Control of The Size of The Human Muscle Mass. 2004

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10.1146/annurev.physiol.66.052102.134444
Annu. Rev. Physiol. 2004. 66:799828

doi: 10.1146/annurev.physiol.66.052102.134444
c 2004 by Annual Reviews. All rights reserved
Copyright
First published online as a Review in Advance on September 22, 2003
CONTROL OF THE SIZE OF THE

HUMAN MUSCLE MASS
Michael J. Rennie,1,4 Henning Wackerhage,1
Espen E. Spangenburg,3 and Frank W. Booth2
1
Division of Molecular Physiology, School of Life Sciences, University of Dundee,

Dundee, DD1 4HN, Scotland, United Kingdom; 2Department of Biomedical Sciences,
Medical Pharmacology and Physiology, and Dalton Cardiovascular Center, University
of Missouri-Columbia, Columbia, Missouri 65211; current addresses: 3Exercise Biology
Program, University of California, Davis, California 95616; 4University of Nottingham,
Graduate Entry Medical School, City Hospital, Derby, DE22 3NE, United Kingdom;
email: michael.rennie@nottingham.ac.uk; h.wackerhage@dundee.ac.uk;
spangenburge@missouri.edu (current: eespangenburg@ucdavis.edu),
boothf@missouri.edu
Key Words adaptation, physical activity, nutrition, hypertrophy, protein turnover

Abstract This review is divided into two parts, the first dealing with the cell and
molecular biology of muscle in terms of growth and wasting and the second being an
account of current knowledge of physiological mechanisms involved in the alteration
of size of the human muscle mass. Wherever possible, attempts have been made to
interrelate the information in each part and to provide the most likely explanation
for phenomena that are currently only partially understood. The review should be of
interest to cell and molecular biologists who know little of human muscle physiology
and to physicians, physiotherapists, and kinesiologists who may be familiar with the
gross behavior of human muscle but wish to understand more about the underlying
mechanisms of change.
INTRODUCTION
Great strides have been made recently in understanding the regulation of the
size of the muscle mass in humans. Dual X-ray absorptiometry (DEXA) (1, 2)
and magnetic resonance imaging (MRI) (35), together with advances in immunohistochemical muscle fiber typing (6), have allowed the size of the human muscle mass and its components to be defined with previously unparalleled
precision and sensitivity. We are now able to follow accurately small, relatively
slow changes in muscle size during the extended timescales of sarcopenia (7, 8)
and hypertrophy (9). The application of stable isotope tracer technology to the
study of amino acids has markedly increased our knowledge of their transport and
0066-4278/04/0315-0799$14.00
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intermediary metabolism and protein turnover in skeletal muscle (1013), and

positron emission spectroscopy (PET) promises to provide additional information
(14). In parallel, ever more signal transduction pathways involved in the regulation
of muscle growth are being elucidated, and powerful microarray methods enable
identification of genes whose transcription is altered during muscle growth (15).
The explosion of knowledge of the molecular cell biology of skeletal muscle (16,
17) has provided us with concepts, techniques, and reagents with which to probe
the mechanisms underlying the observed changes in muscle mass in response to
altered nutrition and physical activity.1
Hitherto, research on the human muscle mass and muscle growth signaling has
usually been conducted by separate groups of researchers with limited mutual communication. The aim of this article is to review both areas and to show connections
between them. We first discuss recent findings on muscle growth mechanisms; we
then relate these findings to muscle growth in humans.
MUSCLE GROWTH MECHANISMSSIGNAL

TRANSDUCTION AND REGULATION OF
PROTEIN TURNOVER
The specific aim of the first section is to review (a) the signal transduction pathways that sense the muscles environment and respond to various factors within
it, inputting upstream signals to the muscle growth regulation system; (b) the
1
Abbreviations: ADP, adenosine diphosphate; AICAR, 5-aminoimidazole-4-carboxyamide

ribonucleotide; AMP, adenosine monophosphate; AMPK, AMP-dependent protein kinase;
ATP, adenosine triphosphate; 4E-BP1,initiation factor 4E-binding protein 1; CAIN, calcineurin inhibitor; cdk2, cyclin-dependent kinase 2; DEXA, dual X-ray absorptiometry;
eIF2, eukaryotic translation initiation factor 4E; eIF4E, eukaryotic translation initiation
factor 4E; ERK1/2, extracellular signal-regulated kinase 1/2; FAK, focal adhesion kinase;
G1, gap 1 phase of the cell cycle; Gasp-1, growth and differentiation factor-associated serum
protein-1; GDF-8, growth differentiation factor 8/myostatin; GSK3, glycogen synthase
kinase 3; IGF-1, insulin-like growth factor 1 (IGF-1Ea, MGF/IGF-1Eb, and IGF-1Ec are
splice isoforms); JNK, c-Jun N-terminal protein kinase; LIF, leukemia-inhibitory factor;
MEF2, myocyte enhancer factor 2; MGF, mechano-growth factor (synonymous with IGF-1
splice variant IGF-1Eb); MRI, magnetic resonance imaging; mTOR, mammalian target of
rapamycin; MPS, muscle protein synthesis; MPB, muscle protein breakdown; MyoD, myoblast determination factor; NFAT, nuclear factor of activated T-cells; NF-B, nuclear factor
B; p27Kip1, p27 kinase inhibitor protein 1; p38, p38 stress-activated protein kinase; p70
S6k, p70 S6 kinase (S6 is a ribosomal protein); PI3K, phosphatidylinositol 30 -kinase; PET,
positron emission spectroscopy; PKB/AKT, protein kinase B/AKT; PKC, protein kinase
C; PPAR , peroxisome proliferators-activated receptor ; Raptor, mTOR-binding protein;
rhGH, recombinant human growth factor; SHIP-2, SH2-containing inositol polyphosphate
5-phosphatase; SMAD3, human homologue from Drosophila Mad (mothers against decapentplegic) and C. elegans SMA gene; SRE1, serum response element 1; SRF, serum
response factor; TGF-, transforming growth factor-; TNF-, tumor necrosis factor-.
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MUSCLE MASS REGULATION
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transcriptional regulation of myostatin and IGF-1/MGF expression in response

to growth-inducing stimuli; and (c) the specific regulation of muscle growth via
regulation of mRNA translation and satellite cell proliferation in response to myostatin, IGF-1/MGF, and other factors. Most of the research has been carried out
in nonhuman species, but the results are likely to be relevant to the observations
made in human muscle.
Sensing of Growth Stimuli and Transcriptional Regulation

Strenuous, growth-inducing muscle activity is associated with changes in one
or more of variables such as passive- and contraction-induced strain, sarcoplasmic calcium concentration, energy demand, intramuscular oxygen concentration,
availability of hormones, growth factors and cytokines, temperature, and cellular
damage (see Figure 1). A sufficient change in any of these variables will result in
the altered activity of signal transduction pathways that regulate the transcription
of genes differentially expressed during muscle growth. Signal transduction pathways shown to be activated in response to various forms of muscle contraction
include those involving AMPK (18), calcineurin (19), ERK1/2 and p38 (20), JNK
(20, 21) NF-B (22), PI3K-PKB/AKT-mTOR (23), and PKC (24). In addition
to these pathways, many of the transcription factors involved in myogenesis (25,
26) continue to be active in adaptive and regenerative processes in adult muscle.
Thus, strenuous, growth-inducing muscle activity and other growth stimuli are
likely to activate a signal transduction network rather than just one or two signal
transduction pathways. Skeletal muscle hypertrophy signaling appears to mirror,
to some extent, that observed during cardiac hypertrophy (27, 28). Here, we focus
on the calcineurin and mechanical-chemical transduction pathways because these
two signaling systems have been shown to be involved in muscle growth signaling.
CALCINEURIN-SIGNALING Ca2+ acts as a regulatory signal during skeletal muscle
hypertrophy (29) and is of particular interest because during contraction there
is a large transient change in cytosolic Ca2+. Calcineurin is a Ca2+-calmodulinactivated protein phosphatase that dephosphorylates the transcription factor NFAT,
enabling its nuclear translocation and DNA binding. The calcineurin pathway has
been linked not only to the regulation of skeletal muscle bulk growth but also to that
of fast-to-slow phenotype conversion (30) and IGF-1 and Ca2+-induced skeletal
muscle hypertrophy, at least in cultured skeletal muscle (31).
However, regulation of nuclear Ca2+ concentrations may occur independently
of transient changes in cytoplasmic Ca2+ calcium concentrations (32). In heart,
Ca2+-mediated cardiac muscle hypertrophy is induced partly through capacitative
Ca2+ entry from the extracellular space by the way of transient receptor potential
(Trp) proteins (33). It is not yet clear to what extent such a situation could occur
in skeletal muscle, in which a much smaller proportion of Ca2+ flux arises via the
sarcoplasmic reticulum. However, it seems likely that Ca2+ may be differentially
routed toward nuclear Ca2+-induced gene transcription, inducing activation of the
Ca2+-sensitive transcription factor (NFAT).
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Figure 1 Overview of the main events during signal transduction and gene regulation
leading to muscle hypertrophy. (1) Via receptor binding and cellular signals, cytokines
and other growth factors are sensed and activate a network of signal transduction pathways that result (2) in the nuclear translocation or activation of transcription factors.
Active, nuclear transcription factors (together with androgens and glucocorticoids via
their soluble receptors) change the expression of the major muscle growth regulators
IGF-1/MGF and myostatin or other muscle genes including ribosomal RNA (rRNA).
Pathways that regulate translation or satellite cell function may also be activated by
mechanisms other than IGF-1/MGF or myostatin (not shown). (3) IGF-1/MGF and
insulin activate the PI3K-PKB/AKT-mTOR pathway, which enhances protein synthesis via increased translational initiation and the synthesis of ribosomal proteins for
ribosome biogenesis. Availability of essential amino acids will activate mTOR signaling, whereas an increased energy demand sensed by AMPK will inhibit mTOR.
(4) IGF-1/MGF, myostatin, and various other factors regulate an increased proliferation and differentiation of satellite cells.
Activation of NFAT transcriptional signaling is mediated by Ca2+-induced increases in the phosphatase activity of calcineurin, which induces translocation of
cytoplasmic NFAT to the nucleus (34). Overexpression of NFAT in transgenic
mice results in cardiac hypertrophy and its knockout prevents it (35, 36). NFAT
overexpression also results in inactivation of glycogen synthase kinase-3, which
mediates the nuclear location of NFAT (37) and possibly induces skeletal myotube
hypertrophy (38).
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With regard to skeletal muscle hypertrophy in animal models, the role of calcineurin remains controversial owing to the use of cyclosporin A, a nonspecific
inhibitor of calcineurin. Inhibition of the calcineurin pathway in vivo with cyclosporin A prevents overload hypertrophy (39). Interestingly, overexpression of
calcineurin in transgenic mice does not induce skeletal muscle hypertrophy (40,
41), which may indicate that skeletal muscle already contains sufficient calcineurin
activity for muscle growth, and thus the addition of a constitutively active calcineurin is redundant (39). This contention is supported by the finding that cyclosporin blocked the growth of plantaris muscle after induced atrophy, which is
noteworthy because the study clearly demonstrated that inhibition of calcineurin
with cyclosporine is dependent upon the appropriate concentration of cyclosporine,
the muscle, and selection of appropriate time points. Current thought suggests that
the hyperactivation of calcineurin alone is not sufficient to induce skeletal muscle hypertrophy but that activation of various upstream or downstream regulators
in conjunction with calcineurin activation may play a significant role in muscle
hypertrophy (40).
MECHANICAL-CHEMICAL TRANSDUCTION Nearly 30 years ago, Goldberg et al.
summarized their work demonstrating that muscular activity appears to the fundamental determinant of muscle mass (42). This concept has been extended and
reinforced by more recent workers: Various sensors of mechanical strain seem to
possess the ability to translate strain into chemical signals that induce the activation
of the skeletal muscle -actin promoter (43). The existence of a mechano-transduction mechanism in skeletal muscle is reinforced by the tensegrity hypothesis
(44), which suggests that a protein framework within the cell maintains its overall
cellular architecture; in response to mechanical forces, cell structural networks
interact with gene and protein signaling networks to allow cytoskeletal proteins
to reposition and renew themselves, permitting the cell to resist deformation from
the applied forces. A possible candidate sensor of the increase in mechanical strain
is focal adhesion kinase (FAK), a protein localized to the sacrolemma (45, 46);
FAK autokinase activity increases during high mechanical loading. In addition,
during mechanical loading of muscles, there are significant increases in both the
total amount of FAK and its tyrosine phosphorylation status (47). The transcription
factor, serum response factor (SRF), is a substrate of FAK, thereby providing a
transcriptional link between membrane, the genome, and subsequent expression
of muscle protein (43). Furthermore, binding of SRF to the serum response element (SRE1) within the chicken skeletal -actin promoter is both necessary and
sufficient for increased transcriptional activity of the skeletal -actin promoter
(46). The putative link between FAK and SRF has been strengthened by results
indicating that SRF-mediated, skeletal -actin promoter activity is dependent upon
activation of 1D-integrin-RhoA signaling and that this activity can be completely
abolished by cotransfection of a dominant-negative FAK, termed FRNK (48).
Different modes of exercise affect extracellular signal-regulated kinase
(ERK1/2) and the 38-kDa stress-activated protein kinase (p38) in an almost
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universal way (20, 49) that seems to be intensity dependent. However, only those
stimuli likely to result in hypertrophy, such as high-frequency electrical stimulation, increased p70S6 kinase and protein kinase B phosphorylation (49). In a study
designed to untangle the effects of concentric and eccentric contractions on the
phosphorylation of ERK1/2 and p38, Wretman and coworkers applied a panoply
of stimuli to isolated rat extensor digitorum longus muscle in vitro: These included
electrically stimulated concentric (shortening) or eccentric (lengthening) contractions or severe passive stretch, and application of antioxidants likely to counteract
reactive oxygen species and induce intracellular acidosis (50). They concluded that
mechanical activity, whether through contraction or stretch, increased the activity
of both ERK1/2 and p38, whereas the ionic changes and increase in reactive oxygen
species and acidosis exhibited after concentric contraction increased phosphorylation only of ERK1/2. This suggested that high mechanical stress was required for
activation of p38. Because stretch per se does not appear to increase MPS in human
muscle (see below), and because changes in ERK1/2 are common to types of exercise that differ markedly in their sequelae (hypertrophy or mitochondrial biogenesis), the likelihood of these signaling molecules being involved in hypertrophy is
lessened.
TRANSCRIPTIONAL REGULATION Most of the cellular signaling pathways discussed above control the location and activity of transcription factors that, in turn, regulate gene transcription. However, for many years the processes of protein turnover
in skeletal muscle were thought to be modulated without requiring extensive gene
expression, which, when it did occur, was considered a relatively sluggish process
with a long latency, possibly up to days. These concepts are wrong: In addition
to any translational regulation, metabolic alterations, such as an increase in the
availability of insulin and glucose (51), or environmental stimuli such as exercise
(52), can result in increases in gene transcription (not restricted to the so-called
early response genes) within 1.53 h, even in adult human skeletal muscle. Thus
the difference in the timescale between the adaptivity of transcription and the processes of protein turnover may be much less than previously thought. Skeletal
muscle growth regulators such as IGF-1 and other regulatory factors, for instance
cytokines, early genes, signal transduction proteins, and myogenic regulatory factors, are transcriptionally regulated in response to contractile overload induced
by synergist ablation in rat. More microarray studies are needed to elucidate the
behavior of genes during muscle growth in animals and humans. For more detailed reviews concerning the role of gene transcription in muscle hypertrophy, see
Carson (53) and Baar et al. (54).
Regulation of the Expression of the Specific Muscle Growth

Factors IGF-1/MGF and Myostatin
Changing the availability of the muscle growth factors IGF-1/MGF and myostatin
appears to be a central regulatory process in adaptive muscle growth. Obviously,
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IGF-1/MGF and myostatin are not directly regulated by stretch, overload, or muscle contraction but by the signal transduction pathways that sense these stimuli and
consequently regulate the availability of these muscle growth factors for receptor
binding. The protein availability depends on transcriptional regulation, translational regulation, splicing, localization, concentration of binding proteins, and
proteolysis. The major regulatory step controlling the availability of IGF-1/MGF
and myostatin in response growth-inducing stimuli appears to be transcriptional
regulation. The transcriptional regulation of these factors involves some of the
muscular signal transduction pathways mentioned above, as well as some developmental pathways and anabolic and catabolic steroid hormones.
REGULATION OF MYOSTATIN EXPRESSION Myostatin [growth/differentiation factor8 (GDF-8)] is a member of the transforming growth factor- (TGF-) family (55).
Depending upon the site of deletion in the myostatin gene, mice expressing the
modified gene in muscle may exhibit either myofiber hyperplasia or hypertrophy
(see 56 for references). Myostatin-null mice were, paradoxically, shown to be more
susceptible than wild-type mice to hindlimb suspension-induced muscle atrophy
(57). Myostatin expression is environmentally modifiable, i.e., it can be decreased
during reloading but, oddly, it is unchanged during suspension-induced muscle atrophy hindlimb suspension (58). The regulation of myostatin expression appears to
depend on major growth pathways. Binding sites for glucocorticoids, androgens,
thyroid hormone receptors, myogenic differentiation factor 1, MEF2, PPAR , and
NF-B, with appropriate positive and negative effects, have all been predicted for
the myostatin promoter region and for glucocorticoids experimentally confirmed
in human muscle (59, 60).
REGULATION OF IGF-1/MGF EXPRESSION In hypertrophying rodent muscle, IGF-1

mRNA rises nearly threefold within two days of functional overload and remains
elevated thereafter (61), a phenomenon also observed in human skeletal muscle
after a single resistance training bout (62). The increase in IGF-1 immunoreactivity was localized mostly within the fibers of rat anterior tibialis muscle four days
after an eccentric-resistance training program that led eventually to hypertrophy
(63), suggesting that pretranscriptional regulation is probably involved somehow
in the exercise-induced increase. IGF-1 superfusion onto muscle in free-moving
rats produces hypertrophy (64), and a similar maneuver rescues immobilized muscle from aging-associated sarcopenia (65), as does IGF-1 overexpression (66).
The increase in IGF-1 and its splice variant MGF (IGF-1Eb) (see below) in skeletal muscle in response to mechanical loading may be regulated transcriptionally
in rat muscle. However, the mechanisms that regulate MGF expression in response to an increase in muscle tension are currently unknown. Skeletal muscle IGF-1 expression increases in response to growth hormone and testosterone
and decreases in response to glucocorticoid hormones, TNF, and interleukin-1
(67).
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Specific Muscle Growth Regulation

Muscle growth stimuli lead to the activation of a signal transduction network and
to a changed availability of the major muscle growth factors IGF-1/MGF and
myostatin. The activated signal transduction pathways and changed growth factor
availability will then regulate the activity of muscle growth executors, which are
the translational or protein synthesis machinery and satellite cells.
TRANSLATIONAL REGULATION The cellular and molecular mechanisms regulating
the translation of mRNA in muscle have been elucidated to a much higher degree
(68) than those regulating protein breakdown, partly because the protein/synthetic
machinery forms a cohesive metabolic unit centered around the ribosome and the
endoplasmic reticulum. There are a number of systems for achieving proteolysis,
such as the ATP and ubiquitin-dependent proteasome (69), the lysosome, at least
two cytoplasmic systems activated by various concentrations of Ca2+ (70), and
even extracellular, lymphocyte-based systems, which act on muscle (71). There is
good evidence that the myofibrillar apparatus is degraded by the proteasome; however, abundant amounts of proteasome mRNA or proteasome do not automatically
produce an increase in proteolysis. For example, there are cases of paradoxical
changes of proteasome activity in muscle in response to starvation and refeeding
(72).
It is relatively easy to demonstrate regulatory changes in the machinery of protein synthesis, which are consonant with an increase in the synthesis of protein, e.g.,
ribosome, aggregation (73), whereas in the case of protein breakdown, changes in
apparent activity of key components of the system may exist with no, or apparently
opposite, changes in the extent of net protein balance. This has made it difficult
to make much progress in understanding the physiological modulation of muscle
protein breakdown, although some knowledge of the involvement of elements of
signaling pathways also involved in regulation of protein breakdown is now being
accumulated (70).
The mechanisms regulating translational regulation during muscle growth are
becoming increasingly clear (see 7476 for more details). IGF-1 is capable of
promoting muscle growth by activating regulators of translational initiation or efficiency via the PI3K-PKB/AKT-mTOR pathway (76, 77). IGF-1 treatment leads
to an increased phosphorylation of PKB/AKT, mTOR, GSK3, and the translational regulators 4E-BP1 and p70S6k. When phosphorylated, 4E-BP1 detaches
from eIF4E (78) (a translational initiation factor that mediates mRNA binding to
the ribosome) and this initiates translation. Phosphorylated p70S6k promotes the
increased translation of those mRNAs with a 50 -tract of pyrimidine (TOP), i.e.,
a series of cytosine or thymine repeats at the 50 gene terminus (79). All known
ribosomal proteins have a TOP sequence, suggesting that mTOR regulates both
ribosomal biogenesis and translation via p70S6k and 4E-BP1, respectively.
The main response of mTOR-dependent signaling occurs with a latency of only
a few hours after growth-stimulating exercise. Hernandez et al. reported increases
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in PI3K and the translational regulator p70S6k occurring after 6 to 24 h and

protein synthesis itself rising 12 to 24 h after resistance exercise in rat muscle (80).
Similar results are available for human muscle (81). Rat muscles stimulated at highfrequency show p70S6k phosphorylation peaking at 3 to 6 h after stimulation, with
some increased phosphorylation still apparent 36 h later in hypertrophying muscles
(54). The delay in the activation of translational pathways and protein synthesis
might be explained by the time necessary for strain-sensing and signaling, possibly
via IGF-1 or MGF synthesis and secretion.
However, a recent paper shows that translational pathways and regulators are
also transiently activated within 510 min after resistance exercise in rats (81a).
This finding is interesting because a changed IGF-1 or MGF availability is unlikely
to occur minutes after the stimulus and thus suggests other connections between
the signal transduction pathways that sense resistance exercise signals and the
translational regulators.
Essential amino acids stimulate protein synthesis via a nutrient-sensitive complex of two proteins, Raptor and mTOR, which, in humans, are expressed more
in skeletal muscle than in other tissues (82, 83). It is likely that the Raptor-mTOR
complex is destabilized and mTOR and the downstream translational regulators
are activated when essential amino acid availability increases. An additional positive regulator, GL, appears to be involved (83). The binding of GL to mTOR
strongly stimulates the kinase activity of mTOR toward S6K1 and 4E-BP1, an
effect reversed by the stable interaction of Raptor with mTOR. The availability of
essential amino acids sensed by this protein complex activates mTOR, as well as
of the translational regulators eIF2, 4E-BP1, and p70S6k (84), which explains the
observed stimulatory effect on protein synthesis.
In contrast, an increased energy demand (reflected by lowered ATP/ADP ratio,
higher AMP, and lower creatine phosphate concentrations) leads to a depression
of protein synthesis (85). A recently discovered interaction between AMPK and
PKB-mTOR signaling in muscle has provided a possible mechanism for this effect: AMPK is activated by AMP and inhibited by ATP and creatine phosphate
and is involved in the regulation of numerous cellular functions such as mitochondrial biogenesis and fuel metabolism (18, 86). Treatment of rats with the
AMPK-activator, AICAR, resulted in a reduction in skeletal muscle protein synthesis. This was accompanied by a decreased activation of PKB-mTOR and its
downstream targets p70S6k and 4E-BP1 (87).
Regulation of Satellite Cell Proliferation and Differentiation

Muscle fibers are permanently differentiated; therefore, they are incapable of mitotic activity to produce additional myonuclei in times of increased protein synthesis and muscle growth (88). Yet, myonuclear number increases during skeletal
muscle hypertrophy, thereby maintaining the myonuclear domain (the amount of
sarcoplasm managed by a single myonucleus) (89). The predominant source of
the additional myonuclei is satellite cells that are localized in indentations in the
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sarcolemma beneath the basal lamina (90). Less commonly, satellite cells may
possibly fuse with each other to form new fibers (hyperplasia) (90).
The requirement of satellite cell activation for muscle hypertrophy was first
demonstrated by a nontransgenic knockout approach in which mild -irradiation
(which damages DNA while leaving other cellular machinery intact) was employed
to block satellite cell proliferation. In response to functional overload, myonuclear
number or muscle size was not increased in irradiated rat muscles (91). Adams
and coworkers found that most of the hypertrophy potentially achievable during
mechanical overload was prevented by similar treatment for four months (92). Thus
it is likely that neither endogenous mesenchymal stem cells nor extramuscular (e.g.,
bone marrow) stem cells contribute much to the stem cell population of overloaded
muscles, and the proliferation and fusion of existing satellite cells are responsible
for the full load-induced increases observed in the muscle mass.
The limited proliferative capacity and the decrease in satellite cell number
during normal aging may be implicated in atrophy and poor regeneration in elderly subjects (93). The number of satellite cells is thought not to be limiting
to hypertrophy in normal human skeletal muscle, even in the elderly, although it
may be in chronic users of anabolic steroids (94). Numerous growth factors have
been shown to increase satellite cell proliferation. Here we focus on the key muscle
growth regulators IGF-1 and myostatin. The effects of IGF-1 on muscle growth are
pleiotrophic, activating satellite cell proliferation by spurring progression through
G1 to S phase, increasing protein synthesis, decreasing protein degradation, and
decreasing apoptosis. The mechanism by which IGF-I signals satellite cells to
proliferate is by a decrease in p27Kip1 protein concentrations via activation of the
phosphatidylinositol 30 -kinase (PI3K)/protein kinase B (PKB/Akt) signaling (95).
As a result, increased p27Kip1 inhibits cyclin-dependent kinase 2 (cdk2), producing
a late G1 arrest in the satellite cell cycle.
Myostatin inhibits both satellite cell proliferation and differentiation.
Myostatin halts the satellite cell cycle by upregulating p21, which inactivates
cyclin-dependent kinase activity so that retinoblastoma protein is particularly dephosphorylated (96). Myostatin also regulates satellite cell differentiation by inhibiting the expression of the myogenic growth factor, MyoD, via Smad 3 signaling
(97). Reciprocally, MyoD upregulates myostatin to control myogenesis during the
G1 phase of the cell cycle (at least in C2C12 myoblasts) (98).
SUMMARY OF REGULATORY MECHANISMS PRODUCING MUSCLE HYPERTROPHY Resistance exercise and most other muscle growth factors lead to the activation
of a signal transduction network that will regulate the expression of the muscle growth factors IGF-1, MGF, and myostatin. The activated signal transduction
pathways and the changed receptor binding of IGF-1, MGF, and myostatin lead
to the activation of translation or protein synthesis and satellite cell proliferation
and differentation, resulting in muscle growth. Blocking any one of these signal
transduction pathways or factors may limit hypertrophy. However, it is incorrect to conclude that the blocking of hypertrophy by a single pathway or factor
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supports the conclusion that only one mechanism accounts for all of the resistance
exercise or strain-induced hypertrophy of skeletal muscle. Likewise, enhancement
of resistance exercise or strain-induced hypertrophy by a single factor should not
be interpreted to mean that this factor alone is the means whereby increased mechanical load signal are transmitted to muscle growth physiologically. Indeed, the
normal physiological response to produce the full potential hypertrophy during
a load-induced growth of skeletal muscle involves the orchestration of multiple,
simultaneous, and temporarily related sequential signals.
ADAPTATION OF THE HUMAN MUSCLE MASS

The second part of this review is focused on observed changes in human MPS and
breakdown and on translational and transcriptional control mechanisms, insofar
as they act in adult human skeletal muscle, with particular reference to the effects
of nutrition and physical activity.
EFFECTS OF NUTRITION ON SKELETAL MUSCLE

PROTEIN MASS
The influences of food on protein metabolism are separable into two parts: those
brought about through an increase in amino acid availability (e.g., the amino acid
activation of translational regulators via the Raptor-mTOR complex discussed
above) and those resulting from increases in the concentration of hormones and
growth factors (principally insulin and growth hormone/IGF-1) produced after
stimulation by dietary secretogogues (e.g., glucose and amino acids).
Effects of Amino Acids

The discovery of the Raptor-mTOR complex and its likely function as an amino
acid sensor (see above) has provided a likely explanation for the known stimulatory
effect of amino acids on translation and protein synthesis. Here we review human
studies in which the authors investigated this relationship in order to provide
information that can be practically applied by those that wish to increase MPS
in athletes, the elderly, or patients in whom muscle atrophy has occurred because
of diminished protein synthesis. We aim to inform about effective amino acid
concentrations, timings of ingestion, and the combination of amino acid feeding
with resistance exercise.
MUSCLE PROTEIN SYNTHESIS An increase in the supply of amino acids to skeletal
muscle (in many in vitro and in vivo models) stimulates the incorporation of
tracer amino acids into protein (74). This effect can be observed independently of
any hormones, although insulin may enhance it (see below). In human subjects,
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intravenous infusion of mixed amino acids doubles the incorporation of stablelabeled tracer amino acid into anterior tibialis muscle without any increase in the
availability of insulin (99). Modulation of MPS via availability of amino acids
appears to show a sigmoidal relationship; rises and falls in amino acid availability
cause rapid changes in MPS in the basal to postprandial range, with a shallower
slope at the upper and lower concentration limits (100, 101). In humans, the upper
limit of amino acid concentrations at which MPS appears to be saturated is about
50% greater than the blood amino acid concentrations normally achieved after a
meal (101). These and other recent data (109112) make a powerful point: The
amount of amino acids necessary to stimulate MPS in the resting state and after
exercise is in fact small (<10 g) compared with the accepted whole-body protein
requirements (>70 g for most men).
In animal muscle, it is easily demonstrated that the branched chain amino acids
(and leucine in particular) stimulate MPS in muscle cells in tissue culture, in
perfused systems, and in intact mice and rats (102106). A similar effect has been
observed in whole human beings; administration of boluses of single essential
amino acids (including threonine, valine, phenylalanine, and leucine) but not nonessential amino acids (such as proline, glycine, serine, and alanine) markedly
stimulated the incorporation of tracer-labeled amino acids into muscle protein
(107). Could such a stimulation could be sustained in vivo? When large amounts of
leucine were infused in human subjects, the intramuscular concentrations of other
amino acids fell (108), presumably owing to stimulation of MPS (together with
the possible inhibition by leucine of MPB). However, synthesis of protein requires
all 20 physiological amino acids, and those that have the highest concentration
ratio between muscle protein and the free pool will have the largest fall under
situations of net anabolism unless transport from the blood occurs sufficiently
quickly. Unfortunately, the capacity for muscles to continue to produce protein
when the supply of all 20 amino acids is limited is not known.
Studies of the latency and duration of the effect of amino acids on MPS suggest
that it takes 30 min for a stimulatory effect to be detected; thereafter the rate of
increase is rapid, and peak rates are obtained within 60 to 90 min (101). Then MPS
falls back to basal levels despite the continued abundant availability of amino acids,
suggesting that the system is full of protein and is no longer responsive to nutritional
stimulation. The extent of the refractory period before restimulation can occur and
the identity of the mechanisms involved in the switch-off are unknown. When the
limb arterio-venous exchange methods are applied, after increases in blood amino
acid concentration, the apparent increase in net amino acid balance (and in modelderived values for MPS) is greater and occurs more quickly than the increase of the
rate of tracer incorporation into muscle protein (13, 109, 110). There may be two
reasons for this: First, amino acids may in fact be inhibiting MPB more rapidly than
simulating MPS (although this seems unlikely given the results of previous studies)
(111); or second, the apparent increase in the net protein balance may be because
the muscle amino acid pool is overfilled. This latter possibility is acknowledged in a
recent paper from the Galveston group (112). In any case, attributing arterio-venous
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concentration difference flow as signifying apparent increase in net protein

balance should be regarded with caution under circumstances in which blood amino
acid concentrations are changing; when arterial blood amino acid concentrations
are rising (as after an oral dose of amino acids), there is a tendency to overestimate
net muscle balance.
The cellular mechanisms involved are likely to be similar in human and animal muscle with stimulation of p70S6k and 4E-BP1 activation by amino acids
(113).
MUSCLE PROTEIN BREAKDOWN Although there is no doubt that increasing amino
acid concentrations by intravenous infusion, meal feeding, or ingestion of free
amino acids increases MPS, inhibitory effects of amino acids on MPB, which are
relatively easy to detect in animal muscles (70, 114), are, in human, beings absent
or at least much less evident than those on MPS (115, 116). Some of the protein
anabolic effects of a protein meal in vivo may possibly be modulated through
the stimulation of insulin, with consequent inhibitory effects on muscle protein
breakdown, but in our experience they are slight. Certainly, in the postexercise
period increased availability of amino acids enhances MPS without having an
effect on protein breakdown (111).
Effects of Insulin
The effects of insulin on MPS in animals and humans may be different in terms of
sensitivity and responsiveness. Much of the work demonstrating a marked stimulatory effect of insulin on MPS has been carried out in immature rodents or in only
partially differentiated muscle cultured in vitro (117119), and it has been much
harder to obtain consistent results demonstrating a coherent pattern of responsiveness in adult (especially human) MPS to insulin. Two main areas of contention
concern the question of the extent of the human MPS response to insulin and the
dose response characteristics of the system.
MUSCLE PROTEIN SYNTHESIS Barrett and coworkers (120, 121) first raised questions about the efficacy of insulin in human muscle when insulin was supplied to
the forearm by close arterial infusion. No effects of insulin could be discerned on
the disappearance of tracer into protein, i.e., protein synthesis, although there was
a dose-dependent inhibition of protein breakdown. In this experimental model,
protein metabolism in the forearm was assessed on the basis of arterio-venous
balance of amino acids and the dilution across the arm of radio-labeled phenylalanine, an amino acid that is not subject to intermediary metabolism in muscle.
However, the mathematical formula used by these workers produced results that
may be underestimates of the rate of synthesis (see 122, 123 for discussion of
this point). Also, Barrett and colleagues did not take muscle biopsies to check
that the intramuscular concentration of amino acids was sufficient to sustain protein synthesis. Furthermore, as shown by Biolo and coworkers, when a different
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mathematical modeling approach was used for lysine and phenylalanine (a threerather a than a two-pool model) (124), insulin could be shown to stimulate MPS.
This conclusion was supported by independent data showing increased incorporation of stable tracer-labeled leucine into muscle protein sampled in the same period.
Other workers have also demonstrated that insulin will stimulate MPS measured
by incorporation or by limb arterio-venous difference exchangebut only when
sufficient amounts of amino acids are present (116, 125127).
Nevertheless, there are still no data that adequately describe the dose-response
relationship between MPS, measured unequivocally by means of tracer incorporation into protein, and the availability of insulin in blood. There is a pressing need
for construction of a dose-response curve (carried out using somatostatin to inhibit
basal insulin and with insulin added back systematically) that will simultaneously
measure amino acid balance across the limb and tracer incorporation into muscle
protein.
MUSCLE PROTEIN BREAKDOWN The effect of insulin on MPB has been well defined in terms of a decrease in the appearance of amino acids from preparations
of muscle in tissue culture, in isolated whole muscles in perfused systems, and in
measurement of arterio-venous tracer exchange in humans (116, 128). The major
effect of insulin in inhibiting proteolysis appears to be modulated by effects on the
proteasome, the ATP-ubiquitin-dependent proteolytic system that is responsible
for myofibrillar protein breakdown in mammals (129). Despite a wealth of information describing alterations in mRNA and proteasome protein concentrations
through manipulations of nutritional status, it has often been difficult to match
up alterations in skeletal muscle balance or in measured protein breakdown with
changes in the mRNA or proteasome content, e.g., in animals (72). In fact, no such
parallel can be found from results of studies in human subjects as far as we are
aware. In one well-designed study in which protein breakdown (measured as loss
of amino acids from the limb) was elevated by three days of cortisol infusion, no
changes occurred in the components of the proteasome pathway or their mRNA
(130). A similar lack of correspondence between mRNA and protein for proteasome components and changes in net protein loss has been observed in muscle of
lung cancer patients and in patients with acidosis due to renal disease (131, 132).
In short, after a meal and probably after exercise, the insulin-mediated decrease
in MPB appears to be less important for the attainment of net anabolism than the
stimulation of MPS.
Growth Hormone and Insulin-Like Growth Factor-1

Growth hormone has a number of metabolic actions on salt and water balance; fat
metabolism; and, in growing animals and children, muscle and bone growth. Rennie recently reviewed the metabolic effects of growth hormone on human skeletal
muscle and concluded that the balance of evidence suggests there are no major anabolic effects of exogenous rhGH in stimulating muscle protein accretion, muscle
size, muscle strength, or muscle fiber characteristics in normal, healthy adult men
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or women, including the elderly (133). The published data, which have contributed
to this conclusion, include information on incorporation of stable isotope-labeled
amino acids into muscle and measurements of muscle mass and muscle fiber type
using modern imaging and immunohistochemical methods.
There are, nevertheless, strong indications that IGF-1 involvement in metabolism may be locally important in skeletal muscle in humans and may modulate some of the effects of contractile activity in maintaining, or even increasing,
muscle mass.
MGF is elevated in human muscle after exercise (134) but only in young (30year-old) and not in old (75-year-old) subjects. One puzzling feature of this finding
is that the MGF transcripts appear at concentrations that are very much lower than
those of the IGF-1, so the effects of MGF must be because of different targeting
or because the MGF is much more potent than IGF-1.
Although administration of IGF-1 seems to have acute stimulatory anabolic
effects (135, 136) in muscle, long-term systemic administration of IGF-1 without
its binding protein has no anabolic effect on lean body mass in elderly women
(137), whereas a combination of IGF-1 with its binding protein 3 is markedly
anabolic even in burn patients (138).
EFFECTS OF EXERCISE ON MUSCLE PROTEIN TURNOVER

It has long been known that regularly active muscle is able to maximize its mass
despite a poor dietary protein intake; for example, hypertrophy of a muscle can
occur after the ablation of a synergist muscle even in an undernourished animal
(42). Any adaptive responses to increased physical activity that result in an increase
in muscle mass or change in muscle composition must involve alterations of muscle
protein turnover; thus muscle hypertrophy is always associated with increases in
MPS, plus adaptive (likely remodeling related), increases in MPB (139, 140). Of
course, during the upward swing of muscle mass, MPS has to exceed MPB, and
this usually requires amino acids, either dietary or possibly those diverted from
other body tissues.
There are no data available on the rate of MPS during (rather than after) resistance exercise in humans because of the poor time resolution of the methods
available for its measurement. The likelihood that it is unchanged or depressed,
but not raised, has been inferred from studies of walking and bicycling exercise
(141143). The probability of a depression of MPS during resistance exercise is
reinforced by the observation of a fall in incorporation of tracer into protein during
electrically stimulated maximal contractions in perfused rat hindlimb (144). The
extent of the decrement was correlated with falls in creatine phosphate concentration and [ATP]/[ADP]. The associated rise in AMP is likely to activate AMPK,
which in turn would inhibit mTOR-dependent translational regulators during acute
exercise (see above). Bylund-Fellenius and colleagues (144) also reported a fall in
MPB, indicated by a fall in 3-methylhistidine production during exercise, which
is consonant with the fall in intramuscular 3-methylhistidine concentration observed during exercise in human subjects (142). This suggests that both areas of
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muscle protein turnover may be compromised during exercise by a fall in energy

status.
Most studies on the responses to exercise of human muscle protein turnover
have concentrated on postexercise changes after resistance exercise, likely to result
in muscle hypertrophy. The first such study demonstrated that a single bout of highintensity resistance exercise resulted in a doubling of the rate of biceps MPS within
4 h; an elevated but diminishing rate of MPS persisted for 24 h (145). This time
course was confirmed by later work on quadriceps (146), which also indicated a
recovery to within 30% of basal rates by 48 h.
The extent (+80100%) of the anabolic response of MPS to a single bout
of exercise is surprising, because the rate of net accretion of muscle protein is
very much slower than this: It may take 20 weeks of intense resistance exercise
to increase muscle mass by 20%. The explanation is, of course, that MPB is
also elevated after acute exercise (but probably not during it) and that, under
circumstances in which exogenous amino acids are not provided, this usually
exceeds MPS (146) so there is no net protein accretion. However, if food is eaten
or mixed, free amino acids are ingested or infused after intense exercise, then MPS
is stimulated beyond the rate achieved by exercise alone (111, 147149). This effect
is probably synergistic, rather than simply additive, which itself suggests that the
effects of the contractile event(s) and of the amino acids act separately in activating
pathways that eventually stimulate MPS.
Chronic Stretch and Immobilization

A major component of muscle activity in whole musculoskeletal systems is the
stretching of muscles by their antagonists acting in the opposite sense across a
joint; because this stretch itself has been implicated in activating mechanochemical
transduction pathways, there has been a major interest in attempting to separate out
the effects of passive and active tension development. Also, for centuries it has been
recognized that any condition leading to inactivity in muscle is followed by muscle
wastingsarcopenia. The study of both condtions should provide information
allowing us to understand the mechanisms between mechanical strain and muscle
protein growth and wasting.
STRETCH Passive stretch is well established to cause hypertrophy in animal muscle (150); possible mechanisms have been discussed above. Chronically stretched
human multifidus muscle has a higher rate of protein synthesis than flaccid, effectively immobilized muscle (studied on either side of a scoliotic spinal column)
(151). However, there is no evidence of an acute stimulatory effect on protein
synthesis, measured as incorporation of 13C leucine and 27 min of electromyographically silent, intermittent stretch in human muscle, despite isometric exercise
generating the same force for the same period in the same subjects causing a
marked stimulation of 50% (152).
IMMOBILIZATION It has been known for 15 years that immobilization of human
muscle results in a fall in muscle mass caused by a substantial depression in MPS
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accompanied by a smaller fall in muscle protein breakdown so that muscle is in

negative balance (153). This scenario has been confirmed by later studies of bed
rest as a model for immobilization (154). The extent of the wasting is reduced
by local electrical stimulation of muscle, probably through maintenance of translational efficiency that preserves muscle RNA (155). Stress probably acting via
corticosteroids exacerbates muscle wasting in immobilized subjects, and anabolic
steroids and resistance exercise lessen wasting (156).
Timing of Feeding in Relation to Exercise

The timing of the delivery of amino acids may be important in the extent of
stimulation of MPS. Esmark and colleagues carried out a training study over
12 weeks with elderly men who were fed either immediately after exercise or
2 h later; the extent of hypertrophy was measured after 12 weeks (157). In the
group of subjects who ate immediately after exercise, there was a bigger increase
in skeletal muscle mass and fiber diameter. Flakoll and colleagues (158) used a
similar maneuver but made measurements acutely after a single bout of intense
bicycling rather than resistance exercise. The net balance of amino acids across the
previously working legs was greater immediately after exercise than 3 h later. It
has even been shown that amino acid feeding before resistance exercise increases
the post-exercise response of MPS beyond that observed with identical feeding
immediately after exercise (159), an effect the authors ascribe to the increased
prior delivery of amino acids owing to exercise-induced increases in blood flow.
Nevertheless, some contradictory data exist. Rasmussen and colleagues found
no difference in the net balance of amino acids across previously working legs
when examined at 1 or 3 h post-exercise (160). Thus a possible golden period in
which previous contractile activity predisposes muscle to accumulate amino acids
as proteins remains a speculative, no matter how attractive, concept.
Effects of Resistance Training on the Response

of Muscle Protein Turnover
Many of the muscle metabolic systems show adaptations with habitual physical
activity. Whether habitual physical activity results in a chronically altered rate
of muscle protein turnover is currently the subject of some interest. In diabetic
rats trained to perform resistance exercise, Farrell and coworkers demonstrated a
reduced response of MPS to exercise after training (161). However, obtaining a
clear answer to this question for human muscle is difficult. First, the residual effects
of a previous bout of exercise, which may last up to 72 h, depend on intensity.
Second, there is the problem of the habitual dietary intake of athletes who are
subjected to much marketing and coaching information suggesting that they need
to eat large amounts of protein in order to maintain or build muscle mass; this
is a problem because habitually high rates of dietary protein intake lead to the
induction of amino acid catabolic enzymes (particularly of the branched chain and
aromatic amino acids) that decrease the deposition of dietary protein (162, 163).
Until this effect abates (after reducing protein intake), there will be a tendency to
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exhibit negative nitrogen balance, so studies should not be conducted with rapid
variation in dietary protein contents.
There is, in fact, little data on the subject in respect to MPS or even muscle
mass. Studies of military recruits undergoing intense physical training suggest that
there is a loss of body protein over the first few days of training but that adaptation rapidly occurs and nitrogen balance is restored, all at the same rate of dietary
protein intake (164). Butterfield & Calloway found that in young men undergoing physical training, exercise increased the efficiency of protein utilization (165),
i.e., trained subjects would require less protein. Partial validation of this position
was provided by the first of two studies by Phillips and colleagues (166, 167).
When two groups of subjects, one strength-trained and the other sedentary, were
compared, there were no differences in resting post-absorptive MPS or MPB; also
when the post-exercise responses to a single bout of pleiometric exercise at 120%
of each subjects concentric 1 RM were compared, the rise in MPS in the trained
subjects was 50% less than in the sedentary group, and there was no rise in MPB,
which increased by about 40% in the untrained group. Thus net muscle balance
(MPS minus MPB) was improved to the same extent in each group. However,
a different result was obtained in a second longitudinal study of the effects of
8 weeks of resistance training in young previously untrained men, studied in
the fed state at rest and also after a bout of exercise at 80% of their pretraining
1 RM (166). These results suggested that there was no difference in the response
of the subjects in the trained and untrained state to acute exercise; also, rather
oddly, the trained subjects did now show a marked increase in MPB as a result
of exercise. In addition, basal rates of MPS and MPB were in fact now higher in
the trained state; one consequence of this was that the effect of training seemed
to decrease the relative response to exercise, a result that was consonant with the
earlier findingsbut by a different mechanism! All in all, the data on net balance
suggest that there was no effect of training tending to confirm the settled views of
the present authors (143, 148) (although resisted by many athletes, their trainers,
and, of course, sports nutrition companies) that habitual physical activity imposes
no greater demands on protein requirements. As Phillips and coworkers (166) point
out in their discussion, they did not test whether the same relative workload might
affect protein turnover in trained and untrained subjects: It may be that if the above
longitudinal studies had been conducted at the same relative intensity, a different
result might have been obtained.
In the elderly, the rejuvenating effect of training may confound the issue. There
is considerable controversy about whether aging is associated with a fall in muscle
protein turnover [see (168) for review of this topic, which will not be dealt with
further here]. However if it is true that the frail (as opposed to healthy) elderly
show a fall in MPS, as seems likely, then exercise training may normalize it (169).
The mechanism may be by decreasing the amount of TNF- in muscle (170).
Effects of Creatine on Human Muscle Protein Turnover

Dietary supplements containing creatine have become popular with athletes and
trainers hoping to promote greater increase in muscle mass and strength in
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resistance training programs (171173). Measurements of myofibrillar protein

synthesis (as incorporation of 13C leucine) and forearm protein breakdown (as
dilution of deuterated phenylalanine) were unable to discern any differences in
subjects studied before and after creatine supplementation, either in the postabsorptive or the fed state, at rest, or immediately after acute exercise (174, 174a).
These results appear to rule out any acute effect of creatine alone on translation
of pre-existing mRNA or on MPB but do not invalidate the possibility of transcriptional changes or satellite cell activation stimulated by creatine and physical
activity.
Effects of Intensity of Contraction and Metabolic Power

Output on Muscle Protein Turnover
It seems clear that maneuvers resulting in a relatively rapid rise in muscle mass
are all associated with substantial increases, albeit after a short latency, possibly of about one hour, in MPS as a result of translational stimulation produced
by changes in 4E-BP1 and p70S6k phosphorylation (176). These changes are
followed, probably shortly thereafter, by transcriptional changes associated with
intense exercise. Thus questions of the extent and temporal pattern of disturbance
need to be addressed.
In human muscle, our group (M.J. Rennie, D.J.R Cuthbertson, K. Esser &
M. Fedele, unpublished work) consistently observe a long-lasting rise in p70S6k
phosphorylation after acute, high-intensity exercise, with smaller transient rises
in PKB (Akt) phosphorylation, which are associated with a consistent rise in incorporation of tracer-labeled amino acid into muscle protein, whether myofibrillar
or sarcoplasmic. We find no difference in the extent of stimulation of p70S6k or
MPS in different quadriceps in which the same amount of force is applied during
stepping exercise (one leg up, one leg down, while carrying 20% of body weight)
to exhaustion (81). Because concentric exercise is energetically much less efficient
than eccentric exercise and normally requires a higher rate of ATP turnover, this
suggests that the crucial factor in determining the extent of the rise of MPS is force
or intensity rather than ATP turnover, unless there is some threshold effect beyond
which the rise in MPS remains constant.
However, paradoxically, when ATP turnover and the extent of quadriceps motor unit recruitment is kept constant during exercise at 60, 75, and 90% of 1
RM for different numbers of repetitions, the stimulation of MPS is constant
(175).
CONCLUSION
As we have seen, our current ability to describe the adaptive responses of skeletal
muscle to a wide variety of circumstances with changes in mass, composition, and
function is impressive. The time resolution of techniques for measuring changes
in muscle mass and composition and rates of protein turnover have increased
such that we can now make robust measurements of the time courses of, for
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example, the rate of myofibrillar protein synthesis, which was impossible 10 years
ago. Much information about the interrelationships between signaling pathways,
which are important for transcriptional and translational regulation, has been accrued, and we have a much better understanding of the importance of satellite
cells for growth and regeneration of muscle. There are, however, a substantial
number of gaps that need to be filled. We still have no clear idea of the temporal
relationship between the components of amino acid sensing and signaling to the
processes of protein synthesis and breakdown and how these are affected by individual amino acids, insulin, and IGF-1. The exact pathways by which anabolic
and catabolic steroids affect gene transcription and translation of mRNA remain
obscure in human muscle despite the existence of response elements predicted for
the muscle genes; the commonality (if any) of the pathways between myofibers
and satellite cells is not at all well understood. The nature of the dichotomy of
the responses to short-term, high-intensity exercise leading to hypertrophy and
long-term low-intensity exercise leading to mitochondriogenesis and fast-to-slow
fiber type transition remains a mystery. We still require a good description of the
dose-response relationship between exercise intensities and the observed changes
in mass and protein composition, and until we have these, it will be difficult to sort
out the relative contributions of signaling pathways, their commonality, additivity,
or independence from each other in controlling the adaptive responses of muscle.
Nevertheless, the increasing power of post-genomic techniques, particularly the
use of transcriptional profiling and subsequent bioinformatics, should enable us to
identify previously unknown means of controlling transcriptional and translational
events. Perhaps some time in the next 10 years, our view will suddenly snap into
focus, and it will become obvious how, for example, changes in the concentrations
of Ca2+ or AMP can modulate the size and shape of muscle.
ACKNOWLEDGMENTS
Supported by UK Medical Research Council, UK Biotechnology and Biological
Sciences Research Council, The Wellcome Trust, World Anti-Doping Agency,
Diabetes UK (all MJR), Royal Society (HW), and National Institutes of Health
NIH AR19393 (FWB) and NIH AR48514 (EES).
The Annual Review of Physiology is online at http://physiol.annualreviews.org
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Control of The Size of The Human Muscle Mass. 2004

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Annu. Rev. Physiol. 2004. 66:799828

CONTROL OF THE SIZE OF THE

Division of Molecular Physiology, School of Life Sciences, University of Dundee,

Key Words adaptation, physical activity, nutrition, hypertrophy, protein turnover

intermediary metabolism and protein turnover in skeletal muscle (1013), and

MUSCLE GROWTH MECHANISMSSIGNAL

Abbreviations: ADP, adenosine diphosphate; AICAR, 5-aminoimidazole-4-carboxyamide

MUSCLE MASS REGULATION

transcriptional regulation of myostatin and IGF-1/MGF expression in response

Sensing of Growth Stimuli and Transcriptional Regulation

MUSCLE MASS REGULATION

Regulation of the Expression of the Specific Muscle Growth

MUSCLE MASS REGULATION

REGULATION OF IGF-1/MGF EXPRESSION In hypertrophying rodent muscle, IGF-1

Specific Muscle Growth Regulation

MUSCLE MASS REGULATION

in PI3K and the translational regulator p70S6k occurring after 6 to 24 h and

Regulation of Satellite Cell Proliferation and Differentiation

MUSCLE MASS REGULATION

ADAPTATION OF THE HUMAN MUSCLE MASS

EFFECTS OF NUTRITION ON SKELETAL MUSCLE

Effects of Amino Acids

MUSCLE MASS REGULATION

concentration difference flow as signifying apparent increase in net protein

Growth Hormone and Insulin-Like Growth Factor-1

MUSCLE MASS REGULATION

EFFECTS OF EXERCISE ON MUSCLE PROTEIN TURNOVER

muscle protein turnover may be compromised during exercise by a fall in energy

Chronic Stretch and Immobilization

MUSCLE MASS REGULATION

accompanied by a smaller fall in muscle protein breakdown so that muscle is in

Timing of Feeding in Relation to Exercise

Effects of Resistance Training on the Response

Effects of Creatine on Human Muscle Protein Turnover

MUSCLE MASS REGULATION

resistance training programs (171173). Measurements of myofibrillar protein

Effects of Intensity of Contraction and Metabolic Power

of new dual-energy X-ray absorptiometry model. J. Appl. Physiol. 87:1163

MUSCLE MASS REGULATION

reference to limb muscle mass. Clin.

14. Fischman AJ, Yu YM, Livni E, Babich

translocation hypertrophy in cardiomyocytes. J. Biol. Chem. 277:1426673

MUSCLE MASS REGULATION

71. Watford M. 2003. Not all injury-induced

MUSCLE MASS REGULATION

regulation of translation factors.

rapamycin (mTOR) signaling. J. Biol.

MUSCLE MASS REGULATION

123. Wolfe RR, Volpi E. 2001. Insulin protein

thesis in human subjects. Am. J. Physiol.

MUSCLE MASS REGULATION

of muscle protein synthesis in paraspinal

168. Dorrens J, Rennie MJ. 2003. Effects

of oral creatine resistance training on

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