intriguingly, a recent study revealed synergistic functions of Wnt/-catenin and Wnt/PCP pathways in oriented elongation of myocytes during embryonic muscle patterning (205). Thus it is enticing to further speculate that the activated Wnt/-catenin pathway in regenerating myobers may induce Wnt7a secretion and activation of the Wnt/PCP pathway in adjacent satellite stem cells, which in turn would direct their symmetric division and replenish the satellite cell pool. Wnt signaling is also implicated in satellite cell-related transdifferentiation. Our group reported that muscle residing CD45/Sca1 cells increased in number and underwent myogenic differentiation in injured muscles but not in intact muscles (413). CD45/Sca1 cells express Frizzled receptors and upregulated -catenin during regeneration, suggesting the Wnt/-catenin pathway is required for the myogenic commitment of these cells. Indeed, the myogenic commitment of CD45/Sca1 cells can be induced by lithium treatment, or coculture with myoblasts or Wnt secreting cells. Daily injections of Wnt signaling inhibitors, sFRPs, severely reduced the myogenic recruitment of CD45/ Sca1 cells during regeneration. These data further suggest that Wnt signaling is required for muscle regeneration and may increase the myogenic potential of CD45/Sca1 cells (413). Similarly, it was reported that -catenin is required and sufcient for myogenic commitment of P19 embryonic carcinoma cells (408). Of note, a recent study showed that Wnt signaling is important for transdifferentiation of satellite cells into brogenic cells (66). Activated satellite cells from old mice have higher Wnt signaling activity and a greater tendency to assume brogenic fate in vitro, compared with those from young mice. Exposure of activated satellite cells from old mice to young serum or pairing with young mice in a heterochronic parabiotic system reversed
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SATELLITE CELLS AND THE MUSCLE STEM CELL NICHE the Wnt signaling activity and associated brogenic tendency, suggesting they are not intrinsic. Conversely, activated satellite cells from young mice exposed to aged serum or linked parabiotically activated Wnt signaling and became brogenic. These observations indicated that the brogenic transdifferentiation of satellite cells is inuenced by an unknown circulating factor (66). As the effect of this factor can be neutralized by a recombinant secreted form of Frizzled, it was believed that an increase in Wnt ligands in old mice may account for the brogenic transformation observed (66). Notably, an alternative possibility is that certain Wnt inhibitors are decreased in old mice. This possibility is supported by a recent nding that a Wnt binding protein, Klotho, is a circulating hormone and can affect tissue aging (281, 313). Wnt signaling also controls the balance between myogenic and adipogenic potentials of myoblasts in vitro. First, downregulation of Wnt/-catenin signaling mediated by Wnt10b was implicated in the increase of adipogenic differentiation of aged myoblasts (527). Similarly, it was observed that in Wnt10b/ mice, the adipogenic potential of myoblasts increased and excessive lipid accumulated in regenerating myobers (549). A recent mechanistic study indicated that Wnt10b activated the Wnt/-catenin pathway and that SREBP-1c-mediated lipogenesis and insulin resistance reciprocally counteract each other and thus determine the myogenic and adipogenic fate of myoblasts (2). The above-mentioned experiments serve to demonstrate the complexities involved in Wnt regulation of myogenesis. Future studies focused on in vivo regulation of a myogenic to adipogenic switch will elaborate on the physiological relevance of the above experimental evidence.
B) NOTCH SIGNALING.
regeneration (108). Reversely, constitutive Notch activation in satellite cells from Pax7-CreER;ROSANotch resulted in increased Pax7 satellite cells and impaired muscle regeneration (560). In aged muscles, the expression of Notch in satellite cells remains unchanged (107). However, the induction of Delta in myobers is no longer responsive to muscle injury, which results in reduced satellite cell proliferation and impaired muscle regeneration (107). At the onset of myogenic differentiation, however, the inactivation of Notch signaling in myoblasts is required for their fusion (108). Two mechanisms exist to downregulate Notch signaling. The rst involves Numb, a Notch signaling inhibitor, which is asymmetrically partitioned during satellite cell/myoblast division (108, 489). The daughter cell inherits Numb and activates the expression of Desmin leading to differentiation (108). Numb inhibits Notch signaling by inducing ubiquitination of the NICD, which abolishes its activity (21). Second, the activation of Wnt signaling in differentiating myoblasts antagonizes Notch signaling and facilitates terminal differentiation (65). This is supported by observations that activation of Notch signaling is associated with phosphorylation of tyrosine 216 of GSK-3b, whereas Notch inhibitor treatment or activation of Wnt signaling in myoblasts coincided with dephosphorylation of this residue (65). Although the precise mechanism remains ambiguous, the crosslink between Wnt signaling and Notch signaling at Dishevelled and Presenilin has been reported (131). In addition, -catenin has been reported to associate with MyoD and facilitate the transcription activity of MyoD (271). Thus it would be interesting to investigate whether MyoD/-catenin can drive the expression of Notch signaling inhibitors, such as Numb, Itch, or the newly reported bHLH transcription factor Stra13 (511). As both Notch receptors and their ligands are transmembrane proteins, Notch signaling is an important signaling pathway mediating cell-cell communications. Our group recently demonstrated that Megf10, a multiple EGF repeatcontaining membrane protein, may function similar to Delta and Jagged in Notch signaling activation (235). Notch-mediated cell-cell communications, presumably conveyed between bumping satellite cells or between satellite cells and the myober, may serve as a controlling mechanism for satellite cell quiescence and the number of satellite cells on a single myober under physiological conditions. In line with this view, double knockout mice of Hey1 and HeyL, two downstream target genes of Notch signaling, showed remarkably reduced number of satellite cells, which is likely due to failure of satellite cells in keeping quiescence in adult muscle (176). Three Notch receptors are abundantly expressed on satellite cells: Notch1, Notch2, and Notch3. A recent study suggests that Notch3 may act as a Notch1 repressor by activating Nrarp, a negative-feedback regulator of Notch signaling
Notch signaling regulates cell proliferation, differentiation, and cell fate determination (21). The activation of Notch signaling pathway is initiated by the binding of Delta and Jagged family of ligands to Notch transmembrane receptors, the result of which induces sequential enzymatic cleavage of the Notch receptor and release of an active truncated form of Notch, termed the Notch intracellular domain (NICD). Upon enzymatic cleavage, the NICD translocates from the cytoplasm to the nucleus and activates the CSL (CBF1, Suppressor of Hairless and Lag-1) family of transcription factors, leading to target gene expression. Notch signaling plays key roles in skeletal muscle regeneration (reviewed in Ref. 320). Upon muscle injury, the Notch ligand Delta is quickly upregulated in both activated satellite cells and in myobers (108). The upregulation of Delta in satellite cells is accompanied by the appearance of the NICD, indicative of activated Notch signaling. Activation of Notch signaling stimulates the proliferation of satellite cells and their progeny and thus leads to the expansion of proliferating myoblasts. Indeed, inhibition of Notch signaling abolishes satellite cell activation and impairs muscle
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YIN, PRICE, AND RUDNICKI (272). In line with this view, Notch3-decient mice showed markedly increased numbers of sublaminar quiescent satellite cells and muscle hyperplasia after repetitive muscle injuries, which are phenotypically opposite to those from Notch1 mutants. In addition to its functions during muscle regeneration, Notch signaling is also involved in the maintenance of cell quiescence in resting health muscle. It was found that genetic abrogation of Rbpj, the main effector for canonical Notch signaling, specically in satellite cells results in the loss of their quiescent state (356). In Pax7-CT2;Rbpjox/ mice, Tamoxifen induction and Rbpj depletion in satellite cells gradually decreased the number of Pax7 satellite cells, which is accompanied with spontaneous myogenic differentiation and failure of muscle regeneration upon injury. Interestingly, the spontaneous myogenic differentiation of the majority of mutant satellite cells in this model seems to start with G0 (quiescent) satellite cells without entry into S phase in vivo. The above ndings support the notion that Notch signaling is critical for satellite cell activation and proliferation. As Notch signaling can be activated by cell-to-cell contact, it is very intriguing to envision that communal satellite cells existing on the same myober can signal each other. This community niche effect may serve to determine the number of quiescent satellite cells on a myober and/or control the size of the satellite cell pool during regeneration. In this respect, recent studies have revealed a close relationship between Notch signaling and Hippo (Salvador/Warts/ Hippo) signaling pathways in determining cell proliferation and organ size in Drosophila (77, 339, 412). It would be interesting to investigate the interactions of these two pathways in satellite cell activation and proliferation.
C) SPHINGOLIPID SIGNALING. Sphingolipids are a large group of naturally occurring glycolipids, characterized by their sphingoid backbone. Although originally recognized as inert precursors and intermediate products in lipid metabolism, sphingolipids, particularly ceramide, ceramide-1-phosphate, sphingosine, and sphingosine-1phosphate (S1P), have been recently revealed as important bioactive signaling molecules in regulating cell proliferation, migration, death, and senescence (reviewed in Ref. 223). Sphingomyelin is the most abundant component in the sphingolipid pathway and also serves as a precursor of ceramide, sphingosine, and S1P. It was found that sphingomyelin is enriched in plasma membrane of quiescent satellite cells, yet it markedly diminishes after satellite cell activation and reappears in some Pax7/MyoD satellite cells returning to the quiescent state (369). The dynamics of sphingomyelin are connected with the biosynthesis of mitogenic S1P, which promotes satellite cells to enter the cell cycle on ex vivo cultured myobers and improves muscle regeneration (370, 461). On the other hand, pharmacolog-
ical inhibition of sphingomyelin-to-S1P processing reduced the number of activated satellite cells and perturbed muscle regeneration. This action of S1P on satellite cell activation and muscle regeneration is in line with the proliferative, proinammatory (through COX-2) and antiapoptotic (through inhibition of caspase-3 and BAX) functions of S1P-mediated pathways in general. Accumulating evidence indicates that S1P, being one of the more soluble sphingolipids, acts through S1P receptors (S1PRs; a group of highafnity G protein-coupled receptors) on satellite cells in an autocrine/paracrine fashion (76, 122). In addition, abnormal modulation of S1P activity is also involved in the pathology of muscular dystrophy (as exemplied in mdx mice) (317). Our current understanding of the functions of bioactive sphingolipids on satellite cells is far from complete. For example, the role of ceramide, another central player of the sphingolipid signaling pathway, on satellite cell activation/ proliferation/differentiation during muscle regeneration is vastly unknown. Moreover, whether S1P may bind to other intracellular proteins and exert S1PR-independent actions remains to be investigated. 2. The myober niche The myobers are the primary component of the satellite cell niche due to their direct contact with satellite cells. The overarching effect provided by the myober for satellite cells was revealed through selective killing of myobers with Marcaine while leaving the basal lamina intact. This resulted in greater numbers of proliferating satellite cells compared with viable myobers (50). This suggested that the myober emanates a quiescent signal either by its physical association or by releasing chemical compounds (50, 53). In accordance with this hypothesis, recent studies have revealed numerous satellite cell regulatory factors that are presented on myobers or secreted by myobers. First, myobers secrete SDF-1, which serves as ligand to the cell surface receptor CXCR4 on satellite cells (429, 486). SDF1/CXCR4 signaling has been shown to stimulate satellite cell migration (429). In addition, it has been found that the transmembrane Notch ligand Delta is upregulated on myobers after injury, which can activate the Notch signaling cascade in satellite cells and hence induce their proliferation (107). Such an activation signal from myobers is probably amplied by the expression of both Notch receptors and Delta ligands on satellite cells, functioning in autocrine and juxtacrine fashion (108, 280). In aged muscle, both the caliber and the number of myobers decline (202), although the direct effect of these morphological changes is not known. Interestingly, the presence of Delta ligands is not sufciently expressed on aged myobers, an indication of diminished Notch signaling possibly compromising satellite cell activation and muscle regeneration (107).
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SATELLITE CELLS AND THE MUSCLE STEM CELL NICHE 3. ECM and associated factors The basal lamina of the myober is composed of a network of ECM that directly contacts the satellite cell and separates it from the muscle interstitium. The basal lamina of skeletal muscle is composed of type IV collagen, laminin, entactin, bronectin, perlecan, and decorin glycoproteins along with other proteoglycans (459). These ECM molecules are mainly synthesized and excreted by interstitial broblasts but can also be produced and remodeled by myoblasts during muscle development and regeneration (278). Satellite cells reside between the basal lamina, composed primarily of a type IV collagen network, and the apical sarcolemma covered in laminin (568). The basal lamina presents a large number of binding sites for 7/1-integrins; sites that anchor the actin cytoskeleton of satellite cells to the ECM (501; reviewed in Ref. 330). This physical tethering is critical for satellite cell activation as it allows the transduction of extracellular mechanical force into intracellular chemical signals (62; reviewed in Ref. 73). In addition, muscle specic laminin-2 (2/1/1 subunits) and laminin-4 (2/2/ 1) are also associated with myobers though 7/1-integrins and dystroglycan on the surface of myobers (208; reviewed in Ref. 459). Proteoglycans reside on the surface of satellite cells and function as receptors to bind a suite of secreted, yet inactive growth factor precursors. These precursors, including HGF (521), basic broblast growth factor (bFGF) (141), epidermal growth factor (EGF) (193), insulin-like growth factor isoforms (IGF-I, IGF-II) (323) and various Wnt glycoproteins (65, 293), originate from either satellite cells, myobers, interstitial cells, or serum. In resting muscle, the sequestering of inactive growth factors exists as a local reservoir, to facilitate a rapid response to muscle injury. These growth factors can be swiftly rendered active by proteolytic enzymes present in serum or interstitium, such as thrombin, serine proteases, and matrix metalloproteinases (MMPs). This highly coordinated process serves to stimulate satellite cell survival, activation, and proliferation upon muscle injury (249, 288, 386, 521, 576). HGF is a heterodimer of its and subunits, both of which are processed from a single-chain inactive precursor (pro-HGF). HGF is critical for cell growth, migration, and organ morphogenesis through its mitogen, motogen, and morphogen activities (reviewed in Refs. 381, 586). In skeletal muscle, HGF functions in the early phase of muscle regeneration and is one of the key activators of satellite cells (342, 521). In intact muscle, low levels of HGF mRNA can be detected in satellite cells but not in broblasts, suggesting an autocrine function of HGF (13, 484, 521). However, the majority of active and inactive forms of HGF are sequestered by heparan sulfate proteoglycans (HSPGs) within the basal lamina (13, 484, 520, 521). Upon injury, the transcription of HGF is increased in proportion to the degree of injury, and an active form of HGF is released from the ECM without the need of proteolytic cleavage of pro-HGF (484, 520, 521, 525, 569). In vitro
A) HGF/SCATTER FACTOR.
and in vivo data have revealed that release of nitric oxide synthase (NOS) from the basal lamina after myober stretch or damage leads to the production of nitric oxide (NO), which in turn activates MMPs and release HGF from local HSPGs (522, 523, 576). Alternatively, the observed rapid upregulation of HGF following muscle injury is due to release of HGF from intact organs, such as the spleen (513). Released HGF and newly synthesized HGF act directly on satellite cells and myoblasts through the cell surface receptor c-Met found on both quiescent and activated satellite cells (13, 116, 179, 521). Multiple studies have demonstrated that the activation of HGF/c-Met pathway stimulates quiescent satellite cells to enter the cell cycle, increases myoblasts proliferation, and inhibits myogenic differentiation (13, 179, 342, 521). Fittingly, HGF isolated from crushed muscle extracts induces quiescent satellite cell activation, and an anti-HGF antibody abolished this activity (521). Furthermore, direct injection of HGF into injured muscle blocked the regeneration process but increased myoblast numbers (342, 521). Forced expression of a constitutive active form of c-Met in C2C12 myoblasts resulted in the inhibition of differentiation (15). HGF inhibits myoblast differentiation by coordinately repressing transcriptional activity of MRF/E-protein complexes, increasing MyoD inhibitor Twist expression, as well as decreasing p27kip1 expression (179, 306). The dual function of HGF in promoting proliferation and inhibiting differentiation involves sustained activation of MAPK/Erk signaling through binding of Grb2 to phosphorylated c-Met (214, 304, 305). Moreover, HGF promotes satellite cell migration to the site of injury as demonstrated by the in vitro chemotactic activity of this factor on satellite cells and C2C12 myoblasts (49, 512, 551). The function of HGF in muscle regeneration is important during the early phase of repair because over time levels of HGF decline and exogenous HGF does not affect muscle regeneration when administrated at later stages (342, 521). Therefore, these results demonstrate that HGF is a satellite cell activator, playing a critical role in the early stage of muscle regeneration. The activation of satellite cells by HGF is due to both transcription activation of HGF in satellite cells and release of HGF from the ECM by MMPs, which coordinately function in an autocrine and paracrine fashion to induce the proliferation of satellite cells.
B) FIBROBLAST GROWTH FACTORS. Fibroblast growth factors (FGFs) are a large family of mitogens, involved in cell growth, survival, migration, and embryonic development. Numerous FGFs have been found in skeletal muscle in vivo and upon culture and differentiation of myoblasts in vitro (12, 199, 222, 266). Inhibition of endogenous FGF-1 by siRNAs led to myogenic differentiation of myoblasts in vitro, while exogenous FGF-1, -2, -4, and -6 robustly stimulate the proliferation of rat primary myoblasts in vitro
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YIN, PRICE, AND RUDNICKI (266, 483). Of the particular FGF family members, FGF-6 is of particular interest given its muscle specic expression and upregulation during muscle regeneration (134, 172). A study in FGF-6/ mutant mice revealed severe muscle regeneration defects characterized by a reduction in MyoD and Myogenin-expressing cells along with increased collagen deposition and brosis (172). FGF-2 is also likely involved in myoblast proliferation during muscle regeneration as endogenous FGF-2 was found in the basal lamina (113). Moreover, injecting a neutralizing antibody of FGF-2 at the time of injury (297) or injecting exogenous FGF-2 into mdx mice (296) caused a delay in myoblast proliferation and increased myoblast proliferation, respectively. In addition, FGFs also facilitate muscle regeneration through their well-known function in angiogenesis (295). FGF signaling is mediated by virtue of four transmembrane tyrosine kinase receptors known as FGFR1 4, which differ in their specicity of ligand binding. Of these, FGFR1 and FGFR4 are the most prominent receptors in rat satellite cells in vitro (172). In vitro, FGF-1 can induce the expression of FGFR1, and this induction effect can be further augmented by HGF (483). Stable overexpression of FGFR1 increases myoblast proliferation and delays their differentiation, whereas overexpression of a dominant negative form of FGFR1 leads to the opposite effects (463). In skeletal muscle, dimerization of FGFs with FGFRs leads to tyrosine phosphorylation of FGFR and activates the downstream Ras/MAPK pathway. This is supported by the nding that constitutively expressed active RAS in myoblasts induces proliferation and blocks differentiation even in the absence of exogenous FGFs (162). In addition, inhibition of mitogen-activated protein kinase kinase (MAPKK) activity completely abolishes the FGF2-dependent inhibition of myogenic differentiation in vitro (561). Therefore, activation of the Ras/MAPK signaling pathway seems to play a central role in FGF/FGFR-mediated pro-proliferation and anti-differentiation effects in skeletal muscle cells. In addition to the canonical FGF receptors, HSPGs also serve as low-afnity FGF receptors (reviewed in Ref. 427). Although HSPGs are ubiquitously present on most mammalian cells, both quiescent and activated satellite cells specically express syndecan-3 and syndecan-4 (113). Further investigations revealed that syndecan-3/ and syndecan4/ mutant mice display distinct panels of phenotypes, implicating separate roles of these two HSPGs in satellite cell function (115). It is believed that HSPGs interact with both FGFs and FGF receptors to promote ligand recognition (236). In accordance with this, satellite cell activation and proliferation is impaired and MAPK signaling is completely abolished in myoblasts derived from syndecan-4/ mutant mice (115). In contrast, hyperplasia of satellite cells and myonuclei and overactivation of MAPK signaling were observed in syndecan-3-mutant mice, which suggests that an inhibitory mechanism is missing (115). In light of this, the downregulation of syndecan-4 mRNA was observed in turkey satellite cells in response to exogenous FGF-2 (548).
C) IGF. IGF-I and IGF-II play important roles in the regulation of satellite cell activity (reviewed in Ref. 409). IGF-I has pleiotropic functions including anti-inammation, cell migration, and stimulation of both proliferation and differentiation in satellite cells. In contrast, IGF-II is believed to only promote myogenic differentiation (11, 103, 151, 169, 170, 547). Elevation of IGF-I signaling within muscle cells in vitro results in muscle hypertrophy with increased DNA and protein content in muscle (6, 34, 87, 103, 365). The hypertrophic effects of IGF-I are attributed to both the activation of satellite cell proliferation, which gives rise to more myonuclei, and protein synthesis, which increases the cytoplasmic-to-DNA volume ratio (32, 35, 366). IGF-II expression and secretion are elevated prior to myoblast differentiation (171), and knock-down of either IGF-I or IGF-II in vitro results in impaired myogenic differentiated (158, 171). Consistently, IGF2/ mutant mice are 40% lighter compared with the weight of wild-type mice at birth, and this defect persists postnatally (133).
IGF can function in endocrine, autocrine, and paracrine fashions to promote satellite cell proliferation and differentiation, but all of these are mediated by IGF-I binding to the IGF-I receptor (IGF1R), which is a ligand-activated receptor tyrosine kinase. In contrast to IGF-I-induced muscle hypertrophy, IGF1R/ mutant mice display a dystrophic phenotype and usually die at birth due to weak respiratory muscles (315). Activation of IGF1R in satellite cells induces the expression of MRFs (170) and initiates intracellular signaling cascades involving both mitogenic and myogenic responses (110, 367). Two primary signaling pathways are activated by IGF1R. In the rst pathway, activated IGF1R recruits and phosphorylates insulin receptor substrate proteins (IRSs), leading to the activation of phosphatidylinositol 3-kinase (PI3K). Activation of PI3K is involved in multiple cellular processes including an anti-apoptotic effect mediated by activation of the AKT pathway (502), modulation of intracellular calcium levels by the inositol phosphate cascade (156), and promoting protein translation (5). Although evidence supports that IGF-I-dependent satellite cell proliferation is mediated by the AKT/mTOR pathway (220), the activation of PI3K/AKT and p38-MAPK pathways are also involved in myoblast differentiation (197, 539). In the second pathway, IGF1R activates the Ras/Raf/ extracellular response kinases (ERKs) cascade, which in turn activates other protein kinases and several transcription factors (110, 347). The activation of the Ras/Raf/ERK pathway is also required for satellite cell proliferation (110). In addition to the aforementioned pathways, accumulating evidence indicates that the calcium/calcineurin pathway is also involved in IGF-I signaling-dependent muscle differentiation and hypertrophy (137, 173, 366, 479). Specically, it has been revealed that GATA-2-mediated
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SATELLITE CELLS AND THE MUSCLE STEM CELL NICHE myober hypertrophy depends on IGF-I stimulation of the calcineurin-mediated signaling pathway (366). Further evidence of the pleiotropic functions of IGF-I involves a role in anti-inammatation demonstrated by a reduction in chronic inammation upon IGF-I treatment during muscle regeneration (357). Activated satellite cells and cultured myoblasts express insulin-like growth factor binding proteins (IGFBPs), which are a family of secreted proteins that specically bind IGFs and function as carriers during circulation and regulate IGF turnover, transport, and half-life (reviewed in Ref. 253). Of the ve IGFBPs, IGFBP-5 plays a critical role in muscle growth and differentiation. IGFBP-5 expression is induced during differentiation and precedes that of IGF-II in cultured myoblasts (246, 436). It was found that IGFBP-5 functions to promote myogenic differentiation by switching on an IGF-II-mediated positive-feedback loop (436). Knockdown of IGFBP-5 impairs myogenesis and suppresses IGF-II expression (436). Notably, recent studies demonstrated that alternative splicing of IGF-I pre-mRNA gives rise to a unique peptide, termed mechano-growth factor (MGF) (194). MGF promotes myoblast proliferation in vitro (26, 578). However, the existence of MGF and its functions in vivo remain controversial (discussed in Ref. 327).
D) MMPS. E) ECM STIFFNESS. Recent studies reveal a previously unappreciated role for the stiffness of the ECM in regulating satellite cell proliferation and differentiation. Resting healthy skeletal muscles and cultured myotubes possess a similar elastic stiffness (elastic modulus 12 kPa) (106, 152), whereas aged (184, 444) and dystrophic (152) skeletal muscles are apparently stiffer (elastic modulus 418 kPa). These changes of stiffness are presumably due to increased extracellular matrix deposition, in particular collagen deposition by broblasts, a result of repeated muscle regeneration. The signicance of changes in stiffness was evaluated by assessing the proliferation and differentiation ability of myoblasts on various in vitro culturing surfaces. Primary myoblast proliferation on polyacrylamide gels cross-linked with entactin, type IV collagen, and laminin is optimal at an elastic modulus equal to 21 kPa, while it is impaired on softer (3 kPa) or stiffer (80 kPa) culturing substrates (61). Similarly, C2C12 myoblasts optimally differentiate on collagen-coated polyacrylamide gels that mimic the physiological elasticity of skeletal muscle (12 kPa), whereas either softer (5 kPa) or stiffer (420 kPa) gels greatly compromise their differentiation efciency (152). Although the stiffness of the ECM surrounding the satellite cell niche has not been directly measured yet, these in vitro data draw attention to a causal relationship between biophysical stimuli and satellite cell function in vivo.
Matrix metalloproteinases (MMPs) are a family of zinc-dependent enzymes that can degrade components of the extracellular matrix such as collagens, elastin, bronectin, laminin, and proteoglycans. In skeletal muscle, MMPs play an important role in satellite cell activation, migration, and differentiation during muscle regeneration (reviewed in Ref. 86). Of more than 20 MMPs, MMP-2, -3, -7, and -9 were found in skeletal muscle. In particular, MMP-2 and MMP-9, which can degrade denatured collagen types (gelatins) and heparan sulfate proteoglycans, have critical functions on ECM remodeling in skeletal muscle regeneration. Upon injury, MMP-2 is secreted by satellite cells and regenerating myobers, and its activity is elevated in both degenerative and regenerating stages (167, 178, 270). In contrast, MMP-9 is generated by leukocytes and macrophages, and its activity drastically decreases after the degenerative stage (270). In the degeneration stage, activated MMP-2 and MMP-9 degrade collagen IV in the muscle ECM, which allows satellite cells to migrate across the basement membrane to the site of injury (377). In the regeneration stage, it is believed that MMP-2 is involved in remodeling and maintenance of the ECM. Recent studies indicate that NO upregulates enzymatic activity and protein expression levels of MMP-2 (270) and MMP-9, and this activation of MMP-2 is required for the release of HGF from the ECM upon satellite cell activation (575, 576).
B. The Microenvironment Beyond the Immediate Niche

1. Local milieu In addition to the immediate niche surrounding satellite cells, local interstitial cells, motor neurons, blood vessels, and their associated secretable factors reside within skeletal muscle and have the potential to regulate satellite cell function and affect muscle regeneration.
A) INTERSTITIAL CELLS.
Interstitial cells are the major component of the stromal tissue between the basal lamina and epimysial sheath surrounding skeletal muscle. Fibroblasts comprise a major component of the interstitial stromal cell population (51). Fibroblasts secrete growth factors, such as FGFs, and also contribute to the skeletal muscle ECM by depositing collagen, laminin, bronectin, HSPGs, tenascin, and NCAM (185). Increased levels of fat and connective tissue (brosis), evidence for increased numbers of adipocytes and broblasts, respectively, are well documented for several physiological and pathological conditions, such as aging, obesity, and muscular dystrophy (38, 66, 195, 198, 200). It is believed that satellite cells may account for the increase in adipocytes and broblasts due to transdifferentiation along alternative mesenchymal lineages. This notion is supported by the observations that myoblasts can undergo adipogenic differentiation in vitro (239, 310, 485, 579) and satellite cells on single myobers can give rise to
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YIN, PRICE, AND RUDNICKI both adipocytes and broblasts in vitro (23, 66). Recently, two studies revealed that these intramuscular adipocytes and brocytes can arise from muscle residing brocyte/adipocyte progenitors (FAPs) (252, 541). In one study, a population of SM/C-2.6/PDGFR- cells is able to differentiate into adipocytes in culture (541). In vivo, these cells localize to the interstitial space between myobers and muscle bundles. After transplantation into glycerol-injected fatty degenerating muscle, SM/C-2.6/ PDGFR- cells can differentiate into adipocytes, a result that is not observed in normal regenerating muscle (541). In another study, a Sca-1/ CD34 or 7-integrin/CD45/ CD31 cell population was isolated and found to spontaneously form both adipocytes and ER-TR7 broblasts in culture (252). Although the origin of these cells was not directly investigated, it was further demonstrated that these Sca-1/7-integrin cells also express PDGFR-, and count for the vast majority of PDGFR- cells in skeletal muscle (252). This suggests strong similarities exist between the cell populations used in both studies. Consequently, Sca-1/7integrin cells also only give rise to adipocytes in degenerating muscle in vivo, in contrast to their limited adipogenic potential in intact muscle and in injured regenerating muscle. Moreover, a single Sca-1/7-integrin cell was able to differentiate into both adipocytes and broblasts in vitro, indicating that these cells are bipotent and thus termed FAPs (252). Both studies clearly demonstrate that FAPs do not have myogenic potential either in vitro or in vivo, which makes them distinct from satellite cells and other muscle-residing myogenic cells (252, 541). The distinct adipogenic potentials of FAPs in degenerating and regenerating muscles suggest that the differentiation of FAPs is regulated by their local microenvironment. Indeed, both groups demonstrated that FAPs proliferated and transiently increased in number in regenerating muscle without differentiating into adipocytes or broblasts (252, 541). Moreover, when adipogenic FAPs isolated from degenerating muscle were transplanted into regenerating muscle, the regenerative microenvironment was sufcient to inhibit adipogenic differentiation (541). These observations indicate that regenerating muscle provides a specialized microenvironment, which favors myogenic differentiation and maintains FAPs in their undifferentiated state. Importantly, the undifferentiated FAPs in such a microenvironment may facilitate the myogenic differentiation of satellite cells, which is supported by the observation that, in co-culture conditions, FAPs increase the commitment of myoblasts to terminal differentiation (252). IL-6 signaling was implicated in this process as evidenced by induced IL-6 expression in FAPs in response to muscle regeneration (252). In summary, these intriguing results support the hypothesis that skeletal muscle provides a balanced environment for coexistence of both myogenic precursors (myoblasts) and adipogenic/brogenic precursors (FAPs) during muscle regeneration. Regeneration is supported by both satellite cells and FAPs, whereas in degenerating muscle, this balance is disrupted and FAPs differentiate into adipocytes (and presumably also broblasts). These ndings also raise several interesting questions including: How do satellite cells respond to increased adipocytes and broblasts in the aforementioned physiological and pathological conditions? Recent observations regarding the effect of brosis on the stiffness of the ECM raise the question as to whether increased depositions from broblasts or adipocytes can alter myober stiffness and therefore affect the physiological roles attributed to satellite cells (152; discussed in sect. IIIA). Finally, it would be interesting to investigate the embryonic origin and postnatal lineage progression of FAPs, particularly their lineage relationship to the CD45/Sca-1 mesenchymal stem cells found in multiple tissues (316, 401, 417, 441, 509, 519). Further study is required to understand whether other regulatory factors are also involved in the determination of FAP differentiation and whether these factors change in response to various physiological and pathological conditions. In addition to FAPs, recent studies identied telocytes (TCs, formerly called interstitial Cajal-like cells or ICLCs) as a new type of cells within muscle interstitium, which are in close vicinity of satellite cells, myobers, nerve endings, and blood vessels (414). Unlike satellite cells and broblasts, skeletal muscle TCs express the cell surface marker c-kit. Transmission electron microscopy (TEM) examination of TCs in muscle and studies on TCs from other tissues suggest TCs transmit intercellular signaling by shedding/intaking microvesicles (also called exosomes), which are enriched for proteins and RNAs (230, 414, 543). Although their exact role in muscle regeneration is still unknown, the nding that these cells secrete VEGF suggests telocytes are an important player in promoting satellite cells self-renewal, facilitating vasculogenesis, and preventing brosis (132; further discussed in sect. IIIB1C). Another cellular component of skeletal muscle interstitium is the SP, a population of cells characterized by their expression of Abcg2 and hence the ability to efux Hoechst dye. A recent study indicated that endothelial cells and interstitial cells constitute the major fraction of skeletal muscle SP (146). Ablation of Abcg2 impairs skeletal muscle regeneration. In addition, a small percentage of these SP cells have myogenic potential and may contribute to myogenic regeneration in injured muscle (discussed in sect. IID).
B) MOTOR NEURONS.
It is well known that denervation results in progressive skeletal muscle atrophy. During acute denervation of muscle, the percentage of satellite cells increases during the rst week, indicating a proliferation phase similar to muscle injury (468). However, long-term denervation
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SATELLITE CELLS AND THE MUSCLE STEM CELL NICHE results in a drastic decline in satellite cell numbers (442, 550), which is at least partially due to decreased mitotic capability and increased apoptosis of satellite cells. Experiments illustrate that an absence of PCNA (proliferating cell nuclear antigen)-positive satellite cell can be found on myobers denervated for more than 1 wk. This implies that long-term denervation may cause satellite cells to lose their capability to enter the mitotic cell cycle (282). Second, satellite cells from muscle denervated for 6 and 10 wk displayed a twofold increase of apoptosis, compared with control cells from normal innervated muscle (248). Although the underlying mechanism of a neural inuence on satellite cell behavior is still elusive, neurotrophins such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are involved. NGF is expressed in developing muscles (563), and its expression is downregulated after birth (153). The expression of NGF reappears in adult muscle under several pathological conditions such as muscular dystrophy (537) and amyotrophic lateral sclerosis (283), wherein expression of NGF was found in regenerating myobers and connective tissue broblasts within the damaged muscles (99, 537), suggesting that it may be involved in muscle regeneration (340). Indeed, ectopic expression of NGF neutralizing antibodies in vivo causes muscle dystrophy (448). Within skeletal muscle, NGF seems to bind to its low-afnity receptor p75NTR (138), which is expressed in satellite cells (358) and human primary myoblasts and myotubes (33). The expression of both NGF and p75NTR is upregulated during primary myoblast differentiation in vitro, and they function to stimulate morphological changes involved in myoblast fusion (138). Similar to NGF, developing muscles express high levels of BDNF, whereas in adult myobers it is not detectable (201, 358). BDNF is present in most adult satellite cells, and its expression is correlated with Pax3 expression (358). In cultured primary myoblasts, the expression of BDNF is decreased dramatically during myogenic differentiation; in concordance, a reduction in endogenous BDNF leads to early myogenic differentiation, while addition of exogenous BDNF can reverse this phenotype (358). In vivo, BDNF/ satellite cells are decreased and hence compromise muscle regeneration (102). These observations suggest that the function of BDNF in adult skeletal muscle is to maintain satellite cells in their quiescent state and prevent their myogenic differentiation (358). This is consistent with the observation that neural electrical activity stimulates the activation of satellite cells (reviewed in Ref. 470) and represses the expression of BDNF (358). Since the TrkB receptor of BDNF was not detected in skeletal muscle, BDNF signaling is proposed to occur via the p75NTR in a similar fashion to NGF. Taken together, these data indicate that neurotrophic factors function in an autocrine fashion to regulate satellite cell behavior and muscle regeneration. Thus it is conceivable that systematic release of neurotrophic factors after denervation may also exert similar regulatory roles on satellite cell activation and differentiation. In addition, denervation can also cause secondary effects on satellite cells by directly inuencing the physiological properties of myobers (229). Moreover, it has been recently found that satellite cells may control myober innervation during muscle regeneration by secreting semaphorin 3A, a well-known factor involved in axon guidance and growth (524). This nding further emphasizes the notion that proper muscle regeneration relies on the dynamic interaction of satellite cells with their niche. In aged muscle, examination of neuromuscular junctions by EM revealed decreases in nerve terminal area, mitochondria and synaptic vesicles, along with occasional denervated postsynaptic regions (159). These changes, in addition to progressive myober atrophy, may potentially disturb signals between myobers and satellite cells.
C) VASCULATURE.
Skeletal muscle is nourished by the microvascular network. The importance of this niche component is reected by the fact that most satellite cells are closely associated with capillaries in intact adult muscle (100, 465). It is also well known that angiogenesis and myogenesis proceed at the same time during muscle regeneration (321). Vascular endothelial growth factor (VEGF) plays an important role in satellite cell function and muscle regeneration (416). It has been reported that overexpression of VEGF by adenovirus can stimulate satellite cell proliferation and improve myober regeneration in vivo (20). A recent study revealed that in coculture, endothelial cells promote myoblasts proliferation by secreting a panel of growth factors, such as IGF-I, HGF, FGF, platelet-derived growth factor-BB (PDGF-BB), and VEGF (100). In addition, it was found that periendothelial cells (smooth muscle cells and endomysial broblasts) promote a subset of myoblasts (presumably reserve cells) to return to the quiescent state (100). This procedure mimics the self-renewal of satellite cells during muscle regeneration. Indeed, recent studies demonstrated that the Tie-2 receptor is preferentially expressed by quiescent satellite cells and angiopoietin-1/Tie-2 signaling acts through ERK1/2 pathway to promote the reentry to quiescence and thus self-renewal of a subset of satellite cells (3, 100). Based on these observations, it was proposed that during muscle regeneration, while vessels are not stabilized, endothelial cells and myogenic precursors interact with each other to promote both myogenesis and angiogenesis. Once homeostasis of muscle is achieved, the proximity of satellite cells and periendothelial cells permits angiopoietin-1, which is secreted by periendothelial cells, to bind Tie-2 receptors on satellite cells to simultaneously stabilize vessels and promote satellite cell quiescence (4, 100). In addition to endothelial cells, satellite cells and myoblasts, differentiating myobers also generate VEGF within skele-
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YIN, PRICE, AND RUDNICKI tal muscle (70, 92, 189). VEGF can function in an autocrine fashion through VEGF receptors present on various myogenic cells to stimulate migration, prevent apoptosis, and promote differentiation (92, 189). In addition, VEGF stimulation can reportedly activate the Akt pathway and promote myober hypertrophy (70, 514). In aged muscle, it was observed that while myobers lose their close contact with the microvascular network, there is a corresponding VEGF level decrease (451). In addition, endothelial nitric oxide synthase (eNOS) secreted by endothelial cells is also decreased in aged muscle (580; reviewed in Ref. 67). Taken together, recent studies have begun to unveil interactions between satellite cells and cells within the microvasculature, experiments that imply a potentially profound functional role necessitating the close proximity of satellite cells to the microvasculature. Future studies are needed to further elucidate these interactions, particularly those of periendothelial cells, during muscle regeneration. 2. Systemic milieu
A) IMMUNE CELLS. Only a small number of immune cells reside within intact skeletal muscle. During the early stages of muscle injury, immune cells are recruited and play important roles in the regeneration process (reviewed in Ref. 532). Upon injury, immune cells rapidly inltrate the muscle to remove necrotic tissue and secrete soluble factors that serve to activate satellite cells (reviewed in Ref. 530). As such, immune cells constitute a transient local environment for satellite cells. Depletion of macrophages and monocytes impairs subsequent muscle regeneration (206). Satellite cells and immune cells attract one another through chemokines (chemoattraction) (440). Satellite cells have been demonstrated to secrete a panel of pro-inammatory cytokines, such as IL-1, IL-6, and TNF-, to facilitate immune cell inltration and function (reviewed in Ref. 92). In turn, immune cells secrete a wealth of diffusible factors, such as growth factors, IL-6, globular adiponectin, ECM components, and ECM remodeling MMPs. These diffusible factors generate ECM chemoattractive fragments, help satellite cells escape from the basal lamina of myobers, and promote satellite cell proliferation. In addition, cell-to-cell contact between immune cells and satellite cells protects satellite cells from apoptosis (503). B) IL-6. IL-6 is a ubiquitous pleiotropic cytokine, which can be produced by many cell types, such as hematopoietic cells, broblasts, and vascular endothelial cells. Although IL-6 is primarily produced following an immune response, convincing evidence demonstrates that IL-6 is also involved in satellite cell-mediated muscle hypertrophy and regeneration. Chronic systematic elevation of IL-6 leads to muscle atrophy in aging and disease states (29, 212; reviewed in Ref. 154). Likewise, transgenic mice overexpressing IL-6 display a muscle wasting (cachexia) phenotype (538). It is also well documented that exercise causes an increase in IL-6 levels within muscle (533; reviewed in Ref. 403). During regeneration, satellite cells, myobers, and neutrophils are the principal sources of IL-6, the expression of which is regulated by calcineurin-NFAT, NF-B, AP-1, IL-1, and NO signaling pathways (74, 333, 583; reviewed in Ref. 403).
The IL-6 receptor (IL-6R) is expressed on the myober sarcolemma and is responsive to exercise (268). Musclederived IL-6 can act in an autocrine fashion by binding to the IL-6R on the sarcolemma and activate the JAK/STAT3 signaling pathway (480; reviewed in Refs. 403, 430). Binding of IL-6 to the receptor IL-6R leads to JAK2 phosphorylation and subsequent STAT3 phosphorylation. Phosphorylated STAT3 dimerizes and translocates to the nucleus where it acts as a transcription factor for target gene activation. It has been shown that IL-6 can also induce satellite cell proliferation (80). Recently, it was demonstrated that IL-6 is involved in satellite cell-mediated muscle hypertrophy (480). Although early studies demonstrated that muscle regeneration in IL-6/ null mice was comparable to that of wild type (556), a recent study reported a blunted hypertrophic response and less contribution of satellite cell myonuclei to regenerating myobers (480). Furthermore, it was shown that the proliferation of satellite cells from IL-6/ mice was impaired both in vivo and in vitro, which is due to the attenuation of STAT3 signaling (480).
C) ANDROGENS. The musculature of men and woman differs in mass, ber size, and various other physiological properties. These differences are in part due to the anabolic actions of circulating androgens, e.g., testosterone, on muscle size and muscle strength (reviewed in Refs. 97, 228). Androgens bind to androgen receptors (AR) and lead to the dimerization and nuclear translocation of AR. In the nucleus, AR homodimers bind to the DNA motifs or androgen response elements (AREs) and activate transcriptional target genes.
Aged muscle displays a functional decit in the immune cells surrounding the satellite cell niche. In vitro studies indicate that the capabilities of free radical generation, phagocytosis, and chemotaxis are decreased in aged immune cells (25). The perturbation between satellite cells and immune cells impedes satellite cell activation and migration.
Satellite cells express androgen receptors and are receptive to androgen signaling (143); however, the endogenous androgens acting on satellite cells have yet to be
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SATELLITE CELLS AND THE MUSCLE STEM CELL NICHE determined. Exogenous testosterone increases satellite cell numbers by promoting satellite cell activation and proliferation (255, 494). This function is predicted to involve the induction of Notch signaling in satellite cells (494). Furthermore, androgen administration causes increased myonuclei and muscle hypertrophy in a dosedependent manner (254, 493, 495). Multiple mechanisms have been implicated in androgen-induced muscle hypertrophy. First, androgen administration has been shown to elevate local IGF-I levels (165, 307) through a postulated induction of IGF1R expression on satellite cells (529). Androgen administration can also elevate intracellular calcium and inositol 1,4,5-trisphosphate (IP3) levels, which induces phosphorylation of ERK1/2 and contributes to affect the IGF pathway (157). Additionally, androgen may promote muscle hypertrophy by counteracting the catabolic effect of glucocorticoid hormones and promote the myogenic differentiation (48, 496). During aging, systemic levels of androgens decline, which is concomitant with a loss in muscle mass and a gain in fat mass (228, 544).
D) NITRIC OXIDE. NO is a diffusible small molecule, which can
of HGF from the ECM (575, 576). MMP-2 was demonstrated to be involved in this process (575). In addition, it was also suggested that NO may regulate satellite cell migration (104) and prevent brosis by inhibiting transforming growth factor- signaling during muscle regeneration (126).
IV. CONCLUDING REMARKS AND PERSPECTIVES

Compelling evidence indicates that adult satellite cells represent a heterogeneous population of stem cells and committed myogenic progenitors in skeletal muscle. At the population level, the stem cell characteristics of satellite cells are well represented by their remarkable and sustained ability to support skeletal muscle regeneration. At the individual level, satellite cells vary in their self-renewal, proliferation, and myogenic differentiation potential. These intrinsic differences of satellite cells likely reect the distinct needs of 1) maintaining a sustainable reservoir of stem cells, 2) producing sufcient numbers of myogenic cells, and 3) generating, during the course of muscle regeneration, functional contractile muscular structures. Throughout regeneration, the hierarchical and collaborative behaviors of satellite cells are inuenced by changes in their niche. These changes include diverse molecules, cells, and structures that constitute a dynamic niche continually inuencing the multiple tasks set forth for satellite cells. Satellite cells are an ideal cellular model system to study adult stem cells and tissue regeneration. Extensive studies over the last three decades have accumulated much knowledge and insights. Satellite cells are currently not applicable to regenerative medicine due to difculties in their isolation and loss of stemness ex vivo. However, satellite cell-based cell therapy would greatly benet from future studies in lineage progression to better delineate satellite cell hierarchy along with physiologically relevant interactions between satellite cells and other myogenic cells. Moreover, such issues may be resolved following the maturation of techniques involving the generation of iPS or other types of ES-like multipotent cells. If so, the broad interest of future studies should focus on identication of the intrinsic and extrinsic regulatory mechanisms that govern satellite cell commitment and differentiation throughout the muscle regeneration. Future advances in system biology and bioengineering may hopefully harness these previous achievements towards developing therapeutic approaches for sarcopenia and muscle dystrophic diseases.
freely pass through cell membranes. It can be produced by nitric oxide synthase (NOS) in diverse cell types, including epithelial cells, endothelial cells, broblasts, hepatocytes, macrophages, and skeletal muscle cells (60). Currently three NOS isoforms exist: endothelial NOS (eNOS), neuronal NOS (nNOS), and inducible NOS (iNOS) (394). NO has profound functions in intact muscle as well as during muscle regeneration (reviewed in Ref. 505). In skeletal muscle, nNOS is constitutively expressed within the sarcolemma of myobers (275). Loss of nNOS from the sarcolemma (e.g., as a result of a dystrophin deciency) leads to inammation and myober lysis, implicating a protective function for NO in skeletal muscle (89). iNOS levels are extremely low in intact muscle, yet drastically induced by macrophages and myobers in response to muscle injury (449; reviewed in Ref. 262). In the degenerating phase, NO, generated by macrophages and myobers, promotes the lysis of necrotic myobers by macrophages while reducing other inammation-induced damage (375; reviewed in Ref. 505). During regeneration, NO induces satellite cell activation, as evidenced by the inhibitory effect of L-arginine methyl ester (L-NAME), a NOS inhibitor, on satellite cell activation (16). NOS inhibition prevents the binding of HGF to the c-Met receptor on satellite cells, whereas treatment with L-arginine, the NOS substrate, resulted in an increase in satellite cell activation. Accordingly, iNOS/ mice display delayed satellite cell activation following muscle injury, although injured muscles were still able to regenerate (16). The function of NO-dependent satellite cell activation stems from the ability of NO to promote the release
ACKNOWLEDGMENTS
We credit L. Bucklin for the human leg anatomy image used in FIGURE 3 and Alexander Grayston for critical review of the manuscript.
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YIN, PRICE, AND RUDNICKI Address for reprint requests and other correspondence: M. A. Rudnicki, Ottawa Hospital Research Institute, 501 Smyth Rd., Ottawa, Ontario, Canada K1H 8L6 (e-mail: mrudnicki@ohri.ca).
17. Angelini C, Di Mauro S, Margreth A. Relationship of serum enzyme changes to muscle damage in vitamin E deciency of the rabbit. Sperimentale 118: 349 369, 1968. 18. Armand O, Boutineau AM, Mauger A, Pautou MP, Kieny M. Origin of satellite cells in avian skeletal muscles. Arch Anat Microsc Morphol Exp 72: 163181, 1983. 19. Armstrong RB. Initial events in exercise-induced muscular injury. Med Sci Sports Exercise 22: 429 435, 1990.
DISCLOSURES
No conicts of interest, nancial or otherwise, are declared by the authors.
20. Arsic N, Zacchigna S, Zentilin L, Ramirez-Correa G, Pattarini L, Salvi A, Sinagra G, Giacca M. Vascular endothelial growth factor stimulates skeletal muscle regeneration in vivo. Mol Ther 10: 844 854, 2004. 21. Artavanis-Tsakonas S, Rand MD, Lake RJ. Notch signaling: cell fate control and signal integration in development. Science 284: 770 776, 1999. 22. Asakura A, Hirai H, Kablar B, Morita S, Ishibashi J, Piras BA, Christ AJ, Verma M, Vineretsky KA, Rudnicki MA. Increased survival of muscle stem cells lacking the MyoD gene after transplantation into regenerating skeletal muscle. Proc Natl Acad Sci USA 104: 1655216557, 2007. 23. Asakura A, Komaki M, Rudnicki M. Muscle satellite cells are multipotential stem cells that exhibit myogenic, osteogenic, adipogenic differentiation. Differentiation 68: 245 253, 2001. 24. Asakura A, Seale P, Girgis-Gabardo A, Rudnicki MA. Myogenic specication of side population cells in skeletal muscle. J Cell Biol 159: 123134, 2002. 25. Ashcroft GS, Mills SJ, Ashworth JJ. Ageing and wound healing. Biogerontology 3: 337 345, 2002. 26. Ates K, Yang SY, Orrell RW, Sinanan AC, Simons P, Solomon A, Beech S, Goldspink G, Lewis MP. The IGF-I splice variant MGF increases progenitor cells in ALS, dystrophic, and normal muscle. FEBS Lett 581: 27272732, 2007. 27. Bachrach E, Li S, Perez AL, Schienda J, Liadaki K, Volinski J, Flint A, Chamberlain J, Kunkel LM. Systemic delivery of human microdystrophin to regenerating mouse dystrophic muscle by muscle progenitor cells. Proc Natl Acad Sci USA 101: 35813586, 2004. 28. Baldwin KM, Haddad F. Effects of different activity and inactivity paradigms on myosin heavy chain gene expression in striated muscle. J Appl Physiol 90: 345357, 2001. 29. Baltgalvis KA, Berger FG, Pena MM, Davis JM, Muga SJ, Carson JA. Interleukin-6 and cachexia in ApcMin/ mice. Am J Physiol Regul Integr Comp Physiol 294: R393R401, 2008. 30. Bansal D, Miyake K, Vogel SS, Groh S, Chen CC, Williamson R, McNeil PL, Campbell KP. Defective membrane repair in dysferlin-decient muscular dystrophy. Nature 423: 168 172, 2003. 31. Barberi T, Bradbury M, Dincer Z, Panagiotakos G, Socci ND, Studer L. Derivation of engraftable skeletal myoblasts from human embryonic stem cells. Nat Med 13: 642 648, 2007. 32. Bark TH, McNurlan MA, Lang CH, Garlick PJ. Increased protein synthesis after acute IGF-I or insulin infusion is localized to muscle in mice. Am J Physiol Endocrinol Metab 275: E118 E123, 1998. 33. Baron P, Scarpini E, Meola G, Santilli I, Conti G, Pleasure D, Scarlato G. Expression of the low-afnity NGF receptor during human muscle development, regeneration, and in tissue culture. Muscle Nerve 17: 276 284, 1994. 34. Barton-Davis ER, Shoturma DI, Musaro A, Rosenthal N, Sweeney HL. Viral mediated expression of insulin-like growth factor I blocks the aging-related loss of skeletal muscle function. Proc Natl Acad Sci USA 95: 1560315607, 1998. 35. Barton-Davis ER, Shoturma DI, Sweeney HL. Contribution of satellite cells to IGF-I induced hypertrophy of skeletal muscle. Acta Physiol Scand 167: 301305, 1999. 36. Bashir R, Britton S, Strachan T, Keers S, Vaadaki E, Lako M, Richard I, Marchand S, Bourg N, Argov Z, Sadeh M, Mahjneh I, Marconi G, Passos-Bueno MR, Moreira Ede S, Zatz M, Beckmann JS, Bushby K. A gene related to Caenorhabditis elegans spermatogenesis factor fer-1 is mutated in limb-girdle muscular dystrophy type 2B. Nat Genet 20: 37 42, 1998. 37. Beauchamp JR, Heslop L, Yu DS, Tajbakhsh S, Kelly RG, Wernig A, Buckingham ME, Partridge TA, Zammit PS. Expression of CD34 and Myf5 denes the majority of quiescent adult skeletal muscle satellite cells. J Cell Biol 151: 12211234, 2000.
REFERENCES
1. Abedi M, Greer DA, Colvin GA, Demers DA, Dooner MS, Harpel JA, Weier HU, Lambert JF, Quesenberry PJ. Robust conversion of marrow cells to skeletal muscle with formation of marrow-derived muscle cell colonies: a multifactorial process. Exp Hematol 32: 426 434, 2004. 2. Abiola M, Favier M, Christodoulou-Vafeiadou E, Pichard AL, Martelly I, Guillet-Deniau I. Activation of Wnt/beta-catenin signaling increases insulin sensitivity through a reciprocal regulation of Wnt10b and SREBP-1c in skeletal muscle cells. PLoS One 4: e8509, 2009. 3. Abou-Khalil R, Le Grand F, Pallafacchina G, Valable S, Authier FJ, Rudnicki MA, Gherardi RK, Germain S, Chretien F, Sotiropoulos A, Lafuste P, Montarras D, Chazaud B. Autocrine and paracrine angiopoietin 1/Tie-2 signaling promotes muscle satellite cell self-renewal. Cell Stem Cell 5: 298 309, 2009. 4. Abou-Khalil R, Mounier R, Chazaud B. Regulation of myogenic stem cell behavior by vessel cells: the menage a trois of satellite cells, periendothelial cells and endothelial cells. Cell Cycle 9: 892 896, 2010. 5. Adams GR. Autocrine and/or paracrine insulin-like growth factor-I activity in skeletal muscle. Clin Orthop Relat Res S188 196, 2002. 6. Adams GR, McCue SA. Localized infusion of IGF-I results in skeletal muscle hypertrophy in rats. J Appl Physiol 84: 1716 1722, 1998. 7. Alderton JM, Steinhardt RA. How calcium inux through calcium leak channels is responsible for the elevated levels of calcium-dependent proteolysis in dystrophic myotubes. Trends Cardiovasc Med 10: 268 272, 2000. 8. Alfaro LA, Dick SA, Siegel AL, Anonuevo AS, McNagny KM, Megeney LA, Cornelison DD, Rossi FM. CD34 promotes satellite cell motility and entry into proliferation to facilitate efcient skeletal muscle regeneration. Stem Cells 29: 2030 2041, 2011. 9. Allbrook DB, Han MF, Hellmuth AE. Population of muscle satellite cells in relation to age and mitotic activity. Pathology 3: 223243, 1971. 10. Allen RE, Boxhorn LK. Inhibition of skeletal muscle satellite cell differentiation by transforming growth factor-beta. J Cell Physiol 133: 567572, 1987. 11. Allen RE, Boxhorn LK. Regulation of skeletal muscle satellite cell proliferation and differentiation by transforming growth factor-beta, insulin-like growth factor I, and broblast growth factor. J Cell Physiol 138: 311315, 1989. 12. Allen RE, Dodson MV, Luiten LS. Regulation of skeletal muscle satellite cell proliferation by bovine pituitary broblast growth factor. Exp Cell Res 152: 154 160, 1984. 13. Allen RE, Sheehan SM, Taylor RG, Kendall TL, Rice GM. Hepatocyte growth factor activates quiescent skeletal muscle satellite cells in vitro. J Cell Physiol 165: 307312, 1995. 14. Allouh MZ, Yablonka-Reuveni Z, Rosser BW. Pax7 reveals a greater frequency and concentration of satellite cells at the ends of growing skeletal muscle bers. J Histochem Cytochem 56: 77 87, 2008. 15. Anastasi S, Giordano S, Sthandier O, Gambarotta G, Maione R, Comoglio P, Amati P. A natural hepatocyte growth factor/scatter factor autocrine loop in myoblast cells and the effect of the constitutive Met kinase activation on myogenic differentiation. J Cell Biol 137: 10571068, 1997. 16. Anderson JE. A role for nitric oxide in muscle repair: nitric oxide-mediated activation of muscle satellite cells. Mol Biol Cell 11: 1859 1874, 2000.
54

38. Beggs ML, Nagarajan R, Taylor-Jones JM, Nolen G, Macnicol M, Peterson CA. Alterations in the TGFbeta signaling pathway in myogenic progenitors with age. Aging Cell 3: 353361, 2004. 39. Belcastro AN, Shewchuk LD, Raj DA. Exercise-induced muscle injury: a calpain hypothesis. Mol Cell Biochem 179: 135145, 1998. 40. Ben-Yair R, Kalcheim C. Lineage analysis of the avian dermomyotome sheet reveals the existence of single cells with both dermal and muscle progenitor fates. Development 132: 689 701, 2005. 41. Benchaouir R, Meregalli M, Farini A, DAntona G, Belicchi M, Goyenvalle A, Battistelli M, Bresolin N, Bottinelli R, Garcia L, Torrente Y. Restoration of human dystrophin following transplantation of exon-skipping-engineered DMD patient stem cells into dystrophic mice. Cell Stem Cell 1: 646 657, 2007. 42. Benezra R, Davis RL, Lassar A, Tapscott S, Thayer M, Lockshon D, Weintraub H. Id: a negative regulator of helix-loop-helix DNA binding proteins. Control of terminal myogenic differentiation. Ann NY Acad Sci 599: 111, 1990. 43. Benezra R, Davis RL, Lockshon D, Turner DL, Weintraub H. The protein Id: a negative regulator of helix-loop-helix DNA binding proteins. Cell 61: 49 59, 1990. 44. Bergstrom DA, Penn BH, Strand A, Perry RL, Rudnicki MA, Tapscott SJ. Promoterspecic regulation of MyoD binding and signal transduction cooperate to pattern gene expression. Mol Cell 9: 587 600, 2002. 45. Berkes CA, Tapscott SJ. MyoD and the transcriptional control of myogenesis. Semin Cell Dev Biol 16: 585595, 2005. 46. Besson V, Smeriglio P, Wegener A, Relaix F, Nait Oumesmar B, Sassoon DA, Marazzi G. PW1 gene/paternally expressed gene 3 (PW1/Peg3) identies multiple adult stem and progenitor cell populations. Proc Natl Acad Sci USA 108: 11470 11475, 2011. 47. Bhagavati S, Xu W. Generation of skeletal muscle from transplanted embryonic stem cells in dystrophic mice. Biochem Biophys Res Commun 333: 644 649, 2005. 48. Bhasin S, Taylor WE, Singh R, Artaza J, Sinha-Hikim I, Jasuja R, Choi H, GonzalezCadavid NF. The mechanisms of androgen effects on body composition: mesenchymal pluripotent cell as the target of androgen action. J Gerontol A Biol Sci Med Sci 58: M1103M1110, 2003. 49. Bischoff R. Chemotaxis of skeletal muscle satellite cells. Dev Dyn 208: 505515, 1997. 50. Bischoff R. Interaction between satellite cells and skeletal muscle bers. Development 109: 943952, 1990. 51. Bischoff R. Regeneration of single skeletal muscle bers in vitro. Anat Rec 182: 215 235, 1975. 52. Bischoff R. The satellite cell and muscle regeneration. Myology 97118, 1994. 53. Bischoff R. A satellite cell mitogen from crushed adult muscle. Dev Biol 115: 140 147, 1986. 54. Bittner RE, Schofer C, Weipoltshammer K, Ivanova S, Streubel B, Hauser E, Freilinger M, Hoger H, Elbe-Burger A, Wachtler F. Recruitment of bone-marrow-derived cells by skeletal and cardiac muscle in adult dystrophic mdx mice. Anat Embryol 199: 391396, 1999. 55. Bjerknes M, Cheng H. Gastrointestinal stem cells. II. Intestinal stem cells. Am J Physiol Gastrointest Liver Physiol 289: G381G387, 2005. 56. Blais A, Tsikitis M, Acosta-Alvear D, Sharan R, Kluger Y, Dynlacht BD. An initial blueprint for myogenic differentiation. Genes Dev 19: 553569, 2005. 57. Blaivas M, Carlson BM. Muscle ber branching difference between grafts in old and young rats. Mech Ageing Dev 60: 4353, 1991. 58. Blaveri K, Heslop L, Yu DS, Rosenblatt JD, Gross JG, Partridge TA, Morgan JE. Patterns of repair of dystrophic mouse muscle: studies on isolated bers. Dev Dyn 216: 244 256, 1999. 59. Bockhold KJ, Rosenblatt JD, Partridge TA. Aging normal and dystrophic mouse muscle: analysis of myogenicity in cultures of living single bers. Muscle Nerve 21: 173183, 1998. 60. Bogdan C. Nitric oxide and the regulation of gene expression. Trends Cell Biol 11: 66 75, 2001. 61. Boonen KJ, Rosaria-Chak KY, Baaijens FP, van der Schaft DW, Post MJ. Essential environmental cues from the satellite cell niche: optimizing proliferation and differentiation. Am J Physiol Cell Physiol 296: C1338 C1345, 2009. 62. Boppart MD, Burkin DJ, Kaufman SJ. Alpha7beta1-integrin regulates mechanotransduction and prevents skeletal muscle injury. Am J Physiol Cell Physiol 290: C1660 C1665, 2006. 63. Bosnakovski D, Xu Z, Li W, Thet S, Cleaver O, Perlingeiro RC, Kyba M. Prospective isolation of skeletal muscle stem cells with a Pax7 reporter. Stem Cells 26: 3194 3204, 2008. 64. Bourke DL, Ontell M. Branched myobers in long-term whole muscle transplants: a quantitative study. Anat Rec 209: 281288, 1984. 65. Brack AS, Conboy IM, Conboy MJ, Shen J, Rando TA. A temporal switch from notch to Wnt signaling in muscle stem cells is necessary for normal adult myogenesis. Cell Stem Cell 2: 50 59, 2008. 66. Brack AS, Conboy MJ, Roy S, Lee M, Kuo CJ, Keller C, Rando TA. Increased Wnt signaling during aging alters muscle stem cell fate and increases brosis. Science 317: 807 810, 2007. 67. Brandes RP, Fleming I, Busse R. Endothelial aging. Cardiovasc Res 66: 286 294, 2005. 68. Brazelton TR, Nystrom M, Blau HM. Signicant differences among skeletal muscles in the incorporation of bone marrow-derived cells. Dev Biol 262: 64 74, 2003. 69. Brockes JP, Kumar A. Plasticity and reprogramming of differentiated cells in amphibian regeneration. Nat Rev Mol Cell Biol 3: 566 574, 2002. 70. Bryan BA, Walshe TE, Mitchell DC, Havumaki JS, Saint-Geniez M, Maharaj AS, Maldonado AE, DAmore PA. Coordinated vascular endothelial growth factor expression and signaling during skeletal myogenic differentiation. Mol Biol Cell 19: 994 1006, 2008. 71. Buckingham M. Myogenic progenitor cells and skeletal myogenesis in vertebrates. Curr Opin Genet Dev 16: 525532, 2006. 72. Buckingham M, Bajard L, Chang T, Daubas P, Hadchouel J, Meilhac S, Montarras D, Rocancourt D, Relaix F. The formation of skeletal muscle: from somite to limb. J Anat 202: 59 68, 2003. 73. Burkin DJ, Kaufman SJ. The alpha7beta1 integrin in muscle development and disease. Cell Tissue Res 296: 183190, 1999. 74. Cahill CM, Rogers JT. Interleukin (IL) 1beta induction of IL-6 is mediated by a novel phosphatidylinositol 3-kinase-dependent AKT/IkappaB kinase alpha pathway targeting activator protein-1. J Biol Chem 283: 25900 25912, 2008. 75. Cairns J. Mutation selection and the natural history of cancer. Nature 255: 197200, 1975. 76. Calise S, Blescia S, Cencetti F, Bernacchioni C, Donati C, Bruni P. Sphingosine 1-phosphate stimulates proliferation and migration of satellite cells: role of S1P receptors. Biochim Biophys Acta 1823: 439 450, 2012. 77. Camargo FD, Gokhale S, Johnnidis JB, Fu D, Bell GW, Jaenisch R, Brummelkamp TR. YAP1 increases organ size and expands undifferentiated progenitor cells. Curr Biol 17: 2054 2060, 2007. 78. Camargo FD, Green R, Capetanaki Y, Jackson KA, Goodell MA. Single hematopoietic stem cells generate skeletal muscle through myeloid intermediates. Nat Med 9: 1520 1527, 2003. 79. Campion DR. The muscle satellite cell: a review. Int Rev Cytol 87: 225251, 1984. 80. Cantini M, Carraro U. Macrophage-released factor stimulates selectively myogenic cells in primary muscle culture. J Neuropathol Exp Neurol 54: 121128, 1995. 81. Cantini M, Giurisato E, Radu C, Tiozzo S, Pampinella F, Senigaglia D, Zaniolo G, Mazzoleni F, Vitiello L. Macrophage-secreted myogenic factors: a promising tool for greatly enhancing the proliferative capacity of myoblasts in vitro and in vivo. Neurol Sci 23: 189 194, 2002. 82. Cao B, Zheng B, Jankowski RJ, Kimura S, Ikezawa M, Deasy B, Cummins J, Epperly M, Qu-Petersen Z, Huard J. Muscle stem cells differentiate into haematopoietic lineages but retain myogenic potential. Nat Cell Biol 5: 640 646, 2003.
55

83. Cao Y, Kumar RM, Penn BH, Berkes CA, Kooperberg C, Boyer LA, Young RA, Tapscott SJ. Global and gene-specic analyses show distinct roles for Myod and Myog at a common set of promoters. EMBO J 25: 502511, 2006. 84. Cao Y, Yao Z, Sarkar D, Lawrence M, Sanchez GJ, Parker MH, MacQuarrie KL, Davison J, Morgan MT, Ruzzo WL, Gentleman RC, Tapscott SJ. Genome-wide MyoD binding in skeletal muscle cells: a potential for broad cellular reprogramming. Dev Cell 18: 662 674, 2010. 85. Caplan AI. All MSCs are pericytes? Cell Stem Cell 3: 229 230, 2008. 86. Carmeli E, Moas M, Reznick AZ, Coleman R. Matrix metalloproteinases and skeletal muscle: a brief review. Muscle Nerve 29: 191197, 2004. 87. Chakravarthy MV, Davis BS, Booth FW. IGF-I restores satellite cell proliferative potential in immobilized old skeletal muscle. J Appl Physiol 89: 13651379, 2000. 88. Chang H, Yoshimoto M, Umeda K, Iwasa T, Mizuno Y, Fukada S, Yamamoto H, Motohashi N, Miyagoe-Suzuki Y, Takeda S, Heike T, Nakahata T. Generation of transplantable, functional satellite-like cells from mouse embryonic stem cells. FASEB J 23: 19071919, 2009. 89. Chao DS, Gorospe JR, Brenman JE, Rafael JA, Peters MF, Froehner SC, Hoffman EP, Chamberlain JS, Bredt DS. Selective loss of sarcolemmal nitric oxide synthase in Becker muscular dystrophy. J Exp Med 184: 609 618, 1996. 90. Charge SB, Brack AS, Hughes SM. Aging-related satellite cell differentiation defect occurs prematurely after Ski-induced muscle hypertrophy. Am J Physiol Cell Physiol 283: C1228 C1241, 2002. 91. Chazaud B, Brigitte M, Yacoub-Youssef H, Arnold L, Gherardi R, Sonnet C, Lafuste P, Chretien F. Dual and benecial roles of macrophages during skeletal muscle regeneration. Exerc Sport Sci Rev 37: 18 22, 2009. 92. Chazaud B, Sonnet C, Lafuste P, Bassez G, Rimaniol AC, Poron F, Authier FJ, Dreyfus PA, Gherardi RK. Satellite cells attract monocytes and use macrophages as a support to escape apoptosis and enhance muscle growth. J Cell Biol 163: 11331143, 2003. 93. Chen JF, Mandel EM, Thomson JM, Wu Q, Callis TE, Hammond SM, Conlon FL, Wang DZ. The role of microRNA-1 and microRNA-133 in skeletal muscle proliferation and differentiation. Nature Genet 38: 228 233, 2006. 94. Chen JF, Tao Y, Li J, Deng Z, Yan Z, Xiao X, Wang DZ. microRNA-1 and microRNA206 regulate skeletal muscle satellite cell proliferation and differentiation by repressing Pax7. J Cell Biol 190: 867 879, 2010. 95. Chen X, Mao Z, Liu S, Liu H, Wang X, Wu H, Wu Y, Zhao T, Fan W, Li Y, Yew DT, Kindler PM, Li L, He Q, Qian L, Fan M. Dedifferentiation of adult human myoblasts induced by ciliary neurotrophic factor in vitro. Mol Biol Cell 16: 3140 3151, 2005. 96. Chen Y, Lin G, Slack JM. Control of muscle regeneration in the Xenopus tadpole tail by Pax7. Development 133: 23032313, 2006. 97. Chen Y, Zajac JD, MacLean HE. Androgen regulation of satellite cell function. J Endocrinol 186: 2131, 2005. 98. Cheung TH, Quach NL, Charville GW, Liu L, Park L, Edalati A, Yoo B, Hoang P, Rando TA. Maintenance of muscle stem-cell quiescence by microRNA-489. Nature 482: 524 528, 2012. 99. Chevrel G, Hohlfeld R, Sendtner M. The role of neurotrophins in muscle under physiological and pathological conditions. Muscle Nerve 33: 462 476, 2006. 100. Christov C, Chretien F, Abou-Khalil R, Bassez G, Vallet G, Authier FJ, Bassaglia Y, Shinin V, Tajbakhsh S, Chazaud B, Gherardi RK. Muscle satellite cells and endothelial cells: close neighbors and privileged partners. Mol Biol Cell 18: 13971409, 2007. 101. Cinnamon Y, Ben-Yair R, Kalcheim C. Differential effects of N-cadherin-mediated adhesion on the development of myotomal waves. Development 133: 11011112, 2006. 102. Clow C, Jasmin BJ. Skeletal muscle-derived BDNF regulates satellite cell differentiation and muscle regeneration. Mol Biol Cell 2010. 103. Coleman ME, DeMayo F, Yin KC, Lee HM, Geske R, Montgomery C, Schwartz RJ. Myogenic vector expression of insulin-like growth factor I stimulates muscle cell differentiation and myober hypertrophy in transgenic mice. J Biol Chem 270: 12109 12116, 1995. 104. Collins-Hooper H, Woolley TE, Dyson L, Patel A, Potter P, Baker RE, Gaffney EA, Maini PK, Dash PR, Patel K. Age-related changes in speed and mechanism of adult skeletal muscle stem cell migration. Stem Cells 30: 11821195, 2012. 105. Collins CA, Olsen I, Zammit PS, Heslop L, Petrie A, Partridge TA, Morgan JE. Stem cell function, self-renewal, and behavioral heterogeneity of cells from the adult muscle satellite cell niche. Cell 122: 289 301, 2005. 106. Collinsworth AM, Zhang S, Kraus WE, Truskey GA. Apparent elastic modulus and hysteresis of skeletal muscle cells throughout differentiation. Am J Physiol Cell Physiol 283: C1219 C1227, 2002. 107. Conboy IM, Conboy MJ, Smythe GM, Rando TA. Notch-mediated restoration of regenerative potential to aged muscle. Science 302: 15751577, 2003. 108. Conboy IM, Rando TA. The regulation of Notch signaling controls satellite cell activation and cell fate determination in postnatal myogenesis. Dev Cell 3: 397 409, 2002. 109. Conboy MJ, Karasov AO, Rando TA. High incidence of non-random template strand segregation and asymmetric fate determination in dividing stem cells and their progeny. PLoS Biol 5: e102, 2007. 110. Coolican SA, Samuel DS, Ewton DZ, McWade FJ, Florini JR. The mitogenic and myogenic actions of insulin-like growth factors utilize distinct signaling pathways. J Biol Chem 272: 6653 6662, 1997. 111. Cooper RN, Tajbakhsh S, Mouly V, Cossu G, Buckingham M, Butler-Browne GS. In vivo satellite cell activation via Myf5 and MyoD in regenerating mouse skeletal muscle. J Cell Sci 112: 28952901, 1999. 112. Corbel SY, Lee A, Yi L, Duenas J, Brazelton TR, Blau HM, Rossi FM. Contribution of hematopoietic stem cells to skeletal muscle. Nat Med 9: 1528 1532, 2003. 113. Cornelison DD, Filla MS, Stanley HM, Rapraeger AC, Olwin BB. Syndecan-3 and syndecan-4 specically mark skeletal muscle satellite cells and are implicated in satellite cell maintenance and muscle regeneration. Dev Biol 239: 79 94, 2001. 114. Cornelison DD, Olwin BB, Rudnicki MA, Wold BJ. MyoD(/) satellite cells in singleber culture are differentiation defective and MRF4 decient. Dev Biol 224: 122137, 2000. 115. Cornelison DD, Wilcox-Adelman SA, Goetinck PF, Rauvala H, Rapraeger AC, Olwin BB. Essential and separable roles for Syndecan-3 and Syndecan-4 in skeletal muscle development and regeneration. Genes Dev 18: 22312236, 2004. 116. Cornelison DD, Wold BJ. Single-cell analysis of regulatory gene expression in quiescent and activated mouse skeletal muscle satellite cells. Dev Biol 191: 270 283, 1997. 117. Cox DM, Du M, Marback M, Yang EC, Chan J, Siu KW, McDermott JC. Phosphorylation motifs regulating the stability and function of myocyte enhancer factor 2A. J Biol Chem 278: 1529715303, 2003. 118. Crisan M, Yap S, Casteilla L, Chen CW, Corselli M, Park TS, Andriolo G, Sun B, Zheng B, Zhang L, Norotte C, Teng PN, Traas J, Schugar R, Deasy BM, Badylak S, Buhring HJ, Giacobino JP, Lazzari L, Huard J, Peault B. A perivascular origin for mesenchymal stem cells in multiple human organs. Cell Stem Cell 3: 301313, 2008. 119. Crist CG, Montarras D, Pallafacchina G, Rocancourt D, Cumano A, Conway SJ, Buckingham M. Muscle stem cell behavior is modied by microRNA-27 regulation of Pax3 expression. Proc Natl Acad Sci USA 106: 1338313387, 2009. 120. Csete M, Walikonis J, Slawny N, Wei Y, Korsnes S, Doyle JC, Wold B. Oxygenmediated regulation of skeletal muscle satellite cell proliferation and adipogenesis in culture. J Cell Physiol 189: 189 196, 2001. 121. dAlbis A, Lenfant-Guyot M, Janmot C, Chanoine C, Weinman J, Gallien CL. Regulation by thyroid hormones of terminal differentiation in the skeletal dorsal muscle. I. Neonate mouse. Dev Biol 123: 2532, 1987. 122. Danieli-Betto D, Peron S, Germinario E, Zanin M, Sorci G, Franzoso S, Sandona D, Betto R. Sphingosine 1-phosphate signaling is involved in skeletal muscle regeneration. Am J Physiol Cell Physiol 298: C550 C558, 2010. 123. Darabi R, Arpke RW, Irion S, Dimos JT, Grskovic M, Kyba M, Perlingeiro RC. Human ES- and iPS-derived myogenic progenitors restore dystrophin and improve contractility upon transplantation in dystrophic mice. Cell Stem Cell 10: 610 619, 2012. 124. Darabi R, Gehlbach K, Bachoo RM, Kamath S, Osawa M, Kamm KE, Kyba M, Perlingeiro RC. Functional skeletal muscle regeneration from differentiating embryonic stem cells. Nat Med 14: 134 143, 2008.
56

125. Darabi R, Santos FN, Filareto A, Pan W, Koene R, Rudnicki MA, Kyba M, Perlingeiro RC. Assessment of the myogenic stem cell compartment following transplantation of Pax3/Pax7-induced embryonic stem cell-derived progenitors. Stem Cells 29: 777 790, 2011. 126. Darmani H, Crossan J, McLellan SD, Meek D, Adam C. Expression of nitric oxide synthase and transforming growth factor-beta in crush-injured tendon and synovium. Mediators Inamm 13: 299 305, 2004. 127. Day K, Shefer G, Richardson JB, Enikolopov G, Yablonka-Reuveni Z. Nestin-GFP reporter expression denes the quiescent state of skeletal muscle satellite cells. Dev Biol 304: 246 259, 2007. 128. Day K, Shefer G, Shearer A, Yablonka-Reuveni Z. The depletion of skeletal muscle satellite cells with age is concomitant with reduced capacity of single progenitors to produce reserve progeny. Dev Biol 340: 330 343, 2010. 129. De Angelis L, Berghella L, Coletta M, Lattanzi L, Zanchi M, Cusella-De Angelis MG, Ponzetto C, Cossu G. Skeletal myogenic progenitors originating from embryonic dorsal aorta coexpress endothelial and myogenic markers and contribute to postnatal muscle growth and regeneration. J Cell Biol 147: 869 878, 1999. 130. De Castro Rodrigues A, Andreo JC, de Mattos Rodrigues SP. Myonuclei and satellite cells in denervated rat muscles: an electron microscopy study. Microsurgery 26: 396 398, 2006. 131. De Strooper B, Annaert W. Where Notch and Wnt signaling meet. The presenilin hub. J Cell Biol 152: F1720, 2001. 132. Deasy BM, Feduska JM, Payne TR, Li Y, Ambrosio F, Huard J. Effect of VEGF on the regenerative capacity of muscle stem cells in dystrophic skeletal muscle. Mol Ther J Am Soc Gene Ther 17: 1788 1798, 2009. 133. DeChiara TM, Efstratiadis A, Robertson EJ. A growth-deciency phenotype in heterozygous mice carrying an insulin-like growth factor II gene disrupted by targeting. Nature 345: 78 80, 1990. 134. deLapeyriere O, Ollendorff V, Planche J, Ott MO, Pizette S, Coulier F, Birnbaum D. Expression of the Fgf6 gene is restricted to developing skeletal muscle in the mouse embryo. Development 118: 601 611, 1993. 135. Dellavalle A, Maroli G, Covarello D, Azzoni E, Innocenzi A, Perani L, Antonini S, Sambasivan R, Brunelli S, Tajbakhsh S, Cossu G. Pericytes resident in postnatal skeletal muscle differentiate into muscle bres and generate satellite cells. Nature Commun 2: 499, 2011. 136. Dellavalle A, Sampaolesi M, Tonlorenzi R, Tagliaco E, Sacchetti B, Perani L, Innocenzi A, Galvez BG, Messina G, Morosetti R, Li S, Belicchi M, Peretti G, Chamberlain JS, Wright WE, Torrente Y, Ferrari S, Bianco P, Cossu G. Pericytes of human skeletal muscle are myogenic precursors distinct from satellite cells. Nat Cell Biol 9: 255267, 2007. 137. Delling U, Tureckova J, Lim HW, De Windt LJ, Rotwein P, Molkentin JD. A calcineurinNFATc3-dependent pathway regulates skeletal muscle differentiation and slow myosin heavy-chain expression. Mol Cell Biol 20: 6600 6611, 2000. 138. Deponti D, Buono R, Catanzaro G, De Palma C, Longhi R, Meneveri R, Bresolin N, Bassi MT, Cossu G, Clementi E, Brunelli S. The low-afnity receptor for neurotrophins p75NTR plays a key role for satellite cell function in muscle repair acting via RhoA. Mol Biol Cell 20: 3620 3627, 2009. 139. Dey BK, Gagan J, Dutta A. miR-206 and -486 induce myoblast differentiation by downregulating Pax7. Mol Cell Biol 31: 203214, 2011. 140. Dezawa M, Ishikawa H, Itokazu Y, Yoshihara T, Hoshino M, Takeda S, Ide C, Nabeshima Y. Bone marrow stromal cells generate muscle cells and repair muscle degeneration. Science 309: 314 317, 2005. 141. DiMario J, Bufnger N, Yamada S, Strohman RC. Fibroblast growth factor in the extracellular matrix of dystrophic (mdx) mouse muscle. Science 244: 688 690, 1989. 142. Doherty MJ, Ashton BA, Walsh S, Beresford JN, Grant ME, Caneld AE. Vascular pericytes express osteogenic potential in vitro and in vivo. J Bone Miner Res 13: 828 838, 1998. 143. Doumit ME, Cook DR, Merkel RA. Testosterone up-regulates androgen receptors and decreases differentiation of porcine myogenic satellite cells in vitro. Endocrinology 137: 13851394, 1996. 144. Doumit ME, Merkel RA. Conditions for isolation and culture of porcine myogenic satellite cells. Tissue Cell 24: 253262, 1992. 145. Dourdin N, Balcerzak D, Brustis JJ, Poussard S, Cottin P, Ducastaing A. Potential m-calpain substrates during myoblast fusion. Exp Cell Res 246: 433 442, 1999. 146. Doyle MJ, Zhou S, Tanaka KK, Pisconti A, Farina NH, Sorrentino BP, Olwin BB. Abcg2 labels multiple cell types in skeletal muscle and participates in muscle regeneration. J Cell Biol 195: 147163, 2011. 147. Doyonnas R, LaBarge MA, Sacco A, Charlton C, Blau HM. Hematopoietic contribution to skeletal muscle regeneration by myelomonocytic precursors. Proc Natl Acad Sci USA 101: 1350713512, 2004. 148. Dreyfus PA, Chretien F, Chazaud B, Kirova Y, Caramelle P, Garcia L, Butler-Browne G, Gherardi RK. Adult bone marrow-derived stem cells in muscle connective tissue and satellite cell niches. Am J Pathol 164: 773779, 2004. 149. Duckmanton A, Kumar A, Chang YT, Brockes JP. A single-cell analysis of myogenic dedifferentiation induced by small molecules. Chem Biol 12: 11171126, 2005. 150. Enesco M, Puddy D. Increase in the number of nuclei and weight in skeletal muscle of rats of various ages. Am J Anat 114: 235244, 1964. 151. Engert JC, Berglund EB, Rosenthal N. Proliferation precedes differentiation in IGF-Istimulated myogenesis. J Cell Biol 135: 431 440, 1996. 152. Engler AJ, Grifn MA, Sen S, Bonnemann CG, Sweeney HL, Discher DE. Myotubes differentiate optimally on substrates with tissue-like stiffness: pathological implications for soft or stiff microenvironments. J Cell Biol 166: 877 887, 2004. 153. Ernfors P, Wetmore C, Eriksdotter-Nilsson M, Bygdeman M, Stromberg I, Olson L, Persson H. The nerve growth factor receptor gene is expressed in both neuronal and non-neuronal tissues in the human fetus. Int J Dev Neurosci 9: 57 66, 1991. 154. Ershler WB, Keller ET. Age-associated increased interleukin-6 gene expression, latelife diseases, and frailty. Annu Rev Med 51: 245270, 2000. 155. Esner M, Meilhac SM, Relaix F, Nicolas JF, Cossu G, Buckingham ME. Smooth muscle of the dorsal aorta shares a common clonal origin with skeletal muscle of the myotome. Development 133: 737749, 2006. 156. Espinosa A, Estrada M, Jaimovich E. IGF-I and insulin induce different intracellular calcium signals in skeletal muscle cells. J Endocrinol 182: 339 352, 2004. 157. Estrada M, Espinosa A, Muller M, Jaimovich E. Testosterone stimulates intracellular calcium release and mitogen-activated protein kinases via a G protein-coupled receptor in skeletal muscle cells. Endocrinology 144: 3586 3597, 2003. 158. Ewton DZ, Falen SL, Florini JR. The type II insulin-like growth factor (IGF) receptor has low afnity for IGF-I analogs: pleiotypic actions of IGFs on myoblasts are apparently mediated by the type I receptor. Endocrinology 120: 115123, 1987. 159. Fahim MA, Robbins N. Ultrastructural studies of young and old mouse neuromuscular junctions. J Neurocytol 11: 641 656, 1982. 160. Fan Y, Maley M, Beilharz M, Grounds M. Rapid death of injected myoblasts in myoblast transfer therapy. Muscle Nerve 19: 853 860, 1996. 161. Farrington-Rock C, Crofts NJ, Doherty MJ, Ashton BA, Grifn-Jones C, Caneld AE. Chondrogenic and adipogenic potential of microvascular pericytes. Circulation 110: 2226 2232, 2004. 162. Fedorov YV, Rosenthal RS, Olwin BB. Oncogenic Ras-induced proliferation requires autocrine broblast growth factor 2 signaling in skeletal muscle cells. J Cell Biol 152: 13011305, 2001. 163. Feng J, Mantesso A, De Bari C, Nishiyama A, Sharpe PT. Dual origin of mesenchymal stem cells contributing to organ growth and repair. Proc Natl Acad Sci USA 108: 6503 6508, 2011. 164. Fernando P, Kelly JF, Balazsi K, Slack RS, Megeney LA. Caspase 3 activity is required for skeletal muscle differentiation. Proc Natl Acad Sci USA 99: 1102511030, 2002. 165. Ferrando AA, Shefeld-Moore M, Yeckel CW, Gilkison C, Jiang J, Achacosa A, Lieberman SA, Tipton K, Wolfe RR, Urban RJ. Testosterone administration to older men improves muscle function: molecular and physiological mechanisms. Am J Physiol Endocrinol Metab 282: E601E607, 2002.
57

166. Ferrari G, Cusella-De Angelis G, Coletta M, Paolucci E, Stornaiuolo A, Cossu G, Mavilio F. Muscle regeneration by bone marrow-derived myogenic progenitors. Science 279: 1528 1530, 1998. 167. Ferre PJ, Liaubet L, Concordet D, SanCristobal M, Uro-Coste E, Tosser-Klopp G, Bonnet A, Toutain PL, Hatey F, Lefebvre HP. Longitudinal analysis of gene expression in porcine skeletal muscle after post-injection local injury. Pharm Res 24: 1480 1489, 2007. 168. Fielding RA, Manfredi TJ, Ding W, Fiatarone MA, Evans WJ, Cannon JG. Acute phase response in exercise. III. Neutrophil and IL-1 beta accumulation in skeletal muscle. Am J Physiol Regul Integr Comp Physiol 265: R166 R172, 1993. 169. Florini JR, Ewton DZ, Coolican SA. Growth hormone and the insulin-like growth factor system in myogenesis. Endocr Rev 17: 481517, 1996. 170. Florini JR, Ewton DZ, Roof SL. Insulin-like growth factor-I stimulates terminal myogenic differentiation by induction of myogenin gene expression. Mol Endocrinol 5: 718 724, 1991. 171. Florini JR, Magri KA, Ewton DZ, James PL, Grindstaff K, Rotwein PS. Spontaneous differentiation of skeletal myoblasts is dependent upon autocrine secretion of insulinlike growth factor-II. J Biol Chem 266: 1591715923, 1991. 172. Floss T, Arnold HH, Braun T. A role for FGF-6 in skeletal muscle regeneration. Genes Dev 11: 2040 2051, 1997. 173. Friday BB, Horsley V, Pavlath GK. Calcineurin activity is required for the initiation of skeletal muscle differentiation. J Cell Biol 149: 657 666, 2000. 174. Fuchs E. Finding ones niche in the skin. Cell Stem Cell 4: 499 502, 2009. 175. Fuchtbauer EM, Westphal H. MyoD and myogenin are coexpressed in regenerating skeletal muscle of the mouse. Dev Dyn 193: 34 39, 1992. 176. Fukada S. Molecular regulation of muscle stem cells by quiescence genes. Yakugaku zasshi J Pharmaceutical Soc Japan 131: 1329 1332, 2011. 177. Fukada S, Uezumi A, Ikemoto M, Masuda S, Segawa M, Tanimura N, Yamamoto H, Miyagoe-Suzuki Y, Takeda S. Molecular signature of quiescent satellite cells in adult skeletal muscle. Stem Cells 25: 2448 2459, 2007. 178. Fukushima K, Nakamura A, Ueda H, Yuasa K, Yoshida K, Takeda S, Ikeda S. Activation and localization of matrix metalloproteinase-2 and -9 in the skeletal muscle of the muscular dystrophy dog (CXMDJ). BMC Musculoskelet Disord 8: 54, 2007. 179. Gal-Levi R, Leshem Y, Aoki S, Nakamura T, Halevy O. Hepatocyte growth factor plays a dual role in regulating skeletal muscle satellite cell proliferation and differentiation. Biochim Biophys Acta 1402: 39 51, 1998. 180. Galbiati F, Volonte D, Engelman JA, Scherer PE, Lisanti MP. Targeted down-regulation of caveolin-3 is sufcient to inhibit myotube formation in differentiating C2C12 myoblasts. Transient activation of p38 mitogen-activated protein kinase is required for induction of caveolin-3 expression and subsequent myotube formation. J Biol Chem 274: 3031530321, 1999. 181. Galbiati F, Volonte D, Minetti C, Chu JB, Lisanti MP. Phenotypic behavior of caveolin-3 mutations that cause autosomal dominant limb girdle muscular dystrophy (LGMD-1C). Retention of LGMD-1C caveolin-3 mutants within the Golgi complex. J Biol Chem 274: 2563225641, 1999. 182. Galvez BG, Sampaolesi M, Brunelli S, Covarello D, Gavina M, Rossi B, Constantin G, Torrente Y, Cossu G. Complete repair of dystrophic skeletal muscle by mesoangioblasts with enhanced migration ability. J Cell Biol 174: 231243, 2006. 183. Gao C, Chen YG. Dishevelled: the hub of Wnt signaling. Cell Signal 22: 717727, 2010. 184. Gao Y, Kostrominova TY, Faulkner JA, Wineman AS. Age-related changes in the mechanical properties of the epimysium in skeletal muscles of rats. J Biomech 41: 465 469, 2008. 185. Gatchalian CL, Schachner M, Sanes JR. Fibroblasts that proliferate near denervated synaptic sites in skeletal muscle synthesize the adhesive molecules tenascin(J1), NCAM, bronectin, and a heparan sulfate proteoglycan. J Cell Biol 108: 18731890, 1989. 186. Gauthier-Rouviere C, Vandromme M, Tuil D, Lautredou N, Morris M, Soulez M, Kahn A, Fernandez A, Lamb N. Expression and activity of serum response factor is required for expression of the muscle-determining factor MyoD in both dividing and differentiating mouse C2C12 myoblasts. Mol Biol Cell 7: 719 729, 1996. 187. Gayraud-Morel B, Chretien F, Flamant P, Gomes D, Zammit PS, Tajbakhsh S. A role for the myogenic determination gene Myf5 in adult regenerative myogenesis. Dev Biol 312: 1328, 2007. 188. Gensch N, Borchardt T, Schneider A, Riethmacher D, Braun T. Different autonomous myogenic cell populations revealed by ablation of Myf5-expressing cells during mouse embryogenesis. Development 135: 15971604, 2008. 189. Germani A, Di Carlo A, Mangoni A, Straino S, Giacinti C, Turrini P, Biglioli P, Capogrossi MC. Vascular endothelial growth factor modulates skeletal myoblast function. Am J Pathol 163: 14171428, 2003. 190. Gibson MC, Schultz E. The distribution of satellite cells and their relationship to specic ber types in soleus and extensor digitorum longus muscles. Anat Rec 202: 329 337, 1982. 191. Gillespie MA, Le Grand F, Scime A, Kuang S, von Maltzahn J, Seale V, Cuenda A, Ranish JA, Rudnicki MA. p38--dependent gene silencing restricts entry into the myogenic differentiation program. J Cell Biol 187: 9911005, 2009. 192. Gnocchi VF, White RB, Ono Y, Ellis JA, Zammit PS. Further characterisation of the molecular signature of quiescent and activated mouse muscle satellite cells. PLoS One 4: e5205, 2009. 193. Golding JP, Calderbank E, Partridge TA, Beauchamp JR. Skeletal muscle stem cells express anti-apoptotic ErbB receptors during activation from quiescence. Exp Cell Res 313: 341356, 2007. 194. Goldspink G. Research on mechano growth factor: its potential for optimising physical training as well as misuse in doping. Br J Sports Med 39: 787788, 2005. 195. Goldspink G, Fernandes K, Williams PE, Wells DJ. Age-related changes in collagen gene expression in the muscles of mdx dystrophic and normal mice. Neuromuscul Disord 4: 183191, 1994. 196. Goljanek-Whysall K, Sweetman D, Abu-Elmagd M, Chapnik E, Dalmay T, Hornstein E, Munsterberg A. MicroRNA regulation of the paired-box transcription factor Pax3 confers robustness to developmental timing of myogenesis. Proc Natl Acad Sci USA 108: 11936 11941, 2011. 197. Gonzalez I, Tripathi G, Carter EJ, Cobb LJ, Salih DA, Lovett FA, Holding C, Pell JM. Akt2, a novel functional link between p38 mitogen-activated protein kinase and phosphatidylinositol 3-kinase pathways in myogenesis. Mol Cell Biol 24: 36073622, 2004. 198. Goodpaster BH, Wolf D. Skeletal muscle lipid accumulation in obesity, insulin resistance, and type 2 diabetes. Pediatr Diabetes 5: 219 226, 2004. 199. Grass S, Arnold HH, Braun T. Alterations in somite patterning of Myf-5-decient mice: a possible role for FGF-4 and FGF-6. Development 122: 141150, 1996. 200. Greco AV, Mingrone G, Giancaterini A, Manco M, Morroni M, Cinti S, Granzotto M, Vettor R, Camastra S, Ferrannini E. Insulin resistance in morbid obesity: reversal with intramyocellular fat depletion. Diabetes 51: 144 151, 2002. 201. Griesbeck O, Parsadanian AS, Sendtner M, Thoenen H. Expression of neurotrophins in skeletal muscle: quantitative comparison and signicance for motoneuron survival and maintenance of function. J Neurosci Res 42: 2133, 1995. 202. Grimby G, Saltin B. The ageing muscle. Clin Physiol 3: 209 218, 1983. 203. Gros J, Manceau M, Thome V, Marcelle C. A common somitic origin for embryonic muscle progenitors and satellite cells. Nature 435: 954 958, 2005. 204. Gros J, Scaal M, Marcelle C. A two-step mechanism for myotome formation in chick. Dev Cell 6: 875 882, 2004. 205. Gros J, Serralbo O, Marcelle C. WNT11 acts as a directional cue to organize the elongation of early muscle bres. Nature 457: 589 593, 2009. 206. Grounds MD. Phagocytosis of necrotic muscle in muscle isografts is inuenced by the strain, age, and sex of host mice. J Pathol 153: 71 82, 1987. 207. Grounds MD, Garrett KL, Lai MC, Wright WE, Beilharz MW. Identication of skeletal muscle precursor cells in vivo by use of MyoD1 and myogenin probes. Cell Tissue Res 267: 99 104, 1992. 208. Gullberg D, Tiger CF, Velling T. Laminins during muscle development and in muscular dystrophies. Cell Mol Life Sci 56: 442 460, 1999.
58

209. Guo K, Wang J, Andres V, Smith RC, Walsh K. MyoD-induced expression of p21 inhibits cyclin-dependent kinase activity upon myocyte terminal differentiation. Mol Cell Biol 15: 38233829, 1995. 210. Gussoni E, Soneoka Y, Strickland CD, Buzney EA, Khan MK, Flint AF, Kunkel LM, Mulligan RC. Dystrophin expression in the mdx mouse restored by stem cell transplantation. Nature 401: 390 394, 1999. 211. Guttinger M, Ta E, Battaglia M, Coletta M, Cossu G. Allogeneic mesoangioblasts give rise to alpha-sarcoglycan expressing bers when transplanted into dystrophic mice. Exp Cell Res 312: 38723879, 2006. 212. Haddad F, Zaldivar F, Cooper DM, Adams GR. IL-6-induced skeletal muscle atrophy. J Appl Physiol 98: 911917, 2005. 213. Haldar M, Karan G, Tvrdik P, Capecchi MR. Two cell lineages, myf5 and myf5independent, participate in mouse skeletal myogenesis. Dev Cell 14: 437 445, 2008. 214. Halevy O, Cantley LC. Differential regulation of the phosphoinositide 3-kinase and MAP kinase pathways by hepatocyte growth factor vs. insulin-like growth factor-I in myogenic cells. Exp Cell Res 297: 224 234, 2004. 215. Halevy O, Novitch BG, Spicer DB, Skapek SX, Rhee J, Hannon GJ, Beach D, Lassar AB. Correlation of terminal cell cycle arrest of skeletal muscle with induction of p21 by MyoD. Science 267: 1018 1021, 1995. 216. Halevy O, Piestun Y, Allouh MZ, Rosser BW, Rinkevich Y, Reshef R, Rozenboim I, Wleklinski-Lee M, Yablonka-Reuveni Z. Pattern of Pax7 expression during myogenesis in the posthatch chicken establishes a model for satellite cell differentiation and renewal. Dev Dyn 231: 489 502, 2004. 217. Hall-Craggs EC, Seyan HS. Histochemical changes in innervated and denervated skeletal muscle bers following treatment with bupivacaine (marcain). Exp Neurol 46: 345354, 1975. 218. Hamer PW, McGeachie JM, Davies MJ, Grounds MD. Evans Blue Dye as an in vivo marker of myobre damage: optimising parameters for detecting initial myobre membrane permeability. J Anat 200: 69 79, 2002. 219. Hammond CL, Hinits Y, Osborn DP, Minchin JE, Tettamanti G, Hughes SM. Signals and myogenic regulatory factors restrict pax3 and pax7 expression to dermomyotome-like tissue in zebrash. Dev Biol 302: 504 521, 2007. 220. Han B, Tong J, Zhu MJ, Ma C, Du M. Insulin-like growth factor-1 (IGF-1) and leucine activate pig myogenic satellite cells through mammalian target of rapamycin (mTOR) pathway. Mol Reprod Dev 75: 810 817, 2008. 221. Han J, Jiang Y, Li Z, Kravchenko VV, Ulevitch RJ. Activation of the transcription factor MEF2C by the MAP kinase p38 in inammation. Nature 386: 296 299, 1997. 222. Hannon K, Kudla AJ, McAvoy MJ, Clase KL, Olwin BB. Differentially expressed broblast growth factors regulate skeletal muscle development through autocrine and paracrine mechanisms. J Cell Biol 132: 11511159, 1996. 223. Hannun YA, Obeid LM. Principles of bioactive lipid signalling: lessons from sphingolipids. Nat Rev Mol Cell Biol 9: 139 150, 2008. 224. Hansen-Smith FM, Picou D, Golden MH. Muscle satellite cells in malnourished and nutritionally rehabilitated children. J Neurol Sci 41: 207221, 1979. 225. Harel I, Nathan E, Tirosh-Finkel L, Zigdon H, Guimaraes-Camboa N, Evans SM, Tzahor E. Distinct origins and genetic programs of head muscle satellite cells. Dev Cell 16: 822 832, 2009. 226. He L, Papoutsi M, Huang R, Tomarev SI, Christ B, Kurz H, Wilting J. Three different fates of cells migrating from somites into the limb bud. Anat Embryol 207: 29 34, 2003. 227. Hellmuth AE, Allbrook DB. Muscle satellite cell numbers during the postnatal period. J Anat 110: 503, 1971. 228. Herbst KL, Bhasin S. Testosterone action on skeletal muscle. Curr Opin Clin Nutr Metab Care 7: 271277, 2004. 229. Hermanson JW, Moschella MC, Ontell M. Effect of neonatal denervation-reinnervation on the functional capacity of a 129ReJ dy/dy murine dystrophic muscle. Exp Neurol 102: 210 216, 1988. 230. Hinescu ME, Gherghiceanu M, Suciu L, Popescu LM. Telocytes in pleura: two- and three-dimensional imaging by transmission electron microscopy. Cell Tissue Res 343: 389 397, 2011. 231. Hirai H, Verma M, Watanabe S, Tastad C, Asakura Y, Asakura A. MyoD regulates apoptosis of myoblasts through microRNA-mediated down-regulation of Pax3. J Cell Biol 191: 347365, 2010. 232. Hjiantoniou E, Anayasa M, Nicolaou P, Bantounas I, Saito M, Iseki S, Uney JB, Phylactou LA. Twist induces reversal of myotube formation. Differ Res Biol Diversity 76: 182192, 2008. 233. Hollemann D, Budka H, Loscher WN, Yanagida G, Fischer MB, Wanschitz JV. Endothelial and myogenic differentiation of hematopoietic progenitor cells in inammatory myopathies. J Neuropathol Exp Neurol 67: 711719, 2008. 234. Hollenberg SM, Cheng PF, Weintraub H. Use of a conditional MyoD transcription factor in studies of MyoD trans-activation and muscle determination. Proc Natl Acad Sci USA 90: 8028 8032, 1993. 235. Holterman CE, Le Grand F, Kuang S, Seale P, Rudnicki MA. Megf10 regulates the progression of the satellite cell myogenic program. J Cell Biol 179: 911922, 2007. 236. Horowitz A, Tkachenko E, Simons M. Fibroblast growth factor-specic modulation of cellular response by syndecan-4. J Cell Biol 157: 715725, 2002. 237. Horsley V, Friday BB, Matteson S, Kegley KM, Gephart J, Pavlath GK. Regulation of the growth of multinucleated muscle cells by an NFATC2-dependent pathway. J Cell Biol 153: 329 338, 2001. 238. Horsley V, Pavlath GK. Forming a multinucleated cell: molecules that regulate myoblast fusion. Cells Tissues Organs 176: 6778, 2004. 239. Hu E, Tontonoz P, Spiegelman BM. Transdifferentiation of myoblasts by the adipogenic transcription factors PPAR gamma and C/EBP alpha. Proc Natl Acad Sci USA 92: 9856 9860, 1995. 240. Huckins C. The spermatogonial stem cell population in adult rats. I. Their morphology, proliferation and maturation. Anat Rec 169: 533557, 1971. 241. Hughes SM, Blau HM. Migration of myoblasts across basal lamina during skeletal muscle development. Nature 345: 350 353, 1990. 242. Hutcheson DA, Zhao J, Merrell A, Haldar M, Kardon G. Embryonic and fetal limb myogenic cells are derived from developmentally distinct progenitors and have different requirements for beta-catenin. Genes Dev 23: 9971013, 2009. 243. Ikezawa M, Cao B, Qu Z, Peng H, Xiao X, Pruchnic R, Kimura S, Miike T, Huard J. Dystrophin delivery in dystrophin-decient DMDmdx skeletal muscle by isogenic muscle-derived stem cell transplantation. Hum Gene Ther 14: 15351546, 2003. 244. Irintchev A, Zeschnigk M, Starzinski-Powitz A, Wernig A. Expression pattern of Mcadherin in normal, denervated, and regenerating mouse muscles. Dev Dyn 199: 326 337, 1994. 245. Jackson KA, Mi T, Goodell MA. Hematopoietic potential of stem cells isolated from murine skeletal muscle. Proc Natl Acad Sci USA 96: 1448214486, 1999. 246. James PL, Jones SB, Busby WH Jr, Clemmons DR, Rotwein P. A highly conserved insulin-like growth factor-binding protein (IGFBP-5) is expressed during myoblast differentiation. J Biol Chem 268: 2230522312, 1993. 247. Jankowski RJ, Huard J. Establishing reliable criteria for isolating myogenic cell fractions with stem cell properties and enhanced regenerative capacity. Blood Cells Mol Dis 32: 24 33, 2004. 248. Jejurikar SS, Marcelo CL, Kuzon WM Jr. Skeletal muscle denervation increases satellite cell susceptibility to apoptosis. Plast Reconstr Surg 110: 160 168, 2002. 249. Jenniskens GJ, Veerkamp JH, van Kuppevelt TH. Heparan sulfates in skeletal muscle development and physiology. J Cell Physiol 206: 283294, 2006. 250. Jirmanova I, Thesleff S. Ultrastructural study of experimental muscle degeneration and regeneration in the adult rat. Z Zellforsch Mikrosk Anat 131: 7797, 1972. 251. Jockusch H, Voigt S. Migration of adult myogenic precursor cells as revealed by GFP/nLacZ labelling of mouse transplantation chimeras. J Cell Sci 116: 16111616, 2003.
59

252. Joe AW, Yi L, Natarajan A, Le Grand F, So L, Wang J, Rudnicki MA, Rossi FM. Muscle injury activates resident bro/adipogenic progenitors that facilitate myogenesis. Nat Cell Biol 12: 153163, 2010. 253. Jones JI, Clemmons DR. Insulin-like growth factors and their binding proteins: biological actions. Endocr Rev 16: 334, 1995. 254. Joubert Y, Tobin C. Satellite cell proliferation and increase in the number of myonuclei induced by testosterone in the levator ani muscle of the adult female rat. Dev Biol 131: 550 557, 1989. 255. Joubert Y, Tobin C. Testosterone treatment results in quiescent satellite cells being activated and recruited into cell cycle in rat levator ani muscle. Dev Biol 169: 286 294, 1995. 256. Kablar B, Asakura A, Krastel K, Ying C, May LL, Goldhamer DJ, Rudnicki MA. MyoD and Myf-5 dene the specication of musculature of distinct embryonic origin. Biochem Cell Biol 76: 1079 1091, 1998. 257. Kablar B, Krastel K, Tajbakhsh S, Rudnicki MA. Myf5 and MyoD activation dene independent myogenic compartments during embryonic development. Dev Biol 258: 307318, 2003. 258. Kablar B, Krastel K, Ying C, Asakura A, Tapscott SJ, Rudnicki MA. MyoD and Myf-5 differentially regulate the development of limb versus trunk skeletal muscle. Development 124: 4729 4738, 1997. 259. Kablar B, Krastel K, Ying C, Tapscott SJ, Goldhamer DJ, Rudnicki MA. Myogenic determination occurs independently in somites and limb buds. Dev Biol 206: 219 231, 1999. 260. Kablar B, Rudnicki MA. Skeletal muscle development in the mouse embryo. Histol Histopathol 15: 649 656, 2000. 261. Kalcheim C, Ben-Yair R. Cell rearrangements during development of the somite and its derivatives. Curr Opin Genet Dev 15: 371380, 2005. 262. Kaminski HJ, Andrade FH. Nitric oxide: biologic effects on muscle and role in muscle diseases. Neuromuscul Disord 11: 517524, 2001. 263. Kanisicak O, Mendez JJ, Yamamoto S, Yamamoto M, Goldhamer DJ. Progenitors of skeletal muscle satellite cells express the muscle determination gene, MyoD. Dev Biol 332: 131141, 2009. 264. Kardon G, Campbell JK, Tabin CJ. Local extrinsic signals determine muscle and endothelial cell fate and patterning in the vertebrate limb. Dev Cell 3: 533545, 2002. 265. Kassar-Duchossoy L, Giacone E, Gayraud-Morel B, Jory A, Gomes D, Tajbakhsh S. Pax3/Pax7 mark a novel population of primitive myogenic cells during development. Genes Dev 19: 1426 1431, 2005. 266. Kastner S, Elias MC, Rivera AJ, Yablonka-Reuveni Z. Gene expression patterns of the broblast growth factors and their receptors during myogenesis of rat satellite cells. J Histochem Cytochem 48: 1079 1096, 2000. 267. Kazuki Y, Hiratsuka M, Takiguchi M, Osaki M, Kajitani N, Hoshiya H, Hiramatsu K, Yoshino T, Kazuki K, Ishihara C, Takehara S, Higaki K, Nakagawa M, Takahashi K, Yamanaka S, Oshimura M. Complete genetic correction of ips cells from Duchenne muscular dystrophy. Mol Ther 18: 386 393, 2010. 268. Keller P, Penkowa M, Keller C, Steensberg A, Fischer CP, Giralt M, Hidalgo J, Pedersen BK. Interleukin-6 receptor expression in contracting human skeletal muscle: regulating role of IL-6. FASEB J 19: 11811183, 2005. 269. Kelly AM. Perisynaptic satellite cells in the developing and mature rat soleus muscle. Anat Rec 190: 891903, 1978. 270. Kherif S, Lafuma C, Dehaupas M, Lachkar S, Fournier JG, Verdiere-Sahuque M, Fardeau M, Alameddine HS. Expression of matrix metalloproteinases 2 and 9 in regenerating skeletal muscle: a study in experimentally injured and mdx muscles. Dev Biol 205: 158 170, 1999. 271. Kim CH, Neiswender H, Baik EJ, Xiong WC, Mei L. Beta-catenin interacts with MyoD and regulates its transcription activity. Mol Cell Biol 28: 29412951, 2008. 272. Kitamoto T, Hanaoka K. Notch3 null mutation in mice causes muscle hyperplasia by repetitive muscle regeneration. Stem Cells 28: 22052216, 2010. 273. Kitzmann M, Carnac G, Vandromme M, Primig M, Lamb NJ, Fernandez A. The muscle regulatory factors MyoD and myf-5 undergo distinct cell cycle-specic expression in muscle cells. J Cell Biol 142: 14471459, 1998. 274. Knudsen KA, Horwitz AF. Tandem events in myoblast fusion. Dev Biol 58: 328 338, 1977. 275. Kobzik L, Reid MB, Bredt DS, Stamler JS. Nitric oxide in skeletal muscle. Nature 372: 546 548, 1994. 276. Konigsberg IR. Clonal analysis of myogenesis. Science 140: 12731284, 1963. 277. Konigsberg UR, Lipton BH, Konigsberg IR. The regenerative response of single mature muscle bers isolated in vitro. Dev Biol 45: 260 275, 1975. 278. Kovanen V. Intramuscular extracellular matrix: complex environment of muscle cells. Exerc Sport Sci Rev 30: 20 25, 2002. 279. Kuang S, Charge SB, Seale P, Huh M, Rudnicki MA. Distinct roles for Pax7 and Pax3 in adult regenerative myogenesis. J Cell Biol 172: 103113, 2006. 280. Kuang S, Kuroda K, Le Grand F, Rudnicki MA. Asymmetric self-renewal and commitment of satellite stem cells in muscle. Cell 129: 999 1010, 2007. 281. Kurosu H, Ogawa Y, Miyoshi M, Yamamoto M, Nandi A, Rosenblatt KP, Baum MG, Schiavi S, Hu MC, Moe OW, Kuro-o M. Regulation of broblast growth factor-23 signaling by klotho. J Biol Chem 281: 6120 6123, 2006. 282. Kuschel R, Yablonka-Reuveni Z, Bornemann A. Satellite cells on isolated myobers from normal and denervated adult rat muscle. J Histochem Cytochem 47: 13751384, 1999. 283. Kust BM, Copray JC, Brouwer N, Troost D, Boddeke HW. Elevated levels of neurotrophins in human biceps brachii tissue of amyotrophic lateral sclerosis. Exp Neurol 177: 419 427, 2002. 284. Kutcher ME, Herman IM. The pericyte: cellular regulator of microvascular blood ow. Microvasc Res 77: 235246, 2009. 285. LHonore A, Lamb NJ, Vandromme M, Turowski P, Carnac G, Fernandez A. MyoD distal regulatory region contains an SRF binding CArG element required for MyoD expression in skeletal myoblasts and during muscle regeneration. Mol Biol Cell 14: 21512162, 2003. 286. LHonore A, Rana V, Arsic N, Franckhauser C, Lamb NJ, Fernandez A. Identication of a new hybrid serum response factor and myocyte enhancer factor 2-binding element in MyoD enhancer required for MyoD expression during myogenesis. Mol Biol Cell 18: 19922001, 2007. 287. LaBarge MA, Blau HM. Biological progression from adult bone marrow to mononucleate muscle stem cell to multinucleate muscle ber in response to injury. Cell 111: 589 601, 2002. 288. Langsdorf A, Do AT, Kusche-Gullberg M, Emerson CP Jr, Ai X. Sulfs are regulators of growth factor signaling for satellite cell differentiation and muscle regeneration. Dev Biol 311: 464 477, 2007. 289. Lansdorp PM. Immortal strands? Give me a break. Cell 129: 1244 1247, 2007. 290. Larsen BD, Rampalli S, Burns LE, Brunette S, Dilworth FJ, Megeney LA. Caspase 3/caspase-activated DNase promote cell differentiation by inducing DNA strand breaks. Proc Natl Acad Sci USA 107: 4230 4235, 2010. 291. Lassar AB, Davis RL, Wright WE, Kadesch T, Murre C, Voronova A, Baltimore D, Weintraub H. Functional activity of myogenic HLH proteins requires hetero-oligomerization with E12/E47-like proteins in vivo. Cell 66: 305315, 1991. 292. Laterza OF, Lim L, Garrett-Engele PW, Vlasakova K, Muniappa N, Tanaka WK, Johnson JM, Sina JF, Fare TL, Sistare FD, Glaab WE. Plasma MicroRNAs as sensitive and specic biomarkers of tissue injury. Clin Chem 55: 19771983, 2009. 293. Le Grand F, Jones AE, Seale V, Scime A, Rudnicki MA. Wnt7a activates the planar cell polarity pathway to drive the symmetric expansion of satellite stem cells. Cell Stem Cell 4: 535547, 2009. 294. Lee JY, Qu-Petersen Z, Cao B, Kimura S, Jankowski R, Cummins J, Usas A, Gates C, Robbins P, Wernig A, Huard J. Clonal isolation of muscle-derived cells capable of enhancing muscle regeneration and bone healing. J Cell Biol 150: 10851100, 2000.
60

295. Lefaucheur JP, Gjata B, Lafont H, Sebille A. Angiogenic and inammatory responses following skeletal muscle injury are altered by immune neutralization of endogenous basic broblast growth factor, insulin-like growth factor-1 and transforming growth factor-beta 1. J Neuroimmunol 70: 37 44, 1996. 296. Lefaucheur JP, Sebille A. Basic broblast growth factor promotes in vivo muscle regeneration in murine muscular dystrophy. Neurosci Lett 202: 121124, 1995. 297. Lefaucheur JP, Sebille A. Muscle regeneration following injury can be modied in vivo by immune neutralization of basic broblast growth factor, transforming growth factor beta 1 or insulin-like growth factor I. J Neuroimmunol 57: 8591, 1995. 298. Lemercier C, To RQ, Carrasco RA, Konieczny SF. The basic helix-loop-helix transcription factor Mist1 functions as a transcriptional repressor of myoD. EMBO J 17: 14121422, 1998. 299. Lepper C, Conway SJ, Fan CM. Adult satellite cells and embryonic muscle progenitors have distinct genetic requirements. Nature 460: 627 631, 2009. 300. Lepper C, Fan CM. Inducible lineage tracing of Pax7-descendant cells reveals embryonic origin of adult satellite cells. Genesis 48: 424 436, 2010. 301. Lepper C, Partridge TA, Fan CM. An absolute requirement for Pax7-positive satellite cells in acute injury-induced skeletal muscle regeneration. Development 138: 3639 3646, 2011. 302. Leri A, Kajstura J, Anversa P, Frishman WH. Myocardial regeneration and stem cell repair. Curr Probl Cardiol 33: 91153, 2008. 303. Lescaudron L, Peltekian E, Fontaine-Perus J, Paulin D, Zampieri M, Garcia L, Parrish E. Blood borne macrophages are essential for the triggering of muscle regeneration following muscle transplant. Neuromuscul Disord 9: 72 80, 1999. 304. Leshem Y, Gitelman I, Ponzetto C, Halevy O. Preferential binding of Grb2 or phosphatidylinositol 3-kinase to the met receptor has opposite effects on HGF-induced myoblast proliferation. Exp Cell Res 274: 288 298, 2002. 305. Leshem Y, Halevy O. Phosphorylation of pRb is required for HGF-induced muscle cell proliferation and is p27kip1-dependent. J Cell Physiol 191: 173182, 2002. 306. Leshem Y, Spicer DB, Gal-Levi R, Halevy O. Hepatocyte growth factor (HGF) inhibits skeletal muscle cell differentiation: a role for the bHLH protein twist and the cdk inhibitor p27. J Cell Physiol 184: 101109, 2000. 307. Lewis MI, Horvitz GD, Clemmons DR, Fournier M. Role of IGF-I and IGF-binding proteins within diaphragm muscle in modulating the effects of nandrolone. Am J Physiol Endocrinol Metab 282: E483E490, 2002. 308. Li L, Heller-Harrison R, Czech M, Olson EN. Cyclic AMP-dependent protein kinase inhibits the activity of myogenic helix-loop-helix proteins. Mol Cell Biol 12: 4478 4485, 1992. 309. Li L, Zhou J, James G, Heller-Harrison R, Czech MP, Olson EN. FGF inactivates myogenic helix-loop-helix proteins through phosphorylation of a conserved protein kinase C site in their DNA-binding domains. Cell 71: 11811194, 1992. 310. Li Y, Foster W, Deasy BM, Chan Y, Prisk V, Tang Y, Cummins J, Huard J. Transforming growth factor-beta1 induces the differentiation of myogenic cells into brotic cells in injured skeletal muscle: a key event in muscle brogenesis. Am J Pathol 164: 1007 1019, 2004. 311. Lindstrom M, Pedrosa-Domellof F, Thornell LE. Satellite cell heterogeneity with respect to expression of MyoD, myogenin, Dlk1 and c-Met in human skeletal muscle: application to a cohort of power lifters and sedentary men. Histochem Cell Biol 134: 371385, 2010. 312. Lipton BH, Konigsberg IR. A ne-structural analysis of the fusion of myogenic cells. J Cell Biol 53: 348 364, 1972. 313. Liu H, Fergusson MM, Castilho RM, Liu J, Cao L, Chen J, Malide D, Rovira II, Schimel D, Kuo CJ, Gutkind JS, Hwang PM, Finkel T. Augmented Wnt signaling in a mammalian model of accelerated aging. Science 317: 803 806, 2007. 314. Liu J, Aoki M, Illa I, Wu C, Fardeau M, Angelini C, Serrano C, Urtizberea JA, Hentati F, Hamida MB, Bohlega S, Culper EJ, Amato AA, Bossie K, Oeltjen J, Bejaoui K, McKenna-Yasek D, Hosler BA, Schurr E, Arahata K, de Jong PJ, Brown RH Jr. Dysferlin, a novel skeletal muscle gene, is mutated in Miyoshi myopathy and limb girdle muscular dystrophy. Nat Genet 20: 3136, 1998. 315. Liu JP, Baker J, Perkins AS, Robertson EJ, Efstratiadis A. Mice carrying null mutations of the genes encoding insulin-like growth factor I (Igf-1) and type 1 IGF receptor (Igf1r). Cell 75: 59 72, 1993. 316. Liu Y, Gao L, Zuba-Surma EK, Peng X, Kucia M, Ratajczak MZ, Wang W, Enzmann V, Kaplan HJ, Dean DC. Identication of small Sca-1(), Lin(), and CD45() multipotential cells in the neonatal murine retina. Exp Hematol 37: 1096 1107, 2009. 317. Loh KC, Leong WI, Carlson ME, Oskouian B, Kumar A, Fyrst H, Zhang M, Proia RL, Hoffman EP, Saba JD. Sphingosine-1-phosphate enhances satellite cell activation in dystrophic muscles through a S1PR2/STAT3 signaling pathway. PLoS One 7: e37218, 2012. 318. Lu A, Cummins JH, Pollett JB, Cao B, Sun B, Rudnicki MA, Huard J. Isolation of myogenic progenitor populations from Pax7-decient skeletal muscle based on adhesion characteristics. Gene Ther 15: 1116 1125, 2008. 319. Lu J, McKinsey TA, Zhang CL, Olson EN. Regulation of skeletal myogenesis by association of the MEF2 transcription factor with class II histone deacetylases. Mol Cell 6: 233244, 2000. 320. Luo D, Renault VM, Rando TA. The regulation of Notch signaling in muscle stem cell activation and postnatal myogenesis. Semin Cell Dev Biol 16: 612 622, 2005. 321. Luque E, Pena J, Martin P, Jimena I, Vaamonde R. Capillary supply during development of individual regenerating muscle bers. Anat Histol Embryol 24: 87 89, 1995. 322. Ma DK, Bonaguidi MA, Ming GL, Song H. Adult neural stem cells in the mammalian central nervous system. Cell Res 19: 672 682, 2009. 323. Machida S, Booth FW. Insulin-like growth factor 1 and muscle growth: implication for satellite cell proliferation. Proc Nutr Soc 63: 337340, 2004. 324. Mackey AL, Kjaer M, Chari N, Henriksson J, Bojsen-Moller J, Holm L, Kadi F. Assessment of satellite cell number and activity status in human skeletal muscle biopsies. Muscle Nerve 40: 455 465, 2009. 325. Mal A, Sturniolo M, Schiltz RL, Ghosh MK, Harter ML. A role for histone deacetylase HDAC1 in modulating the transcriptional activity of MyoD: inhibition of the myogenic program. EMBO J 20: 1739 1753, 2001. 326. Mansouri A, Stoykova A, Torres M, Gruss P. Dysgenesis of cephalic neural crest derivatives in Pax7/ mutant mice. Development 122: 831 838, 1996. 327. Matheny RW Jr, Nindl BC, Adamo ML. Minireview: Mechano-growth factor: a putative product of IGF-I gene expression involved in tissue repair and regeneration. Endocrinology 151: 865 875, 2010. 328. Matsuda R, Nishikawa A, Tanaka H. Visualization of dystrophic muscle bers in mdx mouse by vital staining with Evans blue: evidence of apoptosis in dystrophin-decient muscle. J Biochem 118: 959 964, 1995. 329. Mauro A. Satellite cell of skeletal muscle bers. J Biophys Biochem Cytol 9: 493 495, 1961. 330. Mayer U. Integrins: redundant or important players in skeletal muscle? J Biol Chem 278: 1458714590, 2003. 331. McGann CJ, Odelberg SJ, Keating MT. Mammalian myotube dedifferentiation induced by newt regeneration extract. Proc Natl Acad Sci USA 98: 13699 13704, 2001. 332. McGeachie JK, Grounds MD. Initiation and duration of muscle precursor replication after mild and severe injury to skeletal muscle of mice. An autoradiographic study. Cell Tissue Res 248: 125130, 1987. 333. McKay BR, De Lisio M, Johnston AP, OReilly CE, Phillips SM, Tarnopolsky MA, Parise G. Association of interleukin-6 signalling with the muscle stem cell response following muscle-lengthening contractions in humans. PLoS One 4: e6027, 2009. 334. McLoon LK, Wirtschafter J. Activated satellite cells in extraocular muscles of normal adult monkeys and humans. Invest Ophthalmol Vis Sci 44: 19271932, 2003. 335. Meech R, Gomez M, Woolley C, Barro M, Hulin JA, Walcott EC, Delgado J, Makarenkova HP. The homeobox transcription factor Barx2 regulates plasticity of young primary myobers. PLoS One 5: e11612, 2010. 336. Meech R, Gonzalez KN, Barro M, Gromova A, Zhuang L, Hulin JA, Makarenkova HP. Barx2 is expressed in satellite cells and is required for normal muscle growth and regeneration. Stem Cells 30: 253265, 2012.
61

337. Meeson AP, Hawke TJ, Graham S, Jiang N, Elterman J, Hutcheson K, Dimaio JM, Gallardo TD, Garry DJ. Cellular and molecular regulation of skeletal muscle side population cells. Stem Cells 22: 13051320, 2004. 338. Megeney LA, Kablar B, Garrett K, Anderson JE, Rudnicki MA. MyoD is required for myogenic stem cell function in adult skeletal muscle. Genes Dev 10: 11731183, 1996. 339. Meignin C, Alvarez-Garcia I, Davis I, Palacios IM. The salvador-warts-hippo pathway is required for epithelial proliferation and axis specication in Drosophila. Curr Biol 17: 18711878, 2007. 340. Menetrey J, Kasemkijwattana C, Day CS, Bosch P, Vogt M, Fu FH, Moreland MS, Huard J. Growth factors improve muscle healing in vivo. J Bone Joint Surg Br 82: 131137, 2000. 341. Merly F, Lescaudron L, Rouaud T, Crossin F, Gardahaut MF. Macrophages enhance muscle satellite cell proliferation and delay their differentiation. Muscle Nerve 22: 724 732, 1999. 342. Miller KJ, Thaloor D, Matteson S, Pavlath GK. Hepatocyte growth factor affects satellite cell activation and differentiation in regenerating skeletal muscle. Am J Physiol Cell Physiol 278: C174 C181, 2000. 343. Minasi MG, Riminucci M, De Angelis L, Borello U, Berarducci B, Innocenzi A, Caprioli A, Sirabella D, Baiocchi M, De Maria R, Boratto R, Jaffredo T, Broccoli V, Bianco P, Cossu G. The meso-angioblast: a multipotent, self-renewing cell that originates from the dorsal aorta and differentiates into most mesodermal tissues. Development 129: 27732783, 2002. 344. Minetti C, Sotgia F, Bruno C, Scartezzini P, Broda P, Bado M, Masetti E, Mazzocco M, Egeo A, Donati MA, Volonte D, Galbiati F, Cordone G, Bricarelli FD, Lisanti MP, Zara F. Mutations in the caveolin-3 gene cause autosomal dominant limb-girdle muscular dystrophy. Nat Genet 18: 365368, 1998. 345. Mitchell KJ, Pannerec A, Cadot B, Parlakian A, Besson V, Gomes ER, Marazzi G, Sassoon DA. Identication and characterization of a non-satellite cell muscle resident progenitor during postnatal development. Nat Cell Biol 12: 257266, 2010. 346. Mizuno Y, Chang H, Umeda K, Niwa A, Iwasa T, Awaya T, Fukada SI, Yamamoto H, Yamanaka S, Nakahata T, Heike T. Generation of skeletal muscle stem/progenitor cells from murine induced pluripotent stem cells. FASEB J 2010. 347. Moelling K, Schad K, Bosse M, Zimmermann S, Schweneker M. Regulation of Raf-Akt Cross-talk. J Biol Chem 277: 31099 31106, 2002. 348. Mokalled MH, Johnson AN, Creemers EE, Olson EN. MASTR directs MyoD-dependent satellite cell differentiation during skeletal muscle regeneration. Genes Dev 26: 190 202, 2012. 349. Montarras D, Lindon C, Pinset C, Domeyne P. Cultured myf5 null and myoD null muscle precursor cells display distinct growth defects. Biol Cell 92: 565572, 2000. 350. Montarras D, Morgan J, Collins C, Relaix F, Zaffran S, Cumano A, Partridge T, Buckingham M. Direct isolation of satellite cells for skeletal muscle regeneration. Science 309: 2064 2067, 2005. 351. Moresi V, Pristera A, Scicchitano BM, Molinaro M, Teodori L, Sassoon D, Adamo S, Coletti D. Tumor necrosis factor-alpha inhibition of skeletal muscle regeneration is mediated by a caspase-dependent stem cell response. Stem Cells 26: 9971008, 2008. 352. Morosetti R, Mirabella M, Gliubizzi C, Broccolini A, De Angelis L, Tagliaco E, Sampaolesi M, Gidaro T, Papacci M, Roncaglia E, Rutella S, Ferrari S, Tonali PA, Ricci E, Cossu G. MyoD expression restores defective myogenic differentiation of human mesoangioblasts from inclusion-body myositis muscle. Proc Natl Acad Sci USA 103: 1699517000, 2006. 353. Morrison JI, Loof S, He P, Simon A. Salamander limb regeneration involves the activation of a multipotent skeletal muscle satellite cell population. J Cell Biol 172: 433 440, 2006. 354. Morrison SJ, Kimble J. Asymmetric and symmetric stem-cell divisions in development and cancer. Nature 441: 1068 1074, 2006. 355. Moss FP, Leblond CP. Nature of dividing nuclei in skeletal muscle of growing rats. J Cell Biol 44: 459 462, 1970. 356. Mourikis P, Sambasivan R, Castel D, Rocheteau P, Bizzarro V, Tajbakhsh S. A critical requirement for notch signaling in maintenance of the quiescent skeletal muscle stem cell state. Stem Cells 30: 243252, 2012. 357. Mourkioti F, Rosenthal N. IGF-1, inammation and stem cells: interactions during muscle regeneration. Trends Immunol 26: 535542, 2005. 358. Mousavi K, Jasmin BJ. BDNF is expressed in skeletal muscle satellite cells and inhibits myogenic differentiation. J Neurosci 26: 5739 5749, 2006. 359. Mu X, Peng H, Pan H, Huard J, Li Y. Study of muscle cell dedifferentiation after skeletal muscle injury of mice with a Cre-Lox system. PLoS One 6: e16699, 2011. 360. Mulvaney DR, Marple DN, Merkel RA. Proliferation of skeletal muscle satellite cells after castration and administration of testosterone propionate. Proc Soc Exp Biol Med 188: 40 45, 1988. 361. Murphy MM, Lawson JA, Mathew SJ, Hutcheson DA, Kardon G. Satellite cells, connective tissue broblasts and their interactions are crucial for muscle regeneration. Development 138: 36253637, 2011. 362. Murre C, McCaw PS, Baltimore D. A new DNA binding and dimerization motif in immunoglobulin enhancer binding, daughterless, MyoD, and myc proteins. Cell 56: 777783, 1989. 363. Murre C, McCaw PS, Vaessin H, Caudy M, Jan LY, Jan YN, Cabrera CV, Buskin JN, Hauschka SD, Lassar AB. Interactions between heterologous helix-loop-helix proteins generate complexes that bind specically to a common DNA sequence. Cell 58: 537544, 1989. 364. Musaro A, Barberi L. Isolation and culture of mouse satellite cells. Methods Mol Biol 633: 101111, 2010. 365. Musaro A, McCullagh K, Paul A, Houghton L, Dobrowolny G, Molinaro M, Barton ER, Sweeney HL, Rosenthal N. Localized Igf-1 transgene expression sustains hypertrophy and regeneration in senescent skeletal muscle. Nat Genet 27: 195200, 2001. 366. Musaro A, McCullagh KJ, Naya FJ, Olson EN, Rosenthal N. IGF-1 induces skeletal myocyte hypertrophy through calcineurin in association with GATA-2 and NF-ATc1. Nature 400: 581585, 1999. 367. Musaro A, Rosenthal N. Maturation of the myogenic program is induced by postmitotic expression of insulin-like growth factor I. Mol Cell Biol 19: 31153124, 1999. 368. Muskiewicz KR, Frank NY, Flint AF, Gussoni E. Myogenic potential of muscle side and main population cells after intravenous injection into sub-lethally irradiated mdx mice. J Histochem Cytochem 53: 861 873, 2005. 369. Nagata Y, Kobayashi H, Umeda M, Ohta N, Kawashima S, Zammit PS, Matsuda R. Sphingomyelin levels in the plasma membrane correlate with the activation state of muscle satellite cells. J Histochem Cytochem 54: 375384, 2006. 370. Nagata Y, Partridge TA, Matsuda R, Zammit PS. Entry of muscle satellite cells into the cell cycle requires sphingolipid signaling. J Cell Biol 174: 245253, 2006. 371. Nakagawa M, Koyanagi M, Tanabe K, Takahashi K, Ichisaka T, Aoi T, Okita K, Mochiduki Y, Takizawa N, Yamanaka S. Generation of induced pluripotent stem cells without Myc from mouse and human broblasts. Nat Biotechnol 26: 101106, 2008. 372. Negroni E, Riederer I, Chaouch S, Belicchi M, Razini P, Di Santo J, Torrente Y, Butler-Browne GS, Mouly V. In vivo myogenic potential of human CD133 musclederived stem cells: a quantitative study. Mol Ther 17: 17711778, 2009. 373. Nelson WJ, Nusse R. Convergence of Wnt, beta-catenin, and cadherin pathways. Science 303: 14831487, 2004. 374. Nguyen HT, Frasch M. MicroRNAs in muscle differentiation: lessons from Drosophila and beyond. Curr Opin Genet Dev 16: 533539, 2006. 375. Nguyen HX, Tidball JG. Interactions between neutrophils and macrophages promote macrophage killing of rat muscle cells in vitro. J Physiol 547: 125132, 2003. 376. Nicolas N, Marazzi G, Kelley K, Sassoon D. Embryonic deregulation of muscle stress signaling pathways leads to altered postnatal stem cell behavior and a failure in postnatal muscle growth. Dev Biol 281: 171183, 2005. 377. Nishimura T, Nakamura K, Kishioka Y, Kato-Mori Y, Wakamatsu J, Hattori A. Inhibition of matrix metalloproteinases suppresses the migration of skeletal muscle cells. J Muscle Res Cell Motil 29: 37 44, 2008. 378. Novitch BG, Mulligan GJ, Jacks T, Lassar AB. Skeletal muscle cells lacking the retinoblastoma protein display defects in muscle gene expression and accumulate in S and G2 phases of the cell cycle. J Cell Biol 135: 441 456, 1996.
62

379. Odelberg SJ, Kollhoff A, Keating MT. Dedifferentiation of mammalian myotubes induced by msx1. Cell 103: 1099 1109, 2000. 380. Ohlstein B, Kai T, Decotto E, Spradling A. The stem cell niche: theme and variations. Curr Opin Cell Biol 16: 693 699, 2004. 381. Ohnishi T, Daikuhara Y. Hepatocyte growth factor/scatter factor in development, inammation and carcinogenesis: its expression and role in oral tissues. Arch Oral Biol 48: 797 804, 2003. 382. Ojima K, Uezumi A, Miyoshi H, Masuda S, Morita Y, Fukase A, Hattori A, Nakauchi H, Miyagoe-Suzuki Y, Takeda S. Mac-1(low) early myeloid cells in the bone marrowderived SP fraction migrate into injured skeletal muscle and participate in muscle regeneration. Biochem Biophys Res Commun 321: 1050 1061, 2004. 383. Okada S, Nonaka I, Chou SM. Muscle ber type differentiation and satellite cell populations in normally grown and neonatally denervated muscles in the rat. Acta Neuropathol 65: 90 98, 1984. 384. Okita K, Ichisaka T, Yamanaka S. Generation of germline-competent induced pluripotent stem cells. Nature 448: 313317, 2007. 385. Olguin HC, Yang Z, Tapscott SJ, Olwin BB. Reciprocal inhibition between Pax7 and muscle regulatory factors modulates myogenic cell fate determination. J Cell Biol 177: 769 779, 2007. 386. Olwin BB, Rapraeger A. Repression of myogenic differentiation by aFGF, bFGF, and K-FGF is dependent on cellular heparan sulfate. J Cell Biol 118: 631 639, 1992. 387. Ono Y, Boldrin L, Knopp P, Morgan JE, Zammit PS. Muscle satellite cells are a functionally heterogeneous population in both somite-derived and branchiomeric muscles. Dev Biol 337: 29 41, 2010. 388. Ono Y, Masuda S, Nam HS, Benezra R, Miyagoe-Suzuki Y, Takeda S. Slow-dividing satellite cells retain long-term self-renewal ability in adult muscle. J Cell Sci 125: 1309 1317, 2012. 389. Orimo S, Hiyamuta E, Arahata K, Sugita H. Analysis of inammatory cells and complement C3 in bupivacaine-induced myonecrosis. Muscle Nerve 14: 515520, 1991. 390. Ornatsky OI, Cox DM, Tangirala P, Andreucci JJ, Quinn ZA, Wrana JL, Prywes R, Yu YT, McDermott JC. Post-translational control of the MEF2A transcriptional regulatory protein. Nucleic Acids Res 27: 2646 2654, 1999. 391. Otto A, Schmidt C, Luke G, Allen S, Valasek P, Muntoni F, Lawrence-Watt D, Patel K. Canonical Wnt signalling induces satellite-cell proliferation during adult skeletal muscle regeneration. J Cell Sci 121: 2939 2950, 2008. 392. Otto A, Schmidt C, Patel K. Pax3 and Pax7 expression and regulation in the avian embryo. Anat Embryol 211: 293310, 2006. 393. Oustanina S, Hause G, Braun T. Pax7 directs postnatal renewal and propagation of myogenic satellite cells but not their specication. EMBO J 23: 3430 3439, 2004. 394. Pacher P, Beckman JS, Liaudet L. Nitric oxide and peroxynitrite in health and disease. Physiol Rev 87: 315 424, 2007. 395. Pajcini KV, Corbel SY, Sage J, Pomerantz JH, Blau HM. Transient inactivation of Rb and ARF yields regenerative cells from postmitotic mammalian muscle. Cell Stem Cell 7: 198 213, 2010. 396. Palacio J, Galdiz JB, Alvarez FJ, Orozco-Levi M, Lloreta J, Gea J. Procion orange tracer dye technique vs. identication of intrabrillar bronectin in the assessment of sarcolemmal damage. Eur J Clin Invest 32: 443 447, 2002. 397. Paliwal P, Conboy IM. Inhibitors of tyrosine phosphatases and apoptosis reprogram lineage-marked differentiated muscle to myogenic progenitor cells. Chem Biol 18: 11531166, 2011. 398. Pallafacchina G, Francois S, Regnault B, Czarny B, Dive V, Cumano A, Montarras D, Buckingham M. An adult tissue-specic stem cell in its niche: a gene proling analysis of in vivo quiescent and activated muscle satellite cells. Stem Cell Res 4: 7791, 2010. 399. Palumbo R, Sampaolesi M, De Marchis F, Tonlorenzi R, Colombetti S, Mondino A, Cossu G, Bianchi ME. Extracellular HMGB1, a signal of tissue damage, induces mesoangioblast migration and proliferation. J Cell Biol 164: 441 449, 2004. 400. Parise G, McKinnell IW, Rudnicki MA. Muscle satellite cell and atypical myogenic progenitor response following exercise. Muscle Nerve 37: 611 619, 2008. 401. Pasquinelli G, Pacilli A, Alviano F, Foroni L, Ricci F, Valente S, Orrico C, Lanzoni G, Buzzi M, Luigi Tazzari P, Pagliaro P, Stella A, Paolo Bagnara G. Multidistrict human mesenchymal vascular cells: pluripotency and stemness characteristics. Cytotherapy 12: 275287, 2010. 402. Patruno M, Caliaro F, Martinello T, Mascarello F. Expression of the paired box domain Pax7 protein in myogenic cells isolated from the porcine semitendinosus muscle after birth. Tissue Cell 40: 1 6, 2008. 403. Pedersen BK, Febbraio MA. Muscle as an endocrine organ: focus on muscle-derived interleukin-6. Physiol Rev 88: 1379 1406, 2008. 404. Peng H, Huard J. Muscle-derived stem cells for musculoskeletal tissue regeneration and repair. Transpl Immunol 12: 311319, 2004. 405. Penn BH, Bergstrom DA, Dilworth FJ, Bengal E, Tapscott SJ. A MyoD-generated feed-forward circuit temporally patterns gene expression during skeletal muscle differentiation. Genes Dev 18: 2348 2353, 2004. 406. Peppiatt CM, Howarth C, Mobbs P, Attwell D. Bidirectional control of CNS capillary diameter by pericytes. Nature 443: 700 704, 2006. 407. Perez-Ruiz A, Ono Y, Gnocchi VF, Zammit PS. beta-Catenin promotes self-renewal of skeletal-muscle satellite cells. J Cell Sci 121: 13731382, 2008. 408. Petropoulos H, Skerjanc IS. Beta-catenin is essential and sufcient for skeletal myogenesis in P19 cells. J Biol Chem 277: 1539315399, 2002. 409. Philippou A, Halapas A, Maridaki M, Koutsilieris M. Type I insulin-like growth factor receptor signaling in skeletal muscle regeneration and hypertrophy. J Musculoskelet Neuronal Interact 7: 208 218, 2007. 410. Phillips WD, Bennett MR. Elimination of distributed synaptic acetylcholine receptor clusters on developing avian fast-twitch muscle bres accompanies loss of polyneuronal innervation. J Neurocytol 16: 785797, 1987. 411. Pietsch J. The effects of colchicine on regeneration of mouse skeletal muscle. Anat Rec 167172, 1961. 412. Polesello C, Tapon N. Salvador-warts-hippo signaling promotes Drosophila posterior follicle cell maturation downstream of notch. Curr Biol 17: 1864 1870, 2007. 413. Polesskaya A, Seale P, Rudnicki MA. Wnt signaling induces the myogenic specication of resident CD45 adult stem cells during muscle regeneration. Cell 113: 841 852, 2003. 414. Popescu LM, Manole E, Serboiu CS, Manole CG, Suciu LC, Gherghiceanu M, Popescu BO. Identication of telocytes in skeletal muscle interstitium: implication for muscle regeneration. J Cell Mol Med 15: 1379 1392, 2011. 415. Pouget C, Pottin K, Jaffredo T. Sclerotomal origin of vascular smooth muscle cells and pericytes in the embryo. Dev Biol 315: 437 447, 2008. 416. Prior BM, Lloyd PG, Yang HT, Terjung RL. Exercise-induced vascular remodeling. Exerc Sport Sci Rev 31: 26 33, 2003. 417. Prockop DJ. Marrow stromal cells as stem cells for nonhematopoietic tissues. Science 276: 7174, 1997. 418. Przybylski RJ, Blumberg JM. Ultrastructural aspects of myogenesis in the chick. Lab Invest 15: 836 863, 1966. 419. Puri PL, Avantaggiati ML, Balsano C, Sang N, Graessmann A, Giordano A, Levrero M. p300 is required for MyoD-dependent cell cycle arrest and muscle-specic gene transcription. EMBO J 16: 369 383, 1997. 420. Puri PL, Sartorelli V. Regulation of muscle regulatory factors by DNA-binding, interacting proteins, and post-transcriptional modications. J Cell Physiol 185: 155173, 2000. 421. Qu-Petersen Z, Deasy B, Jankowski R, Ikezawa M, Cummins J, Pruchnic R, Mytinger J, Cao B, Gates C, Wernig A, Huard J. Identication of a novel population of muscle stem cells in mice: potential for muscle regeneration. J Cell Biol 157: 851 864, 2002. 422. Qu Z, Balkir L, van Deutekom JC, Robbins PD, Pruchnic R, Huard J. Development of approaches to improve cell survival in myoblast transfer therapy. J Cell Biol 142: 12571267, 1998.
63

423. Quinlan JG, Lyden SP, Cambier DM, Johnson SR, Michaels SE, Denman DL. Radiation inhibition of mdx mouse muscle regeneration: dose and age factors. Muscle Nerve 18: 201206, 1995. 424. Rampalli S, Li L, Mak E, Ge K, Brand M, Tapscott SJ, Dilworth FJ. p38 MAPK signaling regulates recruitment of Ash2L-containing methyltransferase complexes to specic genes during differentiation. Nat Struct Mol Biol 14: 1150 1156, 2007. 425. Rando TA, Blau HM. Primary mouse myoblast purication, characterization, and transplantation for cell-mediated gene therapy. J Cell Biol 125: 12751287, 1994. 426. Rantanen J, Hurme T, Lukka R, Heino J, Kalimo H. Satellite cell proliferation and the expression of myogenin and desmin in regenerating skeletal muscle: evidence for two different populations of satellite cells. Lab Invest 72: 341347, 1995. 427. Rapraeger AC. Syndecan-regulated receptor signaling. J Cell Biol 149: 995998, 2000. 428. Rash JE, Fambrough D. Ultrastructural and electrophysiological correlates of cell coupling and cytoplasmic fusion during myogenesis in vitro. Dev Biol 30: 166 186, 1973. 429. Ratajczak MZ, Majka M, Kucia M, Drukala J, Pietrzkowski Z, Peiper S, JanowskaWieczorek A. Expression of functional CXCR4 by muscle satellite cells and secretion of SDF-1 by muscle-derived broblasts is associated with the presence of both muscle progenitors in bone marrow and hematopoietic stem/progenitor cells in muscles. Stem Cells 21: 363371, 2003. 430. Rawlings JS, Rosler KM, Harrison DA. The JAK/STAT signaling pathway. J Cell Sci 117: 12811283, 2004. 431. Relaix F, Montarras D, Zaffran S, Gayraud-Morel B, Rocancourt D, Tajbakhsh S, Mansouri A, Cumano A, Buckingham M. Pax3 and Pax7 have distinct and overlapping functions in adult muscle progenitor cells. J Cell Biol 172: 91102, 2006. 432. Relaix F, Polimeni M, Rocancourt D, Ponzetto C, Schafer BW, Buckingham M. The transcriptional activator PAX3-FKHR rescues the defects of Pax3 mutant mice but induces a myogenic gain-of-function phenotype with ligand-independent activation of Met signaling in vivo. Genes Dev 17: 2950 2965, 2003. 433. Relaix F, Rocancourt D, Mansouri A, Buckingham M. Divergent functions of murine Pax3 and Pax7 in limb muscle development. Genes Dev 18: 1088 1105, 2004. 434. Relaix F, Rocancourt D, Mansouri A, Buckingham M. A Pax3/Pax7-dependent population of skeletal muscle progenitor cells. Nature 435: 948 953, 2005. 435. Relaix F, Weng X, Marazzi G, Yang E, Copeland N, Jenkins N, Spence SE, Sassoon D. Pw1, a novel zinc nger gene implicated in the myogenic and neuronal lineages. Dev Biol 177: 383396, 1996. 436. Ren H, Yin P, Duan C. IGFBP-5 regulates muscle cell differentiation by binding to IGF-II and switching on the IGF-II auto-regulation loop. J Cell Biol 182: 979 991, 2008. 437. Reznik M. Thymidine-3H uptake by satellite cells of regenerating skeletal muscle. J Cell Biol 40: 568 571, 1969. 438. Riuzzi F, Sorci G, Sagheddu R, Donato R. HMGB1-RAGE regulates muscle satellite cell homeostasis through p38-MAPK- and myogenin-dependent repression of Pax7 transcription. J Cell Sci 125: 1440 1454, 2012. 439. Rivier F, Alkan O, Flint AF, Muskiewicz K, Allen PD, Leboulch P, Gussoni E. Role of bone marrow cell trafcking in replenishing skeletal muscle SP and MP cell populations. J Cell Sci 117: 1979 1988, 2004. 440. Robertson TA, Maley MA, Grounds MD, Papadimitriou JM. The role of macrophages in skeletal muscle regeneration with particular reference to chemotaxis. Exp Cell Res 207: 321331, 1993. 441. Rodeheffer MS, Birsoy K, Friedman JM. Identication of white adipocyte progenitor cells in vivo. Cell 135: 240 249, 2008. 442. Rodrigues Ade C, Schmalbruch H. Satellite cells and myonuclei in long-term denervated rat muscles. Anat Rec 243: 430 437, 1995. 443. Rosania GR, Chang YT, Perez O, Sutherlin D, Dong H, Lockhart DJ, Schultz PG. Myoseverin, a microtubule-binding molecule with novel cellular effects. Nature Biotechnol 18: 304 308, 2000. 444. Rosant C, Nagel MD, Perot C. Aging affects passive stiffness and spindle function of the rat soleus muscle. Exp Gerontol 42: 301308, 2007. 445. Rosen GD, Sanes JR, LaChance R, Cunningham JM, Roman J, Dean DC. Roles for the integrin VLA-4 and its counter receptor VCAM-1 in myogenesis. Cell 69: 11071119, 1992. 446. Rosenblatt JD, Lunt AI, Parry DJ, Partridge TA. Culturing satellite cells from living single muscle ber explants. In Vitro Cell Dev Biol Anim 31: 773779, 1995. 447. Rosu-Myles M, Stewart E, Trowbridge J, Ito CY, Zandstra P, Bhatia M. A unique population of bone marrow cells migrates to skeletal muscle via hepatocyte growth factor/c-met axis. J Cell Sci 118: 4343 4352, 2005. 448. Ruberti F, Capsoni S, Comparini A, Di Daniel E, Franzot J, Gononi S, Rossi G, Berardi N, Cattaneo A. Phenotypic knockout of nerve growth factor in adult transgenic mice reveals severe decits in basal forebrain cholinergic neurons, cell death in the spleen, and skeletal muscle dystrophy. J Neurosci 20: 2589 2601, 2000. 449. Rubinstein I, Abassi Z, Coleman R, Milman F, Winaver J, Better OS. Involvement of nitric oxide system in experimental muscle crush injury. J Clin Invest 101: 13251333, 1998. 450. Rudnicki MA, Le Grand F, McKinnell I, Kuang S. The molecular regulation of muscle stem cell function. Cold Spring Harb Symp Quant Biol 73: 323331, 2008. 451. Ryan NA, Zwetsloot KA, Westerkamp LM, Hickner RC, Pofahl WE, Gavin TP. Lower skeletal muscle capillarization and VEGF expression in aged vs. young men. J Appl Physiol 100: 178 185, 2006. 452. Sabourin LA, Girgis-Gabardo A, Seale P, Asakura A, Rudnicki MA. Reduced differentiation potential of primary MyoD/ myogenic cells derived from adult skeletal muscle. J Cell Biol 144: 631 643, 1999. 453. Sabourin LA, Rudnicki MA. The molecular regulation of myogenesis. Clin Genet 57: 16 25, 2000. 454. Sacco A, Doyonnas R, Kraft P, Vitorovic S, Blau HM. Self-renewal and expansion of single transplanted muscle stem cells. Nature 456: 502506, 2008. 455. Sakurai H, Okawa Y, Inami Y, Nishio N, Isobe K. Paraxial mesodermal progenitors derived from mouse embryonic stem cells contribute to muscle regeneration via differentiation into muscle satellite cells. Stem Cells 26: 18651873, 2008. 456. Sambasivan R, Gayraud-Morel B, Dumas G, Cimper C, Paisant S, Kelly RG, Tajbakhsh S. Distinct regulatory cascades govern extraocular and pharyngeal arch muscle progenitor cell fates. Dev Cell 16: 810 821, 2009. 457. Sambasivan R, Yao R, Kissenpfennig A, Van Wittenberghe L, Paldi A, Gayraud-Morel B, Guenou H, Malissen B, Tajbakhsh S, Galy A. Pax7-expressing satellite cells are indispensable for adult skeletal muscle regeneration. Development 138: 36473656, 2011. 458. Sampaolesi M, Torrente Y, Innocenzi A, Tonlorenzi R, DAntona G, Pellegrino MA, Barresi R, Bresolin N, De Angelis MG, Campbell KP, Bottinelli R, Cossu G. Cell therapy of alpha-sarcoglycan null dystrophic mice through intra-arterial delivery of mesoangioblasts. Science 301: 487 492, 2003. 459. Sanes JR. The basement membrane/basal lamina of skeletal muscle. J Biol Chem 278: 1260112604, 2003. 460. Santa Maria L, Rojas CV, Minguell JJ. Signals from damaged but not undamaged skeletal muscle induce myogenic differentiation of rat bone-marrow-derived mesenchymal stem cells. Exp Cell Res 300: 418 426, 2004. 461. Sassoli C, Formigli L, Bini F, Tani A, Squecco R, Battistini C, Zecchi-Orlandini S, Francini F, Meacci E. Effects of S1P on skeletal muscle repair/regeneration during eccentric contraction. J Cell Mol Med 15: 2498 2511, 2011. 462. Scaal M, Christ B. Formation and differentiation of the avian dermomyotome. Anat Embryol 208: 411 424, 2004. 463. Scata KA, Bernard DW, Fox J, Swain JL. FGF receptor availability regulates skeletal myogenesis. Exp Cell Res 250: 10 21, 1999. 464. Schienda J, Engleka KA, Jun S, Hansen MS, Epstein JA, Tabin CJ, Kunkel LM, Kardon G. Somitic origin of limb muscle satellite and side population cells. Proc Natl Acad Sci USA 103: 945950, 2006. 465. Schmalbruch H. The morphology of regeneration of skeletal muscles in the rat. Tissue Cell 8: 673 692, 1976.
64

466. Schmalbruch H, Hellhammer U. The number of nuclei in adult rat muscles with special reference to satellite cells. Anat Rec 189: 169 175, 1977. 467. Schmalbruch H, Lewis DM. Dynamics of nuclei of muscle bers and connective tissue cells in normal and denervated rat muscles. Muscle Nerve 23: 617 626, 2000. 468. Schultz E. Changes in the satellite cells of growing muscle following denervation. Anat Rec 190: 299 311, 1978. 469. Schultz E. A quantitative study of the satellite cell population in postnatal mouse lumbrical muscle. Anat Rec 180: 589 595, 1974. 470. Schultz E. Satellite cell behavior during skeletal muscle growth and regeneration. Med Sci Sports Exerc 21: S181186, 1989. 471. Schultz E. Satellite cell proliferative compartments in growing skeletal muscles. Dev Biol 175: 84 94, 1996. 472. Schultz E, Gibson MC, Champion T. Satellite cells are mitotically quiescent in mature mouse muscle: an EM and radioautographic study. J Exp Zool 206: 451 456, 1978. 473. Schultz E, Jaryszak DL, Valliere CR. Response of satellite cells to focal skeletal muscle injury. Muscle Nerve 8: 217222, 1985. 474. Schwander M, Leu M, Stumm M, Dorchies OM, Ruegg UT, Schittny J, Muller U. Beta1 integrins regulate myoblast fusion and sarcomere assembly. Dev Cell 4: 673 685, 2003. 475. Sciorati C, Galvez BG, Brunelli S, Tagliaco E, Ferrari S, Cossu G, Clementi E. Ex vivo treatment with nitric oxide increases mesoangioblast therapeutic efcacy in muscular dystrophy. J Cell Sci 119: 5114 5123, 2006. 476. Seale P, Ishibashi J, Holterman C, Rudnicki MA. Muscle satellite cell-specic genes identied by genetic proling of MyoD-decient myogenic cell. Dev Biol 275: 287300, 2004. 477. Seale P, Ishibashi J, Scime A, Rudnicki MA. Pax7 is necessary and sufcient for the myogenic specication of CD45:Sca1 stem cells from injured muscle. PLoS Biol 2: E130, 2004. 478. Seale P, Sabourin LA, Girgis-Gabardo A, Mansouri A, Gruss P, Rudnicki MA. Pax7 is required for the specication of myogenic satellite cells. Cell 102: 777786, 2000. 479. Semsarian C, Wu MJ, Ju YK, Marciniec T, Yeoh T, Allen DG, Harvey RP, Graham RM. Skeletal muscle hypertrophy is mediated by a Ca2-dependent calcineurin signalling pathway. Nature 400: 576 581, 1999. 480. Serrano AL, Baeza-Raja B, Perdiguero E, Jardi M, Munoz-Canoves P. Interleukin-6 is an essential regulator of satellite cell-mediated skeletal muscle hypertrophy. Cell Metab 7: 33 44, 2008. 481. Shaq SA, Gorycki MA, Mauro A. Mitosis during postnatal growth in skeletal and cardiac muscle of the rat. J Anat 103: 135141, 1968. 482. Shea KL, Xiang W, LaPorta VS, Licht JD, Keller C, Basson MA, Brack AS. Sprouty1 regulates reversible quiescence of a self-renewing adult muscle stem cell pool during regeneration. Cell Stem Cell 6: 117129, 2010. 483. Sheehan SM, Allen RE. Skeletal muscle satellite cell proliferation in response to members of the broblast growth factor family and hepatocyte growth factor. J Cell Physiol 181: 499 506, 1999. 484. Sheehan SM, Tatsumi R, Temm-Grove CJ, Allen RE. HGF is an autocrine growth factor for skeletal muscle satellite cells in vitro. Muscle Nerve 23: 239 245, 2000. 485. Shefer G, Wleklinski-Lee M, Yablonka-Reuveni Z. Skeletal muscle satellite cells can spontaneously enter an alternative mesenchymal pathway. J Cell Sci 117: 53935404, 2004. 486. Sherwood RI, Christensen JL, Conboy IM, Conboy MJ, Rando TA, Weissman IL, Wagers AJ. Isolation of adult mouse myogenic progenitors: functional heterogeneity of cells within and engrafting skeletal muscle. Cell 119: 543554, 2004. 487. Sherwood RI, Christensen JL, Weissman IL, Wagers AJ. Determinants of skeletal muscle contributions from circulating cells, bone marrow cells, and hematopoietic stem cells. Stem Cells 22: 12921304, 2004. 488. Shi D, Reinecke H, Murry CE, Torok-Storb B. Myogenic fusion of human bone marrow stromal cells, but not hematopoietic cells. Blood 104: 290 294, 2004. 489. Shinin V, Gayraud-Morel B, Gomes D, Tajbakhsh S. Asymmetric division and cosegregation of template DNA strands in adult muscle satellite cells. Nat Cell Biol 8: 677 687, 2006. 490. Siegel AL, Atchison K, Fisher KE, Davis GE, Cornelison DD. 3D timelapse analysis of muscle satellite cell motility. Stem Cells 27: 25272538, 2009. 491. Simone C, Forcales SV, Hill DA, Imbalzano AN, Latella L, Puri PL. p38 pathway targets SWI-SNF chromatin-remodeling complex to muscle-specic loci. Nat Genet 36: 738 743, 2004. 492. Simons M, Mlodzik M. Planar cell polarity signaling: from y development to human disease. Annu Rev Genet 42: 517540, 2008. 493. Sinha-Hikim I, Artaza J, Woodhouse L, Gonzalez-Cadavid N, Singh AB, Lee MI, Storer TW, Casaburi R, Shen R, Bhasin S. Testosterone-induced increase in muscle size in healthy young men is associated with muscle ber hypertrophy. Am J Physiol Endocrinol Metab 283: E154 E164, 2002. 494. Sinha-Hikim I, Cornford M, Gaytan H, Lee ML, Bhasin S. Effects of testosterone supplementation on skeletal muscle ber hypertrophy and satellite cells in community-dwelling older men. J Clin Endocrinol Metab 91: 3024 3033, 2006. 495. Sinha-Hikim I, Roth SM, Lee MI, Bhasin S. Testosterone-induced muscle hypertrophy is associated with an increase in satellite cell number in healthy, young men. Am J Physiol Endocrinol Metab 285: E197E205, 2003. 496. Sinha-Hikim I, Taylor WE, Gonzalez-Cadavid NF, Zheng W, Bhasin S. Androgen receptor in human skeletal muscle and cultured muscle satellite cells: up-regulation by androgen treatment. J Clin Endocrinol Metab 89: 52455255, 2004. 497. Smith CK 2nd, Janney MJ, Allen RE. Temporal expression of myogenic regulatory genes during activation, proliferation, differentiation of rat skeletal muscle satellite cells. J Cell Physiol 159: 379 385, 1994. 498. Snow MH. An autoradiographic study of satellite cell differentiation into regenerating myotubes following transplantation of muscles in young rats. Cell Tissue Res 186: 535540, 1978. 499. Snow MH. Myogenic cell formation in regenerating rat skeletal muscle injured by mincing. II. An autoradiographic study. Anat Rec 188: 201217, 1977. 500. Snow MH. A quantitative ultrastructural analysis of satellite cells in denervated fast and slow muscles of the mouse. Anat Rec 207: 593 604, 1983. 501. Song WK, Wang W, Foster RF, Bielser DA, Kaufman SJ. H36-alpha 7 is a novel integrin alpha chain that is developmentally regulated during skeletal myogenesis. J Cell Biol 117: 643 657, 1992. 502. Song YH, Li Y, Du J, Mitch WE, Rosenthal N, Delafontaine P. Muscle-specic expression of IGF-1 blocks angiotensin II-induced skeletal muscle wasting. J Clin Invest 115: 451 458, 2005. 503. Sonnet C, Lafuste P, Arnold L, Brigitte M, Poron F, Authier FJ, Chretien F, Gherardi RK, Chazaud B. Human macrophages rescue myoblasts and myotubes from apoptosis through a set of adhesion molecular systems. J Cell Sci 119: 24972507, 2006. 504. Spicer DB, Rhee J, Cheung WL, Lassar AB. Inhibition of myogenic bHLH and MEF2 transcription factors by the bHLH protein Twist. Science 272: 1476 1480, 1996. 505. Stamler JS, Meissner G. Physiology of nitric oxide in skeletal muscle. Physiol Rev 81: 209 237, 2001. 506. Stark DA, Karvas RM, Siegel AL, Cornelison DD. Eph/ephrin interactions modulate muscle satellite cell motility and patterning. Development 138: 5279 5289, 2011. 507. Starkey JD, Yamamoto M, Yamamoto S, Goldhamer DJ. Skeletal muscle satellite cells are committed to myogenesis and do not spontaneously adopt nonmyogenic fates. J Histochem Cytochem 59: 33 46, 2011. 508. Steinhardt RA, Bi G, Alderton JM. Cell membrane resealing by a vesicular mechanism similar to neurotransmitter release. Science 263: 390 393, 1994. 509. Summer R, Fitzsimmons K, Dwyer D, Murphy J, Fine A. Isolation of an adult mouse lung mesenchymal progenitor cell population. Am J Respir Cell Mol Biol 37: 152159, 2007. 510. Sun D, Martinez CO, Ochoa O, Ruiz-Willhite L, Bonilla JR, Centonze VE, Waite LL, Michalek JE, McManus LM, Shireman PK. Bone marrow-derived cell regulation of skeletal muscle regeneration. FASEB J 23: 382395, 2009.
65

511. Sun H, Li L, Vercherat C, Gulbagci NT, Acharjee S, Li J, Chung TK, Thin TH, Taneja R. Stra13 regulates satellite cell activation by antagonizing Notch signaling. J Cell Biol 177: 647 657, 2007. 512. Suzuki J, Yamazaki Y, Li G, Kaziro Y, Koide H. Involvement of Ras and Ral in chemotactic migration of skeletal myoblasts. Mol Cell Biol 20: 4658 4665, 2000. 513. Suzuki S, Yamanouchi K, Soeta C, Katakai Y, Harada R, Naito K, Tojo H. Skeletal muscle injury induces hepatocyte growth factor expression in spleen. Biochem Biophys Res Commun 292: 709 714, 2002. 514. Takahashi A, Kureishi Y, Yang J, Luo Z, Guo K, Mukhopadhyay D, Ivashchenko Y, Branellec D, Walsh K. Myogenic Akt signaling regulates blood vessel recruitment during myober growth. Mol Cell Biol 22: 4803 4814, 2002. 515. Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, Yamanaka S. Induction of pluripotent stem cells from adult human broblasts by dened factors. Cell 131: 861 872, 2007. 516. Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult broblast cultures by dened factors. Cell 126: 663 676, 2006. 517. Tamaki T, Akatsuka A, Yoshimura S, Roy RR, Edgerton VR. New ber formation in the interstitial spaces of rat skeletal muscle during postnatal growth. J Histochem Cytochem 50: 10971111, 2002. 518. Tanaka KK, Hall JK, Troy AA, Cornelison DD, Majka SM, Olwin BB. Syndecan-4expressing muscle progenitor cells in the SP engraft as satellite cells during muscle regeneration. Cell Stem Cell 4: 217225, 2009. 519. Tang W, Zeve D, Suh JM, Bosnakovski D, Kyba M, Hammer RE, Tallquist MD, Graff JM. White fat progenitor cells reside in the adipose vasculature. Science 322: 583586, 2008. 520. Tatsumi R, Allen RE. Active hepatocyte growth factor is present in skeletal muscle extracellular matrix. Muscle Nerve 30: 654 658, 2004. 521. Tatsumi R, Anderson JE, Nevoret CJ, Halevy O, Allen RE. HGF/SF is present in normal adult skeletal muscle and is capable of activating satellite cells. Dev Biol 194: 114 128, 1998. 522. Tatsumi R, Hattori A, Ikeuchi Y, Anderson JE, Allen RE. Release of hepatocyte growth factor from mechanically stretched skeletal muscle satellite cells and role of pH and nitric oxide. Mol Biol Cell 13: 2909 2918, 2002. 523. Tatsumi R, Liu X, Pulido A, Morales M, Sakata T, Dial S, Hattori A, Ikeuchi Y, Allen RE. Satellite cell activation in stretched skeletal muscle and the role of nitric oxide and hepatocyte growth factor. Am J Physiol Cell Physiol 290: C1487C1494, 2006. 524. Tatsumi R, Sankoda Y, Anderson JE, Sato Y, Mizunoya W, Shimizu N, Suzuki T, Yamada M, Rhoads RP Jr, Ikeuchi Y, Allen RE. Possible implication of satellite cells in regenerative motoneuritogenesis: HGF upregulates neural chemorepellent Sema3A during myogenic differentiation. Am J Physiol Cell Physiol 297: C238 C252, 2009. 525. Tatsumi R, Sheehan SM, Iwasaki H, Hattori A, Allen RE. Mechanical stretch induces activation of skeletal muscle satellite cells in vitro. Exp Cell Res 267: 107114, 2001. 526. Taulli R, Bersani F, Foglizzo V, Linari A, Vigna E, Ladanyi M, Tuschl T, Ponzetto C. The muscle-specic microRNA miR-206 blocks human rhabdomyosarcoma growth in xenotransplanted mice by promoting myogenic differentiation. J Clin Invest 119: 2366 2378, 2009. 527. Taylor-Jones JM, McGehee RE, Rando TA, Lecka-Czernik B, Lipschitz DA, Peterson CA. Activation of an adipogenic program in adult myoblasts with age. Mech Ageing Dev 123: 649 661, 2002. 528. Theise ND. Gastrointestinal stem cells. III. Emergent themes of liver stem cell biology: niche, quiescence, self-renewal, and plasticity. Am J Physiol Gastrointest Liver Physiol 290: G189 G193, 2006. 529. Thompson SH, Boxhorn LK, Kong WY, Allen RE. Trenbolone alters the responsiveness of skeletal muscle satellite cells to broblast growth factor and insulin-like growth factor I. Endocrinology 124: 2110 2117, 1989. 530. Tidball JG. Inammatory cell response to acute muscle injury. Med Sci Sports Exerc 27: 10221032, 1995. 531. Tidball JG, Daniel TL. Myotendinous junctions of tonic muscle cells: structure and loading. Cell Tissue Res 245: 315322, 1986. 532. Tidball JG, Villalta SA. Regulatory interactions between muscle and the immune system during muscle regeneration. Am J Physiol Regul Integr Comp Physiol 2010. 533. Tomiya A, Aizawa T, Nagatomi R, Sensui H, Kokubun S. Myobers express IL-6 after eccentric exercise. Am J Sports Med 32: 503508, 2004. 534. Torrente Y, Belicchi M, Marchesi C, Dantona G, Cogiamanian F, Pisati F, Gavina M, Giordano R, Tonlorenzi R, Fagiolari G, Lamperti C, Porretti L, Lopa R, Sampaolesi M, Vicentini L, Grimoldi N, Tiberio F, Songa V, Baratta P, Prelle A, Forzenigo L, Guglieri M, Pansarasa O, Rinaldi C, Mouly V, Butler-Browne GS, Comi GP, Biondetti P, Moggio M, Gaini SM, Stocchetti N, Priori A, DAngelo MG, Turconi A, Bottinelli R, Cossu G, Rebulla P, Bresolin N. Autologous transplantation of muscle-derived CD133 stem cells in Duchenne muscle patients. Cell Transplant 16: 563577, 2007. 535. Torrente Y, Belicchi M, Sampaolesi M, Pisati F, Meregalli M, DAntona G, Tonlorenzi R, Porretti L, Gavina M, Mamchaoui K, Pellegrino MA, Furling D, Mouly V, ButlerBrowne GS, Bottinelli R, Cossu G, Bresolin N. Human circulating AC133() stem cells restore dystrophin expression and ameliorate function in dystrophic skeletal muscle. J Clin Invest 114: 182195, 2004. 536. Torrente Y, Tremblay JP, Pisati F, Belicchi M, Rossi B, Sironi M, Fortunato F, El Fahime M, DAngelo MG, Caron NJ, Constantin G, Paulin D, Scarlato G, Bresolin N. Intraarterial injection of muscle-derived CD34()Sca-1() stem cells restores dystrophin in mdx mice. J Cell Biol 152: 335348, 2001. 537. Toti P, Villanova M, Vatti R, Schuerfeld K, Stumpo M, Barbagli L, Malandrini A, Costantini M. Nerve growth factor expression in human dystrophic muscles. Muscle Nerve 27: 370 373, 2003. 538. Tsujinaka T, Ebisui C, Fujita J, Kishibuchi M, Morimoto T, Ogawa A, Katsume A, Ohsugi Y, Kominami E, Monden M. Muscle undergoes atrophy in association with increase of lysosomal cathepsin activity in interleukin-6 transgenic mouse. Biochem Biophys Res Commun 207: 168 174, 1995. 539. Tureckova J, Wilson EM, Cappalonga JL, Rotwein P. Insulin-like growth factor-mediated muscle differentiation: collaboration between phosphatidylinositol 3-kinase-Aktsignaling pathways and myogenin. J Biol Chem 276: 39264 39270, 2001. 540. Tzahor E. Heart and craniofacial muscle development: a new developmental theme of distinct myogenic elds. Dev Biol 327: 273279, 2009. 541. Uezumi A, Fukada S, Yamamoto N, Takeda S, Tsuchida K. Mesenchymal progenitors distinct from satellite cells contribute to ectopic fat cell formation in skeletal muscle. Nat Cell Biol 12: 143152, 2010. 542. Ustanina S, Carvajal J, Rigby P, Braun T. The myogenic factor Myf5 supports efcient skeletal muscle regeneration by enabling transient myoblast amplication. Stem Cells 25: 2006 2016, 2007. 543. Valadi H, Ekstrom K, Bossios A, Sjostrand M, Lee JJ, Lotvall JO. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nature Cell Biol 9: 654 659, 2007. 544. Van den Beld AW, de Jong FH, Grobbee DE, Pols HA, Lamberts SW. Measures of bioavailable serum testosterone and estradiol and their relationships with muscle strength, bone density, and body composition in elderly men. J Clin Endocrinol Metab 85: 3276 3282, 2000. 545. Van Rooij E, Quiat D, Johnson BA, Sutherland LB, Qi X, Richardson JA, Kelm RJ Jr, Olson EN. A family of microRNAs encoded by myosin genes governs myosin expression and muscle performance. Dev Cell 17: 662 673, 2009. 546. Van Rooij E, Sutherland LB, Qi X, Richardson JA, Hill J, Olson EN. Control of stressdependent cardiac growth and gene expression by a microRNA. Science 316: 575 579, 2007. 547. Vandenburgh HH, Karlisch P, Shansky J, Feldstein R. Insulin and IGF-I induce pronounced hypertrophy of skeletal myobers in tissue culture. Am J Physiol Cell Physiol 260: C475C484, 1991. 548. Velleman SG, Li X, Coy CS, McFarland DC. The effect of broblast growth factor 2 on the in vitro expression of syndecan-4 and glypican-1 in turkey satellite cells. Poult Sci 87: 1834 1840, 2008. 549. Vertino AM, Taylor-Jones JM, Longo KA, Bearden ED, Lane TF, McGehee RE Jr, MacDougald OA, Peterson CA. Wnt10b deciency promotes coexpression of myogenic and adipogenic programs in myoblasts. Mol Biol Cell 16: 2039 2048, 2005.
66

550. Viguie CA, Lu DX, Huang SK, Rengen H, Carlson BM. Quantitative study of the effects of long-term denervation on the extensor digitorum longus muscle of the rat. Anat Rec 248: 346 354, 1997. 551. Villena J, Brandan E. Dermatan sulfate exerts an enhanced growth factor response on skeletal muscle satellite cell proliferation and migration. J Cell Physiol 198: 169 178, 2004. 552. Volonte D, Liu Y, Galbiati F. The modulation of caveolin-1 expression controls satellite cell activation during muscle repair. FASEB J 19: 237239, 2005. 553. Wakelam MJ. The fusion of myoblasts. Biochem J 228: 112, 1985. 554. Walker BE. An investigation of skeletal muscle regeneration with radioautography. Anat Rec 350, 1960. 555. Walsh K. Coordinate regulation of cell cycle and apoptosis during myogenesis. Prog Cell Cycle Res 3: 5358, 1997. 556. Warren GL, Hulderman T, Jensen N, McKinstry M, Mishra M, Luster MI, Simeonova PP. Physiological role of tumor necrosis factor alpha in traumatic muscle injury. FASEB J 16: 1630 1632, 2002. 557. Watt DJ, Morgan JE, Clifford MA, Partridge TA. The movement of muscle precursor cells between adjacent regenerating muscles in the mouse. Anat Embryol 175: 527 536, 1987. 558. Wehrman TS, von Degenfeld G, Krutzik PO, Nolan GP, Blau HM. Luminescent imaging of beta-galactosidase activity in living subjects using sequential reporter-enzyme luminescence. Nat Methods 3: 295301, 2006. 559. Weinberg RA. The retinoblastoma protein and cell cycle control. Cell 81: 323330, 1995. 560. Wen Y, Bi P, Liu W, Asakura A, Keller C, Kuang S. Constitutive notch activation upregulates pax7 and promotes the self-renewal of skeletal muscle satellite cells. Mol Cell Biol 32: 2300 2311, 2012. 561. Weyman CM, Wolfman A. Mitogen-activated protein kinase kinase (MEK) activity is required for inhibition of skeletal muscle differentiation by insulin-like growth factor 1 or broblast growth factor 2. Endocrinology 139: 1794 1800, 1998. 562. Whalen RG, Harris JB, Butler-Browne GS, Sesodia S. Expression of myosin isoforms during notexin-induced regeneration of rat soleus muscles. Dev Biol 141: 2440, 1990. 563. Wheeler EF, Bothwell M. Spatiotemporal patterns of expression of NGF and the low-afnity NGF receptor in rat embryos suggest functional roles in tissue morphogenesis and myogenesis. J Neurosci 12: 930 945, 1992. 564. White JD, Scafdi A, Davies M, McGeachie J, Rudnicki MA, Grounds MD. Myotube formation is delayed but not prevented in MyoD-decient skeletal muscle: studies in regenerating whole muscle grafts of adult mice. J Histochem Cytochem 48: 15311544, 2000. 565. Williams AH, Liu N, van Rooij E, Olson EN. MicroRNA control of muscle development and disease. Curr Opin Cell Biol 21: 461 469, 2009. 566. Wilson A, Trumpp A. Bone-marrow haematopoietic-stem-cell niches. Nat Rev Immunol 6: 93106, 2006. 567. Wokke JH, Van den Oord CJ, Leppink GJ, Jennekens FG. Perisynaptic satellite cells in human external intercostal muscle: a quantitative and qualitative study. Anat Rec 223: 174 180, 1989. 568. Woodley DT, Rao CN, Hassell JR, Liotta LA, Martin GR, Kleinman HK. Interactions of basement membrane components. Biochim Biophys Acta 761: 278 283, 1983. 569. Wozniak AC, Anderson JE. Nitric oxide-dependence of satellite stem cell activation and quiescence on normal skeletal muscle bers. Dev Dyn 236: 240 250, 2007. 570. Wu Z, Luby-Phelps K, Bugde A, Molyneux LA, Denard B, Li WH, Suel GM, Garbers DL. Capacity for stochastic self-renewal and differentiation in mammalian spermatogonial stem cells. J Cell Biol 187: 513524, 2009. 571. Wu Z, Woodring PJ, Bhakta KS, Tamura K, Wen F, Feramisco JR, Karin M, Wang JY, Puri PL. p38 and extracellular signal-regulated kinases regulate the myogenic program at multiple steps. Mol Cell Biol 20: 39513964, 2000. 572. Yablonka-Reuveni Z, Rivera AJ. Temporal expression of regulatory and structural muscle proteins during myogenesis of satellite cells on isolated adult rat bers. Dev Biol 164: 588 603, 1994. 573. Yablonka-Reuveni Z, Rudnicki MA, Rivera AJ, Primig M, Anderson JE, Natanson P. The transition from proliferation to differentiation is delayed in satellite cells from mice lacking MyoD. Dev Biol 210: 440 455, 1999. 574. Yaffe D. Cellular aspects of muscle differentiation in vitro. Curr Top Dev Biol 4: 3777, 1969. 575. Yamada M, Sankoda Y, Tatsumi R, Mizunoya W, Ikeuchi Y, Sunagawa K, Allen RE. Matrix metalloproteinase-2 mediates stretch-induced activation of skeletal muscle satellite cells in a nitric oxide-dependent manner. Int J Biochem Cell Biol 40: 2183 2191, 2008. 576. Yamada M, Tatsumi R, Kikuiri T, Okamoto S, Nonoshita S, Mizunoya W, Ikeuchi Y, Shimokawa H, Sunagawa K, Allen RE. Matrix metalloproteinases are involved in mechanical stretch-induced activation of skeletal muscle satellite cells. Muscle Nerve 34: 313319, 2006. 577. Yan D, Dong Xda E, Chen X, Wang L, Lu C, Wang J, Qu J, Tu L. MicroRNA-1/206 targets c-Met and inhibits rhabdomyosarcoma development. J Biol Chem 284: 29596 29604, 2009. 578. Yang SY, Goldspink G. Different roles of the IGF-I Ec peptide (MGF) and mature IGF-I in myoblast proliferation and differentiation. FEBS Lett 522: 156 160, 2002. 579. Yeow K, Phillips B, Dani C, Cabane C, Amri EZ, Derijard B. Inhibition of myogenesis enables adipogenic trans-differentiation in the C2C12 myogenic cell line. FEBS Lett 506: 157162, 2001. 580. Yildiz O. Vascular smooth muscle and endothelial functions in aging. Ann NY Acad Sci 1100: 353360, 2007. 581. Yoshimoto M, Chang H, Shiota M, Kobayashi H, Umeda K, Kawakami A, Heike T, Nakahata T. Two different roles of puried CD45c-KitSca-1Lin cells after transplantation in muscles. Stem Cells 23: 610 618, 2005. 582. Yu J, Vodyanik MA, Smuga-Otto K, Antosiewicz-Bourget J, Frane JL, Tian S, Nie J, Jonsdottir GA, Ruotti V, Stewart R, Slukvin II, Thomson JA. Induced pluripotent stem cell lines derived from human somatic cells. Science 318: 19171920, 2007. 583. Yu Y, Ge N, Xie M, Sun W, Burlingame S, Pass AK, Nuchtern JG, Zhang D, Fu S, Schneider MD, Fan J, Yang J. Phosphorylation of Thr-178 and Thr-184 in the TAK1 T-loop is required for interleukin (IL)-1-mediated optimal NFkappaB and AP-1 activation as well as IL-6 gene expression. J Biol Chem 283: 2449724505, 2008. 584. Zammit PS, Golding JP, Nagata Y, Hudon V, Partridge TA, Beauchamp JR. Muscle satellite cells adopt divergent fates: a mechanism for self-renewal? J Cell Biol 166: 347357, 2004. 585. Zammit PS, Heslop L, Hudon V, Rosenblatt JD, Tajbakhsh S, Buckingham ME, Beauchamp JR, Partridge TA. Kinetics of myoblast proliferation show that resident satellite cells are competent to fully regenerate skeletal muscle bers. Exp Cell Res 281: 39 49, 2002. 586. Zarnegar R, Michalopoulos GK. The many faces of hepatocyte growth factor: from hepatopoiesis to hematopoiesis. J Cell Biol 129: 11771180, 1995. 587. Zhang JM, Wei Q, Zhao X, Paterson BM. Coupling of the cell cycle and myogenesis through the cyclin D1-dependent interaction of MyoD with cdk4. EMBO J 18: 926 933, 1999. 588. Zhang P, Wong C, Liu D, Finegold M, Harper JW, Elledge SJ. p21(CIP1) and p57(KIP2) control muscle differentiation at the myogenin step. Genes Dev 13: 213224, 1999. 589. Zhao M, New L, Kravchenko VV, Kato Y, Gram H, di Padova F, Olson EN, Ulevitch RJ, Han J. Regulation of the MEF2 family of transcription factors by p38. Mol Cell Biol 19: 2130, 1999. 590. Zhong W, Chia W. Neurogenesis and asymmetric cell division. Curr Opin Neurobiol 18: 4 11, 2008.
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Physiol Rev 93: 23 67, 2013 doi:10.1152/physrev.00043.

SATELLITE CELLS AND THE MUSCLE STEM CELL NICHE

I. INTRODUCTION: SATELLITE CELLS AS ADULT STEM CELLS IN MUSCLE

A. A Brief History of Satellite Cells

0031-9333/13 Copyright 2013 the American Physiological Society

B. Identication and Isolation of Satellite Cells

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SATELLITE CELLS AND THE MUSCLE STEM CELL NICHE

MyoD Pax7 Pax3

Satellite Stem Cell Asymmetric division Basal lamina Myonuclei

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C. Heterogeneity of Satellite Cell Population

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E. Origins of Adult Satellite Cells

D. Variance of Satellite Cells Number and Location

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II. FUNCTIONS OF SATELLITE CELLS IN MUSCLE REGENERATION

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A. An Introduction to Muscle Regeneration

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B. Satellite Cell Activation and Differentiation

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C. Satellite Cell Self-Renewal

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D. Contributions and Therapeutic Potential of Nonsatellite Cells in Trauma-Induced Muscle Regeneration

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SATELLITE CELLS AND THE MUSCLE STEM CELL NICHE

E. Satellite Cells in Perinatal/Juvenile Muscle Growth

III. ANATOMIC AND FUNCTIONAL DIMENSIONS OF THE SATELLITE CELL NICHE

A. The Immediate Niche

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YIN, PRICE, AND RUDNICKI

Motor neurons (axons)

Connective tissue Capillaries Adipocytes

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B. The Microenvironment Beyond the Immediate Niche

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IV. CONCLUDING REMARKS AND PERSPECTIVES

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YIN, PRICE, AND RUDNICKI

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SATELLITE CELLS AND THE MUSCLE STEM CELL NICHE