Ageing Research Reviews 26 (2016) 2236

Contents lists available at ScienceDirect

Ageing Research Reviews

journal homepage: www.elsevier.com/locate/arr

Review

Skeletal muscle regeneration and impact of aging and nutrition

Carla Domingues-Faria a,b , Marie-Paule Vasson c,e , Nicolas Goncalves-Mendes c ,
Yves Boirie a,d , Stephane Walrand a,b,
a
Clermont Universit, Universit dAuvergne, Unit de Nutrition Humaine, Equipe NuTriM, CRNH Auvergne; INRA, UMR 1019, UNH, CRNH Auvergne, 63000
Clermont-Ferrand, France
b
INRA, UMR1019, UNH, CRNH Auvergne, 63000 Clermont-Ferrand, France
c
Clermont Universit, Universit dAuvergne, Unit de Nutrition Humaine, Equipe ECREIN, CLARA, CRNH Auvergne; INRA, UMR 1019, UNH, CRNH Auvergne,
63000 Clermont-Ferrand, France
d
CHU Clermont-Ferrand, Service de Nutrition Clinique, 63003 Clermont-Ferrand, France
e
Centre Jean Perrin, Unit de Nutrition, 63000 Clermont-Ferrand, France

a r t i c l e i n f o a b s t r a c t

Article history: After skeletal muscle injury a regeneration process takes place to repair muscle. Skeletal muscle recovery
Received 4 June 2015 is a highly coordinated process involving cross-talk between immune and muscle cells. It is well known
Received in revised form 1 December 2015 that the physiological activities of both immune cells and muscle stem cells decline with advancing age,
Accepted 7 December 2015
thereby blunting the capacity of skeletal muscle to regenerate. The age-related reduction in muscle repair
Available online 9 December 2015
efciency contributes to the development of sarcopenia, one of the most important factors of disability
in elderly people. Preserving muscle regeneration capacity may slow the development of this syndrome.
Keywords:
In this context, nutrition has drawn much attention: studies have demonstrated that nutrients such as
Immunity
Aging
amino acids, n-3 polyunsaturated fatty acids, polyphenols and vitamin D can improve skeletal muscle
Muscle regeneration by targeting key functions of immune cells, muscle cells or both. Here we review the process
Regeneration of skeletal muscle regeneration with a special focus on the cross-talk between immune and muscle cells.
Nutrition We address the effect of aging on immune and skeletal muscle cells involved in muscle regeneration.
Finally, the mechanisms of nutrient action on muscle regeneration are described, showing that quality
of nutrition may help to preserve the capacity for skeletal muscle regeneration with age.
2015 Elsevier B.V. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
2. Immune and muscle cell cross-talk during muscle regeneration and impact of aging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
2.1. Immune cell inltration in muscle lesion and pro-inammatory response development. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .23
2.2. Pro-inammatory macrophages stimulate satellite cell proliferation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
2.3. Pro-inammatory macrophages are converted to anti-inammatory macrophages for further progression of the muscle regeneration
process . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
2.4. Anti-inammatory macrophages stimulate satellite cell differentiation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
2.5. Other immune cells involved in muscle regeneration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
2.6. Myokines in skeletal muscle regeneration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
3. Effect of aging on muscle cell behavior and function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
4. Effect of aging on immune and muscle cell cross-talk and consequences for skeletal muscle repair . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
5. Nutrition and muscle regeneration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31

Corresponding author.
E-mail address: swalrand@clermont.inra.fr (S. Walrand).

http://dx.doi.org/10.1016/j.arr.2015.12.004
1568-1637/ 2015 Elsevier B.V. All rights reserved.
 C. Domingues-Faria et al. / Ageing Research Reviews 26 (2016) 2236 23

6. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
Conicts of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
Acknowledgment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33

1. Introduction response against an antigen. It has been shown that the com-
plement system is rapidly activated in injured muscle, causing
Skeletal muscle is a post-mitotic tissue with a very low turnover immune cell inltration in the lesion site (Frenette et al., 2000).
rate (Spalding et al., 2005). Even so, muscle has a strong ability The involvement of mast cells in the initiation of the pro-
to regenerate after injury. Muscle regeneration is a tightly coordi- inammatory response following muscle damage has also been
nated process composed of four consecutive, interlinked phases: demonstrated. Mast cells secrete pro-inammatory cytokines such
(i) necrosis, (ii) inammation, (iii) activation and differentiation of as tumor necrosis factor- (TNF-) allowing the recruitment of
satellite cells, and (iv) maturation of newly formed muscle bers immune cells at the injury site (Radley and Grounds, 2006).
and remodeling of the regenerated muscle (Barberi et al., 2013). To our knowledge, very little is known about the changes in
After activation and proliferation, satellite cells, i.e., muscle stem mast cell function with advancing age. It has been demonstrated
cells, return to their quiescent state to maintain a pool of satellite in an ischemia-reperfusion model that the number and volume of
cells ready for the next regeneration process. Alternatively, satellite mast cells are increased in aged compared with young rats (Harris
cells differentiate and merge to form new mature multinucleated and Rumbaut, 2001). Mast cells are known to be a source of TNF-
muscle cells, i.e., myobers, or fuse with damaged bers (Hawke , thereby contributing to the low-grade inammation observed
and Garry, 2001). with aging (Payne, 2006). If the number of mast cells is increased
The regulation of proliferation and differentiation processes during skeletal muscle regeneration with aging, we hypothesize
in satellite cells depends in part on immune cell function. Dur- that the recruitment of immune cells at the lesion site could be
ing muscle regeneration, immune cells that have inltrated in altered, impacting the whole process of regeneration.
the lesion develop a pro-inammatory phenotype. The biological Besides mast cells, polynuclear neutrophils (also called neu-
function of the rst immune response is to regulate the immune trophils) are among the immune cells that rstly inltrate muscle
cells themselves, and promote migration of satellite cells to the lesions. They express lymphocyte antigen 6C (Ly6C) and G (Ly6C)
site of injury and proliferation. In turn, muscle cells, both dam- cell surface markers. Neutrophils are also involved in the initia-
aged and intact, modulate the immune response. Neutrophils and tion of pro-inammatory response following muscle injury (Tidball
pro-inammatory macrophages are involved in the lysis of dam- and Villalta, 2010). The inltration of these cells is dependent
aged muscle cells and the phagocytosis and destruction of cell on integrin 2. In rodents, blocking integrin 2 function by tar-
debris. Pro-inammatory macrophages are known to stimulate the geting one of its subunits (CD11b or CD18) before muscle lesion
proliferation of satellite cells. The pro-inammatory phenotype of prevents neutrophil inltration at the site of injury (Pizza et al.,
immune cells then turns into an anti-inammatory one. This pro- 2005; Zerria et al., 2006). Neutrophils phagocyte cellular debris
motes the differentiation of satellite cells, leading to the formation and secrete enzymes such as myeloperoxidase (MPO), cytokines or
or the repair of myobers. The whole process is thus highly regu- reactive oxygen species, which contribute to the lysis of damaged
lated, and requires close cross-talk between immune and muscle muscle bers and the aggravation of muscle injury (Kharraz et al.,
cells during regeneration (Tidball and Villalta, 2010). 2013; Nguyen and Tidball, 2003b). The inhibition of neutrophil
Immunosenescence is characterized by an overall alteration of function results in the preservation of muscle bers close to the
immune cell functions (Shaw et al., 2013; Vasson et al., 2013). injury site (Nguyen and Tidball, 2003b; Zerria et al., 2006). Although
The secretion prole of immune cells is modied, resulting in neutrophils are involved in the lysis of muscle bers and in the
an increase in circulating pro-inammatory cytokines such as phagocytosis of cell debris, their presence is required for an optimal
TNF-, IL-6 or IL-1, and leading to the development of chronic muscle regeneration process. Hence injection of a myotoxin in the
low-grade inammation, called inammaging (Franceschi and muscle of neutrophil-depleted mice results in an incomplete mus-
Campisi, 2014). Knowing that immune cells are in closed cross-talk cle recovery and the persistence of necrotic bers (Teixeira et al.,
with muscle cells during muscle regeneration, immunosenescence 2003).
may impact the process of muscle repair. Immunosenescence have With aging, a clinical study has reported that the circulating
been extensively and recently reviewed elsewhere (Agarwal and neutrophil count remains unchanged (Chatta et al., 1994), while it
Busse, 2010; Fulop et al., 2011; Montoya-Ortiz, 2013; Panda et al., has been demonstrated more recently that a small decrease in neu-
2009; Shaw et al., 2013). In this section, we review the process of trophil number occurs with aging (De Martinis et al., 2004). These
skeletal muscle regeneration with a special focus on the cross-talk conicting results can be explained by the difference in the age
between immune cells and muscle cells. In addition, we point out ranges of the subjects included in the two studies: 7080 versus
the main characteristics of age-related change in immune function 80100 years old (Chatta et al., 1994; De Martinis et al., 2004).
that may impact skeletal muscle regeneration. Among the main functions of this cell type, chemotactism, bac-
tericidy and phagocytosis are blunted with age (Niwa et al., 1989;
2. Immune and muscle cell cross-talk during muscle Wenisch et al., 2000). Thus, if the number of circulating neutrophils
regeneration and impact of aging is modied with aging, jointly with phagocytosis and chemo-
tactism, we suppose that the initiation of the pro-inammatory
2.1. Immune cell inltration in muscle lesion and response following muscle injury could be reduced, affecting skele-
pro-inammatory response development tal muscle repair.
It should be noted that the implication of complement system,
Activation of the complement system following acute muscle mast cells and polynuclear neutrophils in the initiation of immune
injury is involved in the initiation of the inammatory response response were demonstrated in rodent models. Effect of aging on
during muscle regeneration. The complement system is composed mast cell functions implicated in muscle repair was also highlighted
of circulating innate immunity proteins that allow a rapid immune in animal models. Thus investigations are needed to conrm that
24 C. Domingues-Faria et al. / Ageing Research Reviews 26 (2016) 2236
these results are relevant to humans. Of note, the effect of aging on
polynuclear neutrophil functions was evidenced in humans.
Following neutrophil inltration, circulating monocytes
migrate from blood to the site of the lesion, where they differ-
entiate into macrophages, gradually replacing neutrophils as the
main population of immune cells (Tidball et al., 1999; Zerria et al.,
2006). Monocyte migration starts in response to chemokines (such
as interleukin-1 or IL-1, and interleukin-8 or IL-8) secreted by
neutrophils present at the injury site (Pizza et al., 2005). Monocyte
migration also depends on chemokine (CC motif) ligand 2 (CCL2),
also called monocyte chemoattractant protein-1 (MCP1), which
is secreted by injured muscle bers, and resident or inltrated
macrophages in muscle (Lu et al., 2011a). The expression of
monocyte CC chemokine receptor type 2 (CCR2), the receptor
of CCL2, seems important for monocyte migration to the lesion
site, since macrophage inltration is reduced in CCR2/ mice
following injection of cardiotoxin (Martinez et al., 2010).
Chemokines, in particular the CC class partially produced by
macrophages and neutrophils, play an important role in mus-
cle repair. Following muscle cryolesion in mice, the expression
of the three chemokines CCL2, CCL3 and CCL4, jointly with their
main receptors CCR5 and CCR2 is increased (Warren et al., 2004).
Recently, a study has demonstrated that iNOS expression in
macrophages regulates chemokine expression, and its invalidation
leads to increased inltration and accumulation of immune cells
at the lesion site, leading to perturbation of the muscle repair pro-
cess (Rigamonti et al., 2013). The CCL2/CCR2 axis is likely involved
in muscle regeneration, since the neutralization of CCL2 by anti-
body infusion or CCR2 invalidation is associated with a reduction
in macrophage inltration in injured muscle, leading to an incom-
plete process of muscle repair (Ochoa et al., 2007; Warren et al.,
2005, 2004).
Macrophages potentiate their own inltration at the injured site.
Zhang et al. (2013) have demonstrated in an IL6/ mouse model
with a muscle lesion that IL-6 produced by macrophages induces
CCL2 expression through the signal transducer and activator of the
transcription 3 (STAT3) pathway. In this way, macrophages are able
to self-amplify their inltration into a muscle lesion (Zhang et al.,
2013). Macrophages inltrated into injured muscle express specic
markers such as CD86 or iNOS (inducible nitric oxide synthase), and
secrete cytokines/chemokines such as TNF-, IL-1 (interleukin-
1), MCP-1, IFN- (interferon ) and IL-6 (interleukin-6). Due to
this phenotype, these cells are considered pro-inammatory or
M1 cells. M1 macrophages lyze muscle cells and phagocyte cel-
lular debris (Rigamonti et al., 2014; Tidball and Villalta, 2010).
Macrophage phagocytosis can be activated by oxidized low den-
sity lipoprotein (LDL) binding to the membrane CD68 (Ottnad
et al., 1995; Ramprasad et al., 1995). Interestingly, the subset
of neutrophils is able to secrete MPO known to generate reac-
tive species oxidizing LDL (Mertens and Holvoet, 2001; Nguyen
et al., 2005; Nguyen and Tidball, 2003b). In addition, the co-culture
of myobers, neutrophils and macrophages has demonstrated
that neutrophils potentiate macrophage cytotoxicity (Nguyen and
Tidball, 2003a). These data suggest that lysis and phagocytosis func-
tions are regulated by neutrophil and macrophage cross-talk.
Of note, the migration and the inltration of monocytes to the
lesion site, their differentiation into macrophages, the potentiation
of their own inltration, their rst pro-inammatory phenotype
and the implication of chemokines in their recruitment have
been essentially demonstrated in animal models. Their lysis and
phagocytosis functions were essentially evidenced in in vitro mod-
els. Thus, attention have to be paid concerning the rst steps
of macrophage response during muscle regeneration in human
beings.
Lysis and phagocytosis are not the only roles played by M1
macrophages during skeletal muscle regeneration. These cells are
also essential for the attraction of satellite cells to the lesion site
and for their proliferation.
2.2. Pro-inammatory macrophages stimulate satellite cell
proliferation
During muscle regeneration (Fig. 1), M1 macrophages attract
satellite cells to the injured site (Robertson et al., 1993), and stimu-
late their proliferation (Saclier et al., 2013a). Several in vitro studies
have also reported that macrophages migrate towards satellite
cells, and thus potentiate satellite cell proliferation (Arnold et al.,
2007; Merly et al., 1999; Saclier et al., 2013b). Muscle cell pro-
liferation is in part dependent on IL-6 secreted by macrophages
(Zhang et al., 2013), and does not necessarily require any direct con-
tact between macrophages and muscle cells (Cantini et al., 2002).
These ndings have been conrmed in in vivo studies demonstrat-
ing the importance of macrophage/muscle cell cross-talk during
muscle regeneration. In a mouse model of muscle lesion induced
by notexin infusion, the depletion of macrophages in muscle tissue
results in persistence of necrotic bers, and impairs tissue regen-
eration (Arnold et al., 2007). Researchers have also demonstrated
a greater participation of muscle cells in skeletal muscle regenera-
tion in the presence of macrophages: proliferation, migration and
engraftment of myoblasts (activated satellite cells) transplanted in
muscle of dystrophic mice are improved when myoblasts are co-
injected with macrophages, especially M1 macrophages (Bencze
et al., 2012; Lesault et al., 2012). Moreover, macrophages limit
myotube and satellite cell apoptosis during muscle regeneration
(Chazaud et al., 2003; Sonnet et al., 2006). Of note, macrophages
interact with satellite cells to further augment monocyte chemo-
tactism (Chazaud et al., 2003).
Soon after muscle injury, inltrated neutrophils and
macrophages produce the pro-inammatory cytokine TNF-,
which contributes to the pro-inammatory response (Collins and
Grounds, 2001; Zador et al., 2001). Several roles are assigned to
TNF- during muscle regeneration. TNF- production stimulates
iNOS expression in macrophages, resulting in nitric oxide (NO )
production, which promotes muscle damage (Tidball and Villalta,
2010). In vitro, treatment of rodent myoblasts with TNF- increases
their proliferation rate, and in vivo, an intraperitoneal injection
of this cytokine in mice stimulates satellite cell proliferation
(Li, 2003). It has been found that the pro-proliferative effect of
TNF- is dependent on the action of NF-B (nuclear factor-kappa
B). TNF- activates the NF-B pathway in muscle cells, which
positively controls cell proliferation through increased cyclin D1
expression (Guttridge et al., 1999; Langen et al., 2001). Addition-
ally, TNF- inhibits muscle differentiation, causing destabilization
of the mRNA of the myogenic regulatory factor MyoD and the
degradation of the related protein, which is known to regulate the
expression of muscle-specic genes (Langen et al., 2001, 2004).
Interestingly, pro-inammatory cytokines, such as TNF- and IL-1,
but also NO stimulate NF-B activation, which in turns induces
TNF-, IL-1 and iNOS expression. Thus the NF-B pathway activa-
tion is self-amplied. These substances also increase expression
of CCL2 and IL-6, two entities involved in monocyte/macrophage
inltration in muscle lesions (Ghosh et al., 1998; Mourkioti and
Rosenthal, 2008). Not only does TNF- secreted by neutrophils and
M1 macrophages exert a central action in immune cell attraction;
this cytokine also plays a chemoattractant role on satellite cells
at the damaged site of the muscle (Lolmede et al., 2009; Torrente
et al., 2003).
To sum up, TNF- stimulates muscle proliferation and inhibits
muscle differentiation through the NF-B pathway. Nevertheless,
it seems that TNF- also stimulates muscle differentiation at later
stages in the regeneration process, independently of the NF-kB
pathway. In a rodent model of muscle regeneration, the expression
 C. Domingues-Faria et al. / Ageing Research Reviews 26 (2016) 2236 25

Fig. 1. Cross-talk between macrophages, neutrophils and satellite cells during skeletal muscle regeneration. (For interpretation of the references to color in this gure legend,
the reader is referred to the web version of this article.)
Following muscle lesion, immune cells such as neutrophils and macrophages inltrate the injury site. They rstly produce a pro-inammatory response, notably characterized
by the secretion of pro-inammatory cytokines such as TNF-, chemokines such as CCL2, and reactive oxygen species such as NO (blue characters). This pro-inammatory
reaction leads to further recruitment of immune cells at the lesion site, and also attracts and stimulates the proliferation of muscle satellite cells. Of note, the Notch signaling
pathway is activated in proliferating satellite cells to control this process. The pro-inammatory response then turns into an anti-inammatory one. Immune cells secrete
anti-inammatory cytokines (yellow characters). Anti-inammatory macrophages can inhibit the pro-inammatory reaction, and they promote the differentiation of satellite
cells. Wnt signaling is activated in satellite cells during their differentiation, as this pathway regulates the expression of genes related to this process.

of TNF- mRNA is induced following injury, and again one week
later when the muscle differentiation process is already started
(Zador et al., 2001). Thus this cytokine likely has a regulating action
even in the late steps of muscle regeneration, when satellite cells
differentiate. TNF- activates p38 kinase and stimulates the differ-
entiation of C2C12 muscle cells. Inversely, blocking TNF- action
using anti-TNF- or inhibiting p38 kinase activity decreases the
expression of muscle differentiation markers such as MyoD, myo-
genin or myosin (Chen et al., 2007; Wu et al., 2000).
Like TNF-, IL-6 stimulates monocyte/macrophage migration to
the muscle lesion site through the activation of the STAT3 pathway.
This process activates satellite cell proliferation. In IL6/ mice, the
migration and inltration of monocyte/macrophages to the site of
muscle injury is reduced, and as a result satellite cell proliferation is
decreased (Zhang et al., 2013). Of note, IL-6 is produced not only by
macrophages but also by satellite cells and myobers. Interestingly,
the proliferation and migration of myoblasts isolated from IL6/
mice are reduced compared with myoblasts isolated from wild type
mice (Serrano et al., 2008).
IFN- is also involved in muscle regeneration. Satellite cell
proliferation and regenerating ber numbers are diminished in IFN-
/ mice or in mice receiving IFN- receptor antagonist (Cheng
et al., 2008).
The stimulation of satellite cell proliferation by pro-
inammatory macrophages have been demonstrated in in vitro
and animal models. Thus investigations are needed to conrm the
relevance on these results in humans.
2.3. Pro-inammatory macrophages are converted to
anti-inammatory macrophages for further progression of the
muscle regeneration process
Macrophage conversion from a pro-inammatory (M1) to an
anti-inammatory (M2) phenotype is a central process in mus-
cle regeneration (Fig. 1). The M1 population stimulates muscle
proliferation, whereas M2 cells play a key role in the process of dif-
ferentiation, i.e. from satellite cells to myobers (Arnold et al., 2007;
Saclier et al., 2013b). Several molecular and cellular processes are
involved in macrophage phenotype transition. Macrophage phago-
cytosis is one of the mechanisms leading to M1/M2 conversion.
The expression of the anti-inammatory cytokine transforming
growth factor- (TGF-) is enhanced in macrophages cultivated
with lyzed satellite cells (Arnold et al., 2007). If phagocytosis is
26 C. Domingues-Faria et al. / Ageing Research Reviews 26 (2016) 2236
blunted, macrophages retain their M1 phenotype (Arnold et al.,
2007). Interestingly, the type of the element to be phagocyted
inuences M1/M2 conversion. The phagocytosis of apoptotic neu-
trophils inhibits the production of pro-inammatory cytokines,
whereas the production of an anti-inammatory cytokine such as
TGF- is augmented (Fadok et al., 1998). Also, TGF- production
by macrophages following phagocytosis is greater when apop-
totic neutrophils are phagocyted compared with lyzed neutrophils
(Fadok et al., 2001).
Macrophage-secreted cytokines also orchestrate M1/M2 con-
version. The pro-inammatory cytokine IFN- stimulates the M1
and inhibits the M2 phenotype. A reduction in muscle damage
and an increase in M2 macrophage activation have been observed
in IFN-/ dystrophic mice (Villalta et al., 2011a). The anti-
inammatory cytokine TGF- participates in the M1/M2 phenotype
transition, as the treatment of macrophages with lipopolysac-
charide (LPS) and TGF- reduces pro-inammatory cytokine
production compared with treatment with LPS alone (Fadok
et al., 1998). The anti-inammatory cytokine IL-10 reduces M1
macrophage activation and promotes M1/M2 conversion in vitro
and in vivo (Deng et al., 2012; Villalta et al., 2011b)
At the cellular level, the M1/M2 transition is coordinated
by mitogen-activated protein kinase phosphatase-1 (MKP-1),
which regulates the activation of mitogen-activated protein kinase
(MAPK) p38 and the activity of Akt. This pathway allows a con-
trolled conversion from a pro-inammatory phenotype to an
anti-inammatory phenotype in macrophages. The transition of
M1 macrophages to an anti-inammatory phenotype occurs too
early in injured skeletal muscle of MPK-1/ mice, and the expres-
sion of pro-inammatory cytokines persists. Consequently, skeletal
muscle regeneration is incomplete. In addition, p38 induces the
expression of the pro-inammatory cytokine IL-1, which stimu-
lates the expression of TGF-, showing that cytokines themselves
play a role in the M1/M2 transition (Perdiguero et al., 2011).
cAMP response element binding protein (CREB) binding on the
promoter of CCAAT/enhancer binding protein (C/EBP) induces the
expression of C/EBP, leading to the expression of M2 phenotype-
related genes such as IL-10. In mutant mice for the promoter
of C/EBP, leading to the loss of function of this promoter,
macrophage invasion in the muscle lesion site is not modied,
but the expression of M2 specic genes is limited, and so muscle
regeneration is incomplete (Ruffell et al., 2009).
The involvement of adenosine 5 -monophosphate-activated
protein kinase alpha (AMPK) activation in the conversion of
the macrophage phenotype has also been demonstrated. Thus
the inhibition of AMPK in macrophages results in an increase
in LPS-induced pro-inammatory cytokine (TNF-, IL-6) expres-
sions. Conversely, a signicant decrease in the expression of these
cytokines is observed when macrophages express a constitutively
activated form of AMPK (Sag et al., 2008). More recently, a study
has shown in vitro and in vivo that the deletion of the AMPK
gene in macrophages is a limiting factor for their conversion to
M2 phenotype and for muscle regeneration (Mounier et al., 2013).
Interestingly, the activation of AMPK induces CREB activation and
thus stimulates the expression of M2-related genes, and therefore
M1/M2 conversion (Ruffell et al., 2009; Sag et al., 2008).
These different studies show that the conversion of the M1/M2
macrophage phenotype is nely regulated, and that different
molecular targets and pathways are involved. It remains unclear
how all these elements are coordinated and whether other players
are involved for a successful M1/M2 transition.
Of note, the conversion of M1M2 phenotype in macrophages,
the role of cytokines and signaling pathways in this process have
been highlighted in in vitro and animal models.
2.4. Anti-inammatory macrophages stimulate satellite cell
differentiation
The main characteristics of M2 macrophages are that these
cells express different markers such as CD206, CD163 or arginase-
1, and produce anti-inammatory cytokines such as IL-10 or
TGF-. CD206 (or mannose receptor) is involved in the pro-
inammatory response blockage. CD206 binds to MPO and then
internalizes this enzyme in a lysosome, which contributes to
the reduction in both M1 response and muscle lysis (Shepherd
and Hoidal, 1990). CD163 also plays a central role in the inhi-
bition of pro-inammatory response. This cluster is known to
bind and internalize the hemoglobin-haptoglobin complex and to
counteract oxidative damage caused by free radicals produced by
hemoglobin. Also, the internalization of hemoglobin-haptoglobin
complex induces the secretion of the anti-inammatory cytokine
IL-10 (Philippidis et al., 2004). Thus the action of CD206 and CD163
seems to contribute to the promotion of the anti-inammatory
response.
M2 macrophages stimulate muscle cell differentiation, leading
to myober formation or repair (Fig. 1) (Chazaud et al., 2009).
A decrease in the percentage of centrally nucleated myobers,
which is a marker of regeneration, was observed in a murine
model of muscle regeneration characterized by a depletion of
M2 macrophages (Tidball and Wehling-Henricks, 2007). In vitro,
M2 macrophages promote the expression of myogenin, a marker
of muscle differentiation, and myotube formation (Arnold et al.,
2007). A study using human quadriceps biopsies, withdrawn after
exercise, has revealed that M2 macrophages are preferentially
found in areas containing differentiating satellite cells (Saclier et al.,
2013b).
The central importance of M2 macrophages during muscle
repair has been demonstrated by numerous studies. In CCR2/
mice, macrophages do not inltrate muscle lesions, and conse-
quently the efciency of muscle regeneration is blunted. However,
the infusion of IGF-1 (insulin-like growth factor-1), a hormone pro-
duced by M2 macrophages, stimulates muscle repair in CCR2/
mice (Lu et al., 2011b). Furthermore, the lack of M2 macrophages
during the regeneration process leads to delayed angiogenesis, con-
tributing to inefcient muscle repair (Ochoa et al., 2007).
The anti-inammatory response has to cease at the end of
the muscle repair process. A study has demonstrated that when
regeneration is completed, M2 macrophages become inactive,
and consequently anti-inammatory cytokine production is inter-
rupted (Perdiguero et al., 2011). Macrophages then revert to a
quiescent state or are eliminated through apoptosis. Like the
M1/M2 transition, inammatory reaction is stopped by a coordi-
nated action of p38/MKP-1 and AKT (Perdiguero et al., 2011).
With aging, monocyte/macrophage phagocytosis and cytokine
secretions are altered but discrepancies among conclusions still
exist. According to the species, i.e., humans or rodents, the tissue
origin or the nature of the body to be phagocyted, phagocytosis has
been described to be stimulated, inhibited, or unchanged (Gomez
et al., 2008; Shaw et al., 2013). Studies also conict concerning the
capacity of monocytes/macrophages to produce cytokines. Some
have shown that the production of pro-inammatory cytokines by
human monocytes is increased with aging, whereas others have
reported a diminution (Hearps et al., 2012; Nyugen et al., 2010;
Qian et al., 2012; van Duin et al., 2007). Of note, the method used
to stimulate the cells differed among these studies. Also, they were
all conducted in vitro, which meant the cell environment formatted
by aging, which may inuence the function of immune cells, was
missing. Knowing the central role of macrophages in the regula-
tion of the proliferation and the differentiation of satellite cells, we
presume that any changes that occur during aging in macrophage
 C. Domingues-Faria et al. / Ageing Research Reviews 26 (2016) 2236
functions could reduce the capacity of skeletal muscle to regener-
ate.
The stimulation of satellite cell differentiation by anti-
inammatory macrophages have been well described in in vitro
and rodent models. Investigation carried out in humans seems to
be consistent with in vitro and animal models as human quadri-
ceps biopsies have revealed that M2 macrophages are preferentially
found in areas containing differentiating satellite cells (Saclier et al.,
2013b). Interestingly, the effect of aging on macrophage functions
has been essentially demonstrated in humans. Future scientic
works will highlighted the impact of aging on the stimulation of
satellite cell proliferation, on the M1/M2 conversion and on the
promotion of satellite cell differentiation in order to prevent the
effect of aging on macrophage/muscle cell cross-talk.
As seen previously, pro-inammatory M1 macrophages are
converted into anti-inammatory M2 macrophages during skele-
tal muscle regeneration. However, fully polarized M1 and M2
cells in their various versions are extremes of a continuum
(Mantovani et al., 2004). There are actually several populations
of M2 macrophages involved in muscle regeneration: M2a, M2b
and M2c macrophages for which functions were already well
described in reviews (Mantovani et al., 2004; Tidball and Villalta,
2010). Generally speaking, M2a are activated by IL-4 and IL-13 and
these cells reduce the lysis rate of muscle cells induced by M1
macrophages (Villalta et al., 2009). M2b macrophages are activated
by the toll-like receptors (TLR) or immune complexes (antigen-
antibody complex) and are involved in the anti-inammatory
response through cytokine secretion. Finally, M2c are activated by
IL-4 and IL-10, and promote lesion resorption (Tidball and Villalta,
2010). Here we chose to focus on the function of M2 macrophage
population in its entirety. To our knowledge M2a, M2b and M2c
macrophage functions were not yet investigated during skeletal
muscle regeneration and aging.
2.5. Other immune cells involved in muscle regeneration
Neutrophil and macrophage functions during muscle repair
have been thoroughly investigated. However, other types of
immune cells also contribute to this process (Table 1).
In mdx mice, a model of Duchennes muscular dystrophy, or
in muscle-injured mice, CD4+ T cells, CD8+ T cells and natural
killer (NK) cells inltrate the injured site, jointly with macrophages.
These cells are sources of IFN-, a cytokine known to stimulate
satellite cell proliferation. Furthermore, the depletion of CD8+ T
cells reduces the concentration of apoptotic myonuclei, as well
as muscle ber necrosis in mdx mice, demonstrating that these
immune cells are involved in the severity of Duchenne muscular
dystrophy (Cheng et al., 2008; Spencer et al., 1997). It has been
demonstrated in mice decient in CD8+ T cells that these cells are
needed for normal muscle regeneration (Zhang et al., 2014). CD8+ T
cells regulate MCP-1 secretion to recruit M1 macrophages at muscle
injury sites, facilitating myoblast proliferation (Zhang et al., 2014).
With aging, investigations of adaptive immunity have demon-
strated that the reserve pool of naive CD4+ T cells is reduced, and the
CD4+ T cell/CD8+ T cell ratio decreased. Furthermore, the reserve
pool of memory T cells (CD4 + or CD8 +) increases. T cell prolif-
eration requires the presence of IL-2 and IL-2 receptors, both of
which decline with aging (Boren and Gershwin, 2004). In addition,
stimulation of the T cell receptor leads to a decrease in transmem-
brane signaling. This decline leads to a decrease in transcription
factor in T cell and consequently the reduction in gene expres-
sion involved in the induction of the immune response (Boren and
Gershwin, 2004). Finally, the modications of the whole immune
response contributes to the increased levels of circulating pro-
inammatory cytokines leading to a chronic state of low-grade
27
inammation known as Inammaging (Boren and Gershwin, 2004;
Castelo-Branco and Soveral, 2014).
Concerning NK cells, two populations exist in humans: cytotoxic
NK and NK producing cytokines. During aging it has been demon-
strated that the cytotoxicity of NK cells is decreased, while their
number increases (the overall cytotoxicity is therefore preserved).
However, the number of NK cells able to produce cytokines, and
their cytokine secretion, especially of IFN-, decrease (Almeida-
Oliveira et al., 2011; Camous et al., 2012).
Thus we suppose that alterations with aging of the number of
T and NK cells together with changes in their ability to secrete
cytokines could modify the process of muscle regeneration, likely
through a reduction of satellite cell proliferation.
Of note, the total number of B cells diminish with aging. Hence,
the number of naive B cells declines, while the number of mem-
ory B cells increases with age (Montoya-Ortiz, 2013). These B cells
present an increased resistance to apoptosis. Antibody produc-
tion is also modied with aging. This production is lowered with
lower afnities and decreased opsonizing abilities, and the anti-
body response to new antigens is delayed (Castelo-Branco and
Soveral, 2014). To our knowledge, B cell involvement in muscle
repair has not yet been demonstrated
A particular population of lymphocytes, named Treg cells, has
been identied as key modulators of pro- to anti-inammatory
response transition. Following acute injury, Treg cells inltrate the
lesion site, and this inltration coincides with M1/M2 response con-
version (Burzyn et al., 2013). This transition is not possible when
acutely injured mice are depleted in Treg cells (Burzyn et al., 2013).
Additionally, M1 macrophage activation and the production of pro-
inammatory cytokines are increased in mdx mice depleted in Treg
cells (Villalta et al., 2014).
With aging, the number of Treg cells rises whereas their function
is altered, thereby affecting the function of the other immune cells
(Garg et al., 2014). The fact that Treg are unable to modulate pro- to
anti-inammatory response transition may result in an incomplete
regeneration process as we age.
The presence of monocyte-derived dendritic cells has been iden-
tied in a mouse model of acute injury. This immune cell type may
provide longstanding immune surveillance until full restoration of
myober integrity (Brigitte et al., 2010).
It has been demonstrated that cytokine production by dendritic
cells in response to stimulation is reduced in older people (Panda
et al., 2010; Qian et al., 2011). In addition, phagocytosis and migra-
tion are reduced (Agrawal et al., 2007). Thus we presume that
the alteration of dendritic cell function with aging could reduce
their capacity to provide immune surveillance during skeletal mus-
cle regeneration. Consequently, immune response during muscle
repair could be disorganized and not adapted to the muscle regen-
eration context.
Polynuclear eosinophil cells have also been observed in mus-
cle necrotic areas of mdx mice, where they promote myober lysis.
However, this immune cell type has seldom been identied in mus-
cle after acute injury (Wehling-Henricks et al., 2008).
Little is known about the effect of age on polynuclear eosinophil
function. However, Mathur et al. (2008) have highlighted that
degranulation of these cells (as measured by IL-5induced degran-
ulation of eosinophil-derived neurotoxin) and their free radical
production are reduced in asthmatic older people compared with
younger ones. Polynuclear eosinophil are very rarely observed dur-
ing skeletal muscle regeneration and his role is not known.
Taken together, these ndings demonstrate the importance of
immune cells in the orchestration of muscle regeneration. This
being the case, modications of the phenotype, and therefore
the function of these cells, may impact immune and muscle cell
cross-talk, leading to inefcient muscle regeneration. With aging,
28 C. Domingues-Faria et al. / Ageing Research Reviews 26 (2016) 2236

Table 1
Role of immune cells in muscle regeneration and their known cross-talk with other cells.

Immune cells Role in muscle regeneration and known cross-talk References

with other cells

Mast cells Secretion of TNF- for immune cell recruitment at Radley and Grounds (2006)
lesion site

Polynuclear Promotion of myobre lysis in mdx model Wehling-Henricks et al.

eosinophils Very scarce in muscle acute injury (2008)

Polynuclear Muscle lysis and phagocytosis of cellular debris Kharraz et al. (2013), Nguyen and Tidball (2003b) and
neutrophils Teixeira et al. (2003)
Initiation of pro-inammatory response Tidball and Villalta (2010), Zerria et al. (2006) and Pizza
et al. (2005)
Recruitment of immune cells such as macrophages Pizza et al. (2005)

Macrophages Muscle lysis (M1) and phagocytosis of cellular debris
(M1)
Secretion of chemokines
Recruitment of immune cells such as
monocytes/macrophages
Recruitment of satellite cells
Secretion of pro-inammatory cytokines (M1)
Stimulation of the proliferation of satellite cells (M1)
Control their own conversion from M1 to M2
phenotype
Stimulation of the differentiation of satellite cells (M2)
Secretion of anti-inammatory cytokines (M2)
Limitation of myotube and satellite cell apoptosis
Arrest of pro-inammatory response (M2)
Tidball and Villalta (2010), Rigamonti et al. (2014), Ottnad
et al. (1995) and Ramprasad et al. (1995)
Warren et al. (2004), Ochoa et al. (2007), Rigamonti et al.
(2013) and Warren et al. (2005)
Lu et al. (2011a), Martinez et al. (2010) and Zhang et al.
(2013)
Robertson et al.(1993)
Tidball and Villalta (2010)
Saclier et al. (2013a,b), Arnold et al. (2007), Bencze et al.
(2012) and Lesault et al. (2012)
Arnold et al. (2007), Fadok et al. (1998, 2001), Villalta et al.
(2011a,b), Deng et al. (2012), Perdiguero et al. (2011),
Ruffell et al. (2009) and Mounier et al. (2013)
Saclier et al. (2013b), Arnold et al. (2007), Chazaud et al.
(2009), Tidball and Wehling-Henricks (2007) and Lu et al.
(2011b)
Tidball and Villalta (2010)
Chazaud et al. (2003) and Sonnet et al. (2006)
Arnold et al. (2007), Shepherd and Hoidal (1990) and
Philippidis et al. (2004)

NK cells Source of IFN-, which stimulates satellite cell Cheng et al. (2008)
proliferation

Monocyte-derived dendritic cells Immune surveillance Brigitte et al. (2010)

CD4+ T cells Source of IFN-, which stimulates satellite cell Cheng et al. (2008)
proliferation

CD8+ T cells Source of IFN-, which stimulates satellite cell Spencer et al. (1997)
proliferation
Regulate MCP-1 secretion for M1 macrophage Zhang et al. (2014)
recruitment, facilitating satellite cell proliferation

Treg cells Promotion of the conversion of M1 to M2 macrophages Burzyn et al. (2013) and Villalta et al. (2014)

immune function is altered, and this jointly with muscle cell aging
likely contributes to an overall change in muscle repair capacity.
The implication of CD4+ and CD8+ T cells, Treg cells, NK cells,
dendritic cells and polynuclear eosinophils has been evidenced in
animal models of muscle regeneration. Inversely, the effect of aging
has been studied in humans. In this context, the role of CD4+ and
CD8+ T cells, Treg cells, NK cells, dendritic cells and polynuclear
eosinophils in human skeletal muscle repair has to be conrmed.
Furthermore, there is a gap concerning the consequences of the
aging of theses immune cells on muscle regeneration. Additional
studies are needed to bridge this gap.
2.6. Myokines in skeletal muscle regeneration
During skeletal muscle regeneration, immune cells secrete
cytokines to improve satellite cell proliferation or differentiation.
However, skeletal muscle also produces factors that may possibly
inuenced muscle repair process. Cytokines and other peptides that
are produced, expressed and released by muscle bers and exert
autocrine or endocrine effect are classied as myokines (Pedersen,
2011; Pedersen and Febbraio, 2008). According to Pedersen (2011),
contracting skeletal muscle release myokines, which work in
hormone-like fashion, exerting specic endocrine effects on other
organs or which work locally via paracrine mechanisms. Even if
most of myokines have been studied in the context of physical
activity, some of them have been identied during skeletal muscle
regeneration and/or likely have a key role in this process.
In vitro, human myoblasts express and secrete IL-6 in response
to inammatory stimuli mimics by IL-1, TNF- and lipopolysac-
charide (Gallucci et al., 1998). In addition, muscle cell-derived IL-6
stimulates migration and proliferation of muscle cells as these
processes are decreased in myoblasts derived from IL-6/ mice
(Serrano et al., 2008). Of note, immune cells inltrating the mus-
cle following an injury secrete pro-inammatory cytokines. Thus
immune cell-derived cytokines may further stimulate IL-6 pro-
duction by muscle cells. IL-6 is also implicated in the myogenic
differentiation program. In C2C12 muscle cells, interference of IL-6
mRNA reduces C2C12 differentiation whereas IL-6 overexpression
increased muscle differentiation (Baeza-Raja and Munoz-Canoves,
2004; Hoene et al., 2013). Similarly, myotube formation was
impaired in IL-6/ skeletal muscle cells (Hoene et al., 2013). Taken
together, this results demonstrate the key role of IL-6 myokine in
myoblast migration, proliferation and differentiation. As it is pro-
duced by both immune and muscle cells during skeletal muscle
regeneration (Kurek et al., 1996; Zhang et al., 2013), IL-6 is prepon-
derant in this process.
Leukaemia inhibitory factor (LIF) is produced and released from
muscle cells in vitro and from skeletal muscle in vivo, partic-
 C. Domingues-Faria et al. / Ageing Research Reviews 26 (2016) 2236
ularly during exercise (Broholm and Pedersen, 2010). However,
LIF myokine is also produced by muscle cells during regeneration
(Barnard et al., 1994; Kurek et al., 1996). Furthermore, Barnard et al.
(1994) have demonstrated in a rodent model that administration of
LIF to the site of muscle injury results in an increase rate of regen-
eration. This effect is likely due to the modulation of muscle cell
proliferation and differentiation. In vitro, human myoblast prolif-
eration is increased by recombinant LIF and decreased by the siRNA
knockdown of the endogenous LIF receptor (Broholm et al., 2011).
In addition, LIF stimulates C2C12 differentiation trough JAK2/STAT2
pathway (Yang et al., 2009). Thus, LIF myokine is implicated in
skeletal muscle regeneration, probably through its role on muscle
cell proliferation and differentiation.
IL-8 is a myokine and CXC ligand 1 (CXCL-1) is often mentioned
as the functional homologue of IL-8 (Pedersen and Febbraio, 2012).
It has been highlighted that IL-8 and CXCL-1 have a neutrophil
chemoattractant activity (Lira et al., 1994; Pedersen and Febbraio,
2012). To our knowledge, the implication of IL-8 and CXCL-1 in
skeletal muscle regeneration has to be determined. Due to their
chemoattractiveness, the secretion of these compounds by muscle
cells may contribute to the attraction of neutrophils at the injury
site at the beginning of regeneration process.
Human skeletal muscle cells also express and secrete IL-7
(Haugen et al., 2010). In vitro, IL-7 expression increases during dif-
ferentiation of satellite cells into human myotubes, and inversely
the expression of IL-7 receptor decreases (Haugen et al., 2010). IL-7
treatment of satellite cells increases cell migration but inhibits cell
differentiation (Haugen et al., 2010). In a context of muscle regen-
eration, IL-7 may be implicated in the attraction of satellite cells to
the lesion site and may prevent precocious differentiation of these
cells.
It has been demonstrated in vitro that following myotube for-
mation, nascent myotube secretes IL-4 to further recruit myoblasts
in order to merge with nascent myotube, leading to muscle growth
(Horsley et al., 2003). Therefore, during muscle repair, IL-4 may
be secreted by newly formed myober to further enhance their
growth.
With aging, muscle functions decline and it is likely that
myokine production is altered. Consequently, part of skeletal mus-
cle regeneration process that could be dependent of myokines may
be impaired, contributing to the age-related muscle repair inef-
ciency.
3. Effect of aging on muscle cell behavior and function
With aging, muscle regeneration capacity declines (Ehrhardt
and Morgan, 2005). The impoverishment of the reserve pool of
satellite cells contributes to this process (Welle, 2002). It has been
demonstrated that the number of satellite cells per myober in
mice is reduced with aging (Shefer et al., 2006). In humans, this
decrease seems to be more evident for satellite cells associated with
type II myobers, corresponding to the specicity of ber loss with
advancing age, i.e., a specic loss of type II bers (Verdijk et al.,
2014). The reduction in satellite cell number is partly explained by
changes in (i) proliferation, (ii) response to stimuli inducing prolif-
eration, and (iii) capacity to replenish the reserve pool of satellite
cells (Conboy et al., 2005; Day et al., 2010). Barani et al. have demon-
strated that entry into the proliferation phase is delayed for muscle
cells derived from aged compared with young rats. Specically,
the doubling time of these cells is increased, and the expression of
the proliferation marker PCNA in response to proliferating stimuli
is decreased (Barani et al., 2003). Telomere reduction throughout
the proliferation cycles likely contributes to the decrease in the
proliferation capacity of satellite cells, as demonstrated in satel-
lite cells isolated from aged and young individuals (Decary et al.,
29
1997; Hawke and Garry, 2001; Renault et al., 2000). The increased
expression of cell cycle inhibitors seems to contribute to the reduc-
tion in satellite cell proliferation with age (Barberi et al., 2013). The
aged niche disrupts muscle stem cell quiescence and self-renewal
capacity through a constant production of FGF-2 (broblast growth
factor-2), even without muscle lesion (Chakkalakal et al., 2012).
Interestingly, this phenomenon leads to a non-polarized overacti-
vation of the p38 pathway during satellite cell division (Bentzinger
and Rudnicki, 2014).
The differentiation capacity of satellite cells is also reduced with
aging. In vitro, it has been demonstrated that satellite cell entry
into the differentiation program is delayed in aged compared with
young mice, as a result of reduced capacity to proliferate (Shefer
et al., 2006). Furthermore, the number of satellite cells engaged
in the differentiation program (expressing differentiation markers
such as desmin and myogenin) is decreased in aged mice (Charge
et al., 2002; Collins et al., 2007).
Studies have found that the expression of myogenic regulatory
factors (MRF) known to control the differentiation program, such as
Myf-5, MyoD, myogenin, and MRF4/Myf6, is reduced in senescent
human satellite cells and in aged rat muscle (Alway et al., 2002;
Bigot et al., 2008; Degens, 2007). The decrease in MRF expression
is likely due to the increased expression of inhibitors of the differ-
entiation (Id) process (Alway et al., 2002). Finally, the regenerating
myober numbers and the expression of the terminal differentia-
tion marker, i.e. myosin, are reduced in aged mice following a lesion
(Conboy et al., 2003, 2005). Similarly, the differentiation of satellite
cells into myotubes, and the expression of myosin are decreased
in aged rat muscle (Lees et al., 2006). Additionally, the culture of
satellite cells isolated from aged and young subjects has revealed
the altered muscle cell differentiation with aging, illustrated by the
decrease in fusion index and by the reduction in the number of
desmin-positive satellite cells (Beccaco et al., 2007).
Interestingly, a signaling pathway has been identied as respon-
sible, at least in part, for the decrease in muscle regeneration
capacity, namely the Notch signaling pathway (Conboy et al., 2003).
Following muscle lesion, the Notch pathway is activated, promoting
satellite cell proliferation and self-renewal (Fig. 2). In addition, the
inhibition of this pathway allows the cells to enter the differentia-
tion program (Conboy and Rando, 2002). Several in vitro and in vivo
studies have clearly established that the activity of the Notch sig-
naling pathway decreases with aging (Carlson and Faulkner, 1989;
Carlson et al., 2009; Conboy et al., 2003, 2005). Another pathway,
the Wnt signaling pathway, is also involved in the reduction in mus-
cle repair capacity with aging (Arthur and Cooley, 2012). Following
muscle injury, when Notch activity is inhibited to allow muscle
cell differentiation, the Wnt pathway is activated (Fig. 2) (Jang
et al., 2011). It then promotes the entry and progression of satellite
cells through the differentiation program (Brack et al., 2008; Yin
et al., 2013). However, the required balanced activation between
the Notch and Wnt pathways is altered with aging. Furthermore,
the hyperactivity of Wnt signaling leads to exit of satellite cells from
the myogenic differentiation program and induces a brogenic pro-
gram (Brack et al., 2007).
It should be noted that the reduction of the number of satel-
lite cells with aging have been observed in rodents models and in
humans. In addition, the effect of aging of Notch signaling pathway
and its consequence on satellite cells were observed in both rodents
and humans. Similarly, the decrease in satellite cell differentiation
observed in animals was conrmed in humans. Thus future inves-
tigations have to develop strategies to prevent the reduction of
satellite cell proliferation and differentiation associated with aging.
All of these data show that muscle regeneration declines with
aging not only through the intrinsic modications of satellite cells,
but also through the changes in their environment, which has a
direct impact on cell function. Of note, the loss of muscle regenera-
30 C. Domingues-Faria et al. / Ageing Research Reviews 26 (2016) 2236

Fig. 2. Notch and canonical Wnt signaling pathways activated in satellite cells during skeletal muscle differentiation.
After injury the expression of the transmembrane ligand Delta-like is stimulated in satellite cells and myobers. Delta-like binds to Notch receptor, which activates the Notch
pathway. Two proteolytic cleavage events then occur. The rst involves an ADAM protease (a disintegrin and a metalloprotease) cleaving the Notch receptor and generating a
transmembrane fragment of Notch: TM Notch. TM Notch is then cleaved by a -secretase complex, the second cleavage event, leading to the release of the intracellular domain
of Notch: Nicd Notch. Nicd Notch migrates to the nucleus where it acts as a transcription factor. It interacts with RBP-J associated with corepressors allowing the recruitment
of co-activators, and the stimulation of the expression of target genes. These genes are involved in the inhibition of differentiation and the maintenance of cell renewal. The
activation of the Notch pathway promotes the proliferation and renewal of satellite cells following injury, and the inhibition of this pathway by Numb protein allows the
satellite cells to enter the differentiation program. During the differentiation phase, the canonical Wnt pathway is activated. Wnt proteins bind to the Frizzeld (Fzd) receptor
and to the co-receptor low-density lipoprotein receptor-related protein (LRP). Heterotrimeric G proteins and disheveled (Dsh) are then activated, leading to the release of
-catenin from its complex of degradation made of axin, casein kinase 1 (CK1), adenomatous polyposis coli (APC) and serine-threonine kinase glycogen synthase kinase-3
(GSK-3). Thus -catenin accumulates in the cytoplasm and translocates into the nucleus, where it acts as a transcriptional co-activator. -catenin binds to the TCF/LEF
family of transcription factors. In this context, canonical Wnt signaling leads to the expression of genes involved in the regulation of the muscle cell differentiation. During
skeletal muscle regeneration, a switch from Notch to canonical Wnt signaling is necessary for the transition of the proliferation phase to the differentiation phase in satellite
cells.

tion capacity with age appears to be reversible. This observation
opens up the possibility of devising strategies for slowing the
decline of the process.
4. Effect of aging on immune and muscle cell cross-talk and
consequences for skeletal muscle repair
With aging, the efcacy of muscle regeneration is signicantly
decreased. Studies have demonstrated that the reduction in the
potential of muscle to regenerate is due to a decrease in the activa-
tion, proliferation and renewal of the satellite cells, as well as in the
differentiation into myobers, although some of the observations
reported in the literature are controversial (Ciciliot and Schiafno,
2010; Garcia-Prat et al., 2013; Shefer et al., 2006). The alteration
of the immune response with aging is also a muscle regeneration
disturbing factor due to its role in the stimulation of satellite cell
proliferation and differentiation (Shaw et al., 2013). Immunose-
nescence contributes to the development of a chronic low-grade
inammation state. We hypothesize that this phenomenon, in addi-
tion to the age-related changes of muscle cell metabolism and
function, could disrupt the cross-talk between immune and mus-
cle cells, likely contributing to the decrease in muscle regeneration
with age. The dialog between these two cell types has been widely
studied in in vitro muscle regeneration models or using young ani-
mals (for review (Pillon et al., 2013; Tidball and Villalta, 2010)),
but infrequently in a context of aging. During muscle regeneration,
macrophages protect satellite cells from apoptosis (Sonnet et al.,
2006). However, this protection is blunted during aging (Krajnak
et al., 2006). It has been shown that numbers of activated satellite
cells (i.e. those expressing MyoD) increase in both aged (30 month)
and young (3 month) rats after a muscle lesion (Krajnak et al., 2006).
Nevertheless, the number of satellite cells expressing MyoD and the
pro-apoptotic marker Bax were higher in aged rats, contributing to
the reduced muscle regeneration in these animals (Krajnak et al.,
2006).
In vitro, the percentage of satellite cells expressing activated
caspases following TNF- treatment was augmented in muscle cell
population isolated from aged rats (31 months) compared with
adult (9 months) or young rats (3 months) (Jejurikar et al., 2006).
Of note, the expression of the anti-apoptotic marker Bcl-2 (B-cell
lymphoma 2) was reduced in aged compared with adult and young
rats (Jejurikar et al., 2006). These results demonstrate that muscle
 C. Domingues-Faria et al. / Ageing Research Reviews 26 (2016) 2236
satellite cells are likely more sensitive to apoptosis process with
aging.
All these ndings show that environmental and intrinsic
changes in satellite cells with aging make them more suscepti-
ble to apoptosis, rendering muscle regeneration less efcient. In
addition, the increased sensitivity of satellite cells to TNF- implies
that functional and secretory modications of immune cells, jointly
with age-related changes in muscle cells, leads to the perturbation
of immune/muscle cell cross-talk, and thus impairs muscle repair
capacity.
The involvement of functional modications of immune cells
during muscle regeneration and with aging has been demon-
strated in humans. In the basal state, muscles of older men (71
years) contained fewer macrophages than those of young men
(32 years) (Przybyla et al., 2006). Furthermore, pro-inammatory
macrophages were less abundant, whereas the number of anti-
inammatory macrophages remained unchanged compared with
young volunteers (Przybyla et al., 2006). After an acute resistance
exercise, the number of pro- and anti-inammatory macrophages
rose in the muscles of young men, but not in older men (Przybyla
et al., 2006). Interestingly, at the basal state, gene expressions of
pro-inammatory cytokine IL-1 and anti-inammatory cytokines
IL-1RA and IL-10 were increased in muscles of elderly subjects com-
pared with younger ones (Przybyla et al., 2006). After exercise, the
expression of these cytokines was unchanged in older subjects, but
was stimulated in the younger group (Przybyla et al., 2006). It has
also been demonstrated that 2 h after acute exercise, the expres-
sions of pro-inammatory cytokines MCP-1, IL-6 and IL-8 were
greater in elderly than in young subjects, but a 12-week period of
training attenuated this difference (Della Gatta et al., 2014). These
ndings evidence a failure in the regulation of macrophage function
with aging, leading to altered immune response following muscle
injury, and consequently to the modication of immune and mus-
cle cell cross-talk. It is noteworthy that exercise is not equal to
muscle injury as the mechanism of skeletal muscle repair is differ-
ent (Paulsen et al., 2012). To elucidate skeletal muscle regeneration
process in animals, protocols specically designed to induce exten-
sive muscle damages (infusion of cardiotoxin, infusion of myotoxin,
crush injury. . .) have been used. Obviously, such muscle injuries
are ethically non-feasible in humans. Thus, protocols of exercises
have been used to induce muscle lesions in order to study skeletal
muscle regeneration in humans (Przybyla et al., 2006).
An in vitro study clearly demonstrated that aged muscle cells
were less sensitive to immune secretions (Dumke and Lees, 2011). A
T cell-conditioned medium stimulated the proliferation and migra-
tion of satellite cells isolated from muscles of young rats, but failed
to produce the same effects on satellite cells isolated from mus-
cles of old rats. Finally, this environment, i.e., a T cell-conditioned
medium, did not modify the differentiation of satellite cells from
young animals, but inhibited the differentiation of satellite cells
sampled in old rats (Dumke and Lees, 2011).
These results demonstrate that the satellite cell response to
immune cells changes with aging, as well as the immune response
to muscle cells. This alteration likely contributes to the age-related
change in the muscle regeneration process.
Of note in vitro and animal studies have demonstrated that aged
muscle cells are less sensitive to immune cell effects, i.e. protec-
tion from apoptosis and stimulation of proliferation and migration.
In addition, it has been demonstrated in humans that inltration
of immune cells following muscle injury is modied during aging.
This results predicts a possible alteration of the cross-talk between
immune and muscle cells that can possibly alter skeletal muscle
repair. In this context investigations are needed to understand the
consequences of aging on immune and muscle cell cross-talk to
boost muscle repair efciency during aging.
31
The profound changes in the immune and muscle cell functions
disrupt the metabolic and functional cross-talk between these two
cell types, and so modify muscle regeneration. Additional studies
are needed to understand the consequences of aging on muscle
and immune cell function, and thereby on muscle regeneration.
The specic mechanisms and molecular pathways that are modi-
ed with aging remain to be elucidated. Such work will help us to
devise strategies to preserve or improve the capacity of muscle to
regenerate as we age.
5. Nutrition and muscle regeneration
Dietary habits directly impact the capacities of muscle to regen-
erate. In recent years, some studies have demonstrated that diets
and/or nutrients can modulate muscle repair capacity, even in early
life. In mice exposed to a prenatal undernutrition and/or to a post-
natal high-fat diet, frequencies (% of live cells) of skeletal muscle
precursors and muscle regeneration were reduced following freeze
injury (Woo et al., 2011).
Obesity is associated with a decrease in the potential of skeletal
muscle to regenerate (for review (Akhmedov and Berdeaux, 2013)).
In obese individuals, lipids accumulate excessively in adipose tis-
sues, and ectopically in non-adipose tissues like skeletal muscles.
In this tissue, accumulated lipids are likely able to impair the repair
process following injury. Moreover, obesity is recognized as a state
of chronic inammation (Akhmedov and Berdeaux, 2013). Acute
inammation is one of the main steps in the process of muscle
regeneration (Tidball and Villalta, 2010), and so the tight cross-talk
between muscle and immune cells is likely to be modied in such
a situation. Interestingly, loss of muscle mass with no loss of body
weight is systematically reported with aging, as signicant accu-
mulation of body fat occurs. Accumulation of intramuscular fat was
observed in this context (Walrand et al., 2011). Thus aging together
with tissue lipotoxicity likely impairs skeletal muscle regeneration.
Beside the effect of lipid inltration, nutritional strategies to
stimulate muscle regeneration have been attempted. In young
healthy subjects, whey protein supplementation seems to accel-
erate the proliferation of satellite cells following high-intensity
eccentric exercise (Farup et al., 2014). Dietary whey protein is rich
in leucine, an essential amino acid. Pereira et al. (2014a) have
demonstrated that leucine supplementation increases myober
size, and limits the decrease in muscle function and macrophage
inltration following the cryolesion of young rat muscles. How-
ever, the overall macrophage population was investigated without
distinction of phenotypes. Author concluded from this result
that the regenerating muscles supplemented with leucine might
have an acceleration of inammatory process installation and a
more efcient function of immune cells stimulated by increased
amino acid substrates (Pereira et al., 2014a). This modication
of immune response following leucine supplementation likely
improves muscle regeneration capacity. Finally, leucine supple-
mentation increased the expression of type II myosin heavy chain,
limited the development of brosis, and prevented the decrease
in muscle function in regenerating skeletal muscles (Pereira et al.,
2014b).
Beside whey protein, benecial effects of codsh protein on
skeletal muscle recovery have been reported (Dort et al., 2012). In
rats fed with casein or codsh proteins, codsh protein supplemen-
tation decreased M1 macrophage inltration in the muscle lesion,
whereas it increased M2 macrophage inltration and myober
cross-sectional area compared with casein group (Dort et al.,
2012). Authors concluded that effects of codsh protein might
result in a reduced necrotic zone and an accelerated switch of
pro-inammatory M1 macrophages toward the anti-inammatory
phenotype (M2), leading to the enhancement of the muscle repair
32 C. Domingues-Faria et al. / Ageing Research Reviews 26 (2016) 2236
efcacy (Dort et al., 2012). The anti-inammatory action of codsh
protein seems to be driven by its high levels of arginine, glycine,
taurine and lysine (Dort et al., 2013). Taken together, these ndings
show that the quality of dietary proteins is important for improving
skeletal muscle regeneration through the modulation of immune
response.
Long chain n-3 polyunsaturated fatty acids (n-3 PUFAs) such as
docosahexaenoic acid (DHA) or eicosapentaenoic acid (EPA) have
been described as presenting a strong anti-inammatory action
(Calder, 2006). In this context, n-3 PUFAs are likely able to modulate
immune and muscle cell cross-talk.
It has been demonstrated that EPA treatment prevents TNF-
-mediated loss of myosin heavy chain expression in C2C12
myotubes (Magee et al., 2008). Furthermore, EPA protected C2C12
from TNF--mediated cell death and increased myogenic fusion
(Magee et al., 2008).
Treatment with DHA of human myotubes cocultured with
inammatory macrophages reduced the expression of the muscle-
specic ubiquitin ligase muscle RING-nger protein-1 (MuRF1)
involved in proteolysis (Murton et al., 2008). In this context, DHA
may favor protein anabolism by inhibiting proteolysis, which pro-
motes recovery of regenerating skeletal muscles as previously
described for leucine supplementation (Pereira et al., 2014a). These
in vitro studies demonstrate that long chain n-3 PUFAs may have a
benecial effect on skeletal muscle regeneration.
Polyphenols also belong to the family of nutrients displaying
anti-inammatory properties. The intake of these compounds may
therefore modify the cross-talk between immune and muscle cells,
and consequently the time course of muscle regeneration. In rats,
the administration of proanthocyanidolic oligomer (PCO) resulted
in earlier activation of satellite cells following muscle contusion
injury (Myburgh et al., 2012). Neutrophil number was also blunted
and macrophage response was normal but earlier in the muscle
of PCO group. Muscle ber regeneration was more precocious in
the muscle of PCO group (Myburgh et al., 2012). These ndings
demonstrate that the modulation of inammatory response can
improve skeletal muscle regeneration.
The consumption of a diet enriched with green tea extract rich
in polyphenols decreased serum creatine kinase, an indicator of
muscle damage, in mdx mice (Evans et al., 2010). In addition, the
area of muscle ber was increased, whereas regenerating ber area
was reduced. Lastly, NF-B activity was diminished in regenerat-
ing muscle bers of mdx mice supplemented with green tea extract
(Evans et al., 2010). In dystrophic muscle pathology, muscle degen-
eration is a characteristic of the disease and skeletal muscle repair is
unable to occur successfully (Tidball and Wehling-Henricks, 2004).
These results demonstrate that green tea extract decreases dys-
trophic muscle pathology potentially by regulating NF-kB activity
in regenerating muscle bers and by limiting degenerative areas.
Vitamin D is likely a good candidate to stimulate muscle recov-
ery, as immune and muscle cells are preferred targets of this
nutrient (Ceglia and Harris, 2013; Hewison, 2011). Srikuea et al.
(2012) have demonstrated that expressions of vitamin D recep-
tor (VDR) and 25-hydroxyvitamin D3 1--hydroxylase (also called
CYP27B1) were up-regulated following acute lesions in adult mice.
In another animal model, the infusion of vitamin D3 led to an
increase in proliferation and a decrease in apoptosis in injured mus-
cle (Stratos et al., 2013). Owens et al. (2015) have demonstrated
that muscle cell migration dynamics, myotube fusion, differentia-
tion and hyperthophy of myoblasts derived from biopsies of young
volunteers presenting vitamin D insufciency were improved fol-
lowing vitamin D treatment. In a clinical trial, the same research
team highlighted that the supplementation in vitamin D3 of young
men presenting vitamin D insufciency leads to the improvement
of peak torque recovery following damaging eccentric contractions
of the knee extensors (Owens et al., 2015). Taken together, this
results demonstrate the direct effect of vitamin D on muscle cells,
leading to the improvement of skeletal muscle recovery.
Knowing that vitamin D has effects not only on muscle cells
(Ceglia and Harris, 2013), but also on immune cell functions
(Hewison, 2011), it seems important to investigate the action of
vitamin D on specic immune response during muscle regenera-
tion.
In an animal model of skeletal muscle regeneration, the num-
ber of inltrated immune cells on injury site was not modied
by vitamin infusion (Stratos et al., 2013). Of note, in this study,
the overall immune cell population was investigated without dis-
tinction of immune cell types. Interestingly in another rodent
model, vitamin D infusion interfered with the increase in pro-
inammatory cytokine expressions in muscle following intensive
physical exercise in rats (Choi et al., 2013). In addition, it has
been demonstrated that vitamin D-decient subjects displayed a
decrease of blood concentration of anti-inammatory cytokines
IL-10 and IL-13 following physical training, compared to healthy
volunteers. Furthermore, muscle strength was more rapidly recov-
ered in non-decient men (Barker et al., 2013, 2014). Taken
together, this results highlight that vitamin D is able to modulate
circulating and muscle-specic cytokine expression, and possibly
immune and muscle cell cross-talk during muscle repair. These
studies conrm that vitamin D likely modulates immune response
following muscle injury.
Finally, our research group have demonstrated in old rats that
vitamin D deciency down-regulates the Notch pathway, known to
play a leading role in muscle regeneration (Domingues-Faria et al.,
2014). In this context, vitamin D deciency could aggravate the
age-related decrease in muscle regeneration capacity.
Taken together, these results show that the effect of nutrition on
skeletal muscle regeneration efcacy is an emerging topic of inter-
est. Unfortunately, investigations on nutrition and muscle repair in
the context of aging are very scarce. More research are needed in
this scientic area to dene strategies able to prevent ineffective
and/or incomplete muscle repair. This would be of great interest
particularly in older people in which ineffective muscle repair con-
tributes to muscle mass loss and sarcopenia (Walrand et al., 2011).
Nutritional strategies need to be considered not only during aging
but in all situations where muscle repair may be committed: in
pathologies associated with muscle damage, or among athletes,
who regularly undergo muscle regeneration processes.
Note that the effect of n-3 PUFAs on muscle cells have only
been demonstrated in an in vitro model and further conrma-
tion in rodents and/or humans have to be undertaken. However,
the possible benecial effects of nutrition and nutrients, i.e. pro-
teins, polyphenols and vitamin D, in muscle regeneration have been
highlighted in animal models and human. Nutritional strategies
have to be taken into consideration to improve skeletal muscle
regeneration, particularly during aging, but more investigations
are needed in this area. To this day, vitamin D supplementation
seems to be a meaningful nutritional strategy to improve skeletal
muscle regeneration in young and old people. Numerous studies
have demonstrated that immune and muscle cells are vitamin D
targets (Ceglia and Harris, 2013; Hewison, 2011), these two types
of cells being implicated in muscle repair (Tidball and Villalta,
2010). During skeletal muscle regeneration, markers of vitamin D
metabolism are up-regulated showing that vitamin D is implicated
in this process (Srikuea et al., 2012). Clinical trials have demon-
strated that vitamin D insufciency impairs functional recovery
of skeletal muscle after damaging physical exercise (Barker et al.,
2013; Owens et al., 2015). Furthermore, vitamin D supplementa-
tion leads to the improvement of skeletal muscle recovery (Owens
et al., 2015). Thus, vitamin D seems to be a promising nutritional
strategy to stimulate skeletal muscle repair. Interestingly, skele-
tal muscle regeneration capacity is impaired with aging and it is
 C. Domingues-Faria et al. / Ageing Research Reviews 26 (2016) 2236
considered as a key factor of sarcopenia (Decary et al., 1997; Jang
et al., 2011; Lenk et al., 2010). In parallel, vitamin D deciency is
very common in elderly population and has been associated with
muscle weakness (Holick, 2007). In this context, vitamin D sup-
plementation is likely the meaningful strategy to enhance skeletal
muscle regeneration in old subjects in order to limit sarcopenia
development.
6. Conclusion
Muscle regeneration is a highly controlled and complex pro-
cess, with the intervention of many cell types. Any change in the
functional capacities of one of these cells may compromise skeletal
muscle repair. During aging, the alteration of satellite cell activa-
tion, proliferation and differentiation, jointly with the changes in
immune cell functions and ability to secrete key controllers, impair
the capacity of skeletal muscle to regenerate. The decreased ef-
ciency of skeletal muscle recovery is one of the factors contributing
to sarcopenia (Ali and Garcia, 2014; Beyer et al., 2012), dened as
the loss of skeletal muscle mass and strength as we age. Sarcopenia
is one of the most important factors of disability in older people
(Walrand et al., 2011). Thus strategies need to be developed to
counteract or at least to limit the inefciency of muscle repair with
aging. Nutritional strategies seem to be a good and a safe way to
improve muscle regeneration with aging, as some nutrients are able
to modulate immune or muscle cell functions, or both. In this con-
text, the quality of both diet and nutrient supplementation has to
be oriented to improve and maintain muscle regeneration capacity.
Developing these nutritional strategies will be of great interest not
only in the context of aging, but also in all situations leading to mus-
cle damage and consequent muscle regeneration. This can be the
case for chronic pathologies associated with muscle damage such as
cachexia. Finally, some non-pathological situations are associated
with strong and frequent periods of skeletal muscle regeneration,
e.g., among athletes. In this population, dietary prescription has to
consider improvement of both physical performance and muscle
regeneration capacities. A suitable diet could help lower recovery
time, and improve the quality of muscle repair between successive
physical training sessions.
Conicts of interest
All the authors declare that there are no conicts of interest.
Acknowledgment
Figs. 1 and 2 were produced with the assistance of Servier Med-
ical Art.
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