Nutrition, Metabolism & Cardiovascular Diseases (2013) 23, S12eS18

Available online at www.sciencedirect.com

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

REVIEW

Role of satellite cells in muscle growth

and maintenance of muscle mass
G. Pallafacchina a,b,c, B. Blaauw a,c, S. Schiaffino a,b,*
a

Venetian Institute of Molecular Medicine (VIMM), Padova, Italy

Consiglio Nazionale delle Ricerche (CNR) Institute of Neurosciences, Padova, Italy
c
Department of Biomedical Sciences, University of Padova, Padova, Italy
b

Received 16 July 2011; received in revised form 1 February 2012; accepted 6 February 2012
Available online 22 May 2012

KEYWORDS
Skeletal muscle;
Satellite cells;
Muscle hypertrophy;
Muscle atrophy

Abstract Changes in muscle mass may result from changes in protein turnover, reflecting the
balance between protein synthesis and protein degradation, and changes in cell turnover, reflecting the balance between myonuclear accretion and myonuclear loss. Myonuclear accretion, i.e. increase in the number of myonuclei within the muscle fibers, takes place via
proliferation and fusion of satellite cells, myogenic stem cells associated to skeletal muscle
fibers and involved in muscle regeneration. In developing muscle, satellite cells undergo extensive proliferation and most of them fuse with myofibers, thus contributing to the increase in
myonuclei during early postnatal stages. A similar process is induced in adult skeletal muscle
by functional overload and exercise. In contrast, satellite cells and myonuclei may undergo
apoptosis during muscle atrophy, although it is debated whether myonuclear loss occurs in
atrophying muscle. An increase in myofiber size can also occur by changes in protein turnover
without satellite cell activation, e.g. in late phases of postnatal development or in some
models of muscle hypertrophy. The relative role of protein turnover and cell turnover in
muscle adaptation and in the establishment of functional muscle hypertrophy remains to be
established. The identification of the signaling pathways mediating satellite cell activation
may provide therapeutic targets for combating muscle wasting in a variety of pathological
conditions, including cancer cachexia, renal and cardiac failure, neuromuscular diseases, as
well as aging sarcopenia.
2012 Elsevier B.V. All rights reserved.

* Corresponding author. Venetian Institute of Molecular Medicine (VIMM), Via Orus 2, 35129 Padova, Italy. Tel.: 39 49 7923232;
fax: 39 49 7923250.
E-mail address: stefano.schiaffino@unipd.it (S. Schiaffino).
0939-4753/$ - see front matter 2012 Elsevier B.V. All rights reserved.
doi:10.1016/j.numecd.2012.02.002

Satellite cells and muscle growth

Introduction
The regulation of muscle mass has been traditionally
considered in purely biochemical terms as a problem of
protein turnover, namely as the result of the balance
between protein synthesis and protein degradation.
However, it is now clear that cell turnover is also involved in
muscle growth and maintenance of muscle mass: addition of
new myonuclei due to fusion of satellite cells, the stem cells
of skeletal muscle, can take place during myofiber hypertrophy, while loss of myonuclei via apoptosis has been reported during muscle atrophy. One can also envisage an
intermediate level of regulation represented by organelle
turnover, such as myofibril assembly (myofibrillogenesis) and
disassembly, or mitochondrial biogenesis and mitochondrial
loss. In other words, it is now apparent that muscle growth
should be viewed with the eyes of a cell biologist rather than
of a pure biochemist. In this new perspective, we focus here
on satellite cells. While the central role of satellite cells in
muscle regeneration is well established and is not discussed
here (see [1] for a recent review and [2] for a collection of
essays), the role of these cells in muscle hypertrophy is less
clear. In this short overview we address the contribution of
satellite cell to muscle growth, both during development and
in adult skeletal muscle.

Muscle satellite cells

Satellite cells are mononucleated stem cells with myogenic
potential located under the basal lamina of myofibers but
possessing their own plasma membrane, distinct from the
plasma membrane of the myofibers (see [3]). In adult
skeletal muscles satellite cell nuclei represent 3e6% of all
muscle nuclei (nuclei contained within the basal lamina)
and are more frequent in slow compared to fast fibers in rat
and mouse muscles [4]. Satellite cells can be recognized by
the presence of specific markers, including transcription
factors, such as Pax7, or surface membrane proteins, such
as N-CAM, M-cadherin and CD34 (see [5]). Quiescent satellite cells are readily activated by muscle damage and
acquire a new gene expression profile [6], which includes
the up-regulation of myogenic regulatory factors, such as
MyoD and myogenin. Following muscle injury, satellite cells
undergo asymmetric divisions leading to the formation of
undifferentiated cells, which return to quiescence and thus
replenish the satellite cell compartment, and differentiated myoblasts which form new myofibers. The study of
muscle satellite cells is complicated by the existence of
a wide heterogeneity of satellite cell populations, both
with respect to embryological origin (head vs. body
muscles), muscle fiber type (fast vs. slow muscles) and
postnatal stage (neonatal vs. adult satellite cells) [5,7]. In
addition, it has been suggested that the satellite cell pool
may contain both self-renewing stem cells and myogenic
precursors with limited replicative potential [8].

Satellite cells and postnatal muscle growth

Satellite cells are major players in muscle development.
At birth, they represent a substantial proportion of muscle

S13
nuclei, up to 30% in neonatal rat and mouse muscles. The
classical study of Moss and Leblond, based on 3H-thymidine incorporation and autoradiography, showed that
satellite cells undergo extensive proliferation during the
first weeks after birth in rat muscles and that most of
these cells are subsequently incorporated into the growing
myofibers [9]. Myonuclear accretion by satellite cell
proliferation/fusion is likely required for myofiber growth,
in order to maintain a constant myonuclear domain, i.e.
the ratio of cytoplasm to nucleus within the multinucleated muscle fibers (but see below). However, a formal
proof that satellite cell proliferation/fusion is necessary
for myofiber growth is lacking. It is known that Pax7 is an
essential factor for maintaining the satellite cell pool in
neonatal muscle, whereas Pax7 is no longer required for
satellite cell survival and muscle regeneration at later
developmental stages [10], although the issue remains
controversial [11]. Attempts at conditional satellite cell
ablation during the neonatal period using tamoxifen
inducible expression of diphtheria toxin A-chain in Pax7
expressing cells failed because the animals died within
a few days, presumably due to expression of Pax7-driven
Cre in other tissues (C-M Fan, personal communication).
Satellite cell proliferation in developing skeletal muscle is
dependent on innervation, as it is drastically reduced
one day after denervation of neonatal (6-day-old) rat
muscles [12].
Nuclear turnover during postnatal muscle growth has
been recently reinvestigated in a mouse fast-twitch leg
muscle, the extensor digitorum longus [13]. Two stages
were identified (Fig. 1): i) an initial stage, corresponding to
the first three postnatal weeks, characterized by a parallel
increase in number of myonuclei and amount of cytoplasm;
and ii) a later stage after P21 with increase in cytoplasm
and fiber size but without addition of new myonuclei. The
proportion of satellite cells steadily decreases from P6
(about 12% of muscle nuclei) to P21 (about 2%), with no
further change thereafter. Two important lessons can be
learned from this study: first, a muscle fiber can grow in
two ways, either by myonuclear accretion or without
increase in number of myonuclei; second, in mature
muscle fibers the myonuclear domain, i.e. the ratio of
cytoplasm to nucleus, is not fixed but rather flexible.
Actually, myonuclear domain increases throughout postnatal development.

Satellite cells in muscle hypertrophy

In adult skeletal muscle satellite cells are mitotically
quiescent and there is no evidence for myonuclear turnover, except during late stages of life (see below), or during
muscle regeneration, hypertrophy or atrophy. Does proliferation/fusion of satellite cells, such as seen in developing
muscle, take place also during hypertrophy of adult skeletal
muscle? Functional overload-induced by tenotomy or
elimination of synergistic muscles leads to rapid activation
of satellite cells, which undergo proliferation and fuse
with the associated myofibers [4,14a,14b]. Incorporation of
3
H-thymidine in satellite cell nuclei was detected in the rat
soleus muscle few days after tenotomy of the synergistic
gastrocnemius muscle, before any evidence of myofiber

S14

G. Pallafacchina et al.

Figure 1 Postnatal growth of the mouse extensor digitorum longus muscle. A, myofiber cross-sectional area (CSA); B, number of
myonuclei per myofiber. Note that the CSA increases throughout the postnatal period considered (up to 56 days after birth),
whereas the number of myonuclei increases exponentially from P3 to P21, but shows a negligible increase after P21. Modified
from [13].

hypertrophy (Fig. 2). This leads to a marked increase in the

number of satellite cells in hypertrophying muscles (Table
1). Accordingly, in a similar experimental model an
increase in myonuclei was detected during the first week
post-surgery and preceded myofiber hypertrophy [15].
Interestingly, when the hypertrophied muscle was subsequently denervated, the increase in the number of myonuclei was maintained even after three months [15].
Satellite cell proliferation is also induced by exercise, both
in animal models [16] and in humans [17a]. In humans, the
satellite cell pool can increase as early as 4 days after
a single bout of exercise and is maintained at higher levels
following several weeks of training, while cessation of
training leads to a gradual reduction of the satellite cell
pool [17a]. Exercise in humans, like electrical stimulation in
animal models [17b], can induce muscle damage, which is
especially evident following eccentric exercise, such as
downhill running, especially in untrained individuals.
Indeed, most studies showing satellite cell activation have
used a maximal eccentric exercise protocol, although
a significant satellite cell response can be observed also in
the absence of gross muscle damage and without inflammatory cell infiltration [18].

Is satellite cell proliferation/fusion required for muscle

hypertrophy? This question was addressed some years ago in
a Point/Counterpoint debate, however no definitive
conclusion could be reached (see [19,20] and related
comments). Gamma radiation experiments have shown that
overload-dependent muscle hypertrophy [21] and activitydependent satellite cell activation [16] are blocked by Xray or gamma ray radiation, suggesting an obligatory role of
satellite cells in muscle hypertrophy. However, interpretation of this experiment is complicated by possible effects of
gamma radiation on myofiber protein synthesis [22]. Indirect
evidence for a role of satellite cells in human skeletal muscle
was provided by studies comparing individuals showing
variable degree of myofiber hypertrophy after several weeks
of resistance training: individuals developing marked
hypertrophy (responders) had a greater proportion of satellite cells at baseline and greater satellite cell-mediated
myonuclear addition after exercise compared to individuals
who did not exhibit any change in fiber size (non-responders)
[23]. However, different genetic animal models support the
notion that satellite cell activation is not required for muscle
hypertrophy, as discussed in the following section.

Genetic models of muscle hypertrophy

In one genetic model, muscle hypertrophy was produced by
an inducible Akt transgene [24]. Akt is a kinase that
Table 1 Increase in number of satellite cells in the rat
soleus muscle during early stages of compensatory
hypertrophy.a

Figure 2 DNA synthesis in a satellite cell. Electron microscope autoradiography showing 3H-thymidine incorporation in
a satellite cell of the rat soleus muscle 4 days after tenotomy
of the synergistic gastrocnemius muscle. A single injection of
labeled thymidine was given 6 h before muscle removal. The
satellite cell nucleus is overlaid with silver grains, indicating
that it has taken up labeled thymidine during the premitotic
DNA synthesis. From [4].

Days after surgery

% Satellite cells

0
2
5
8

4.9
12.7
17.8
15.1

a
Changes seen in adult rat soleus after tenotomy of the
gastrocnemius muscle. Seven animals were used, and a total of
501 muscle nuclei were counted in electron micrographs from
51 transverse sections, each cut from a different block. Satellite cell number is expressed as percent of total muscle nuclei
(true myonuclei satellite cell nuclei). From [4].

Satellite cells and muscle growth

mediates the effect of insulin-like growth factor 1 (IGF-1)
and promotes protein synthesis, by activating mTOR and
S6K, and inhibits protein degradation by repressing the
transcription factor FoxO [25]. Muscle hypertrophy caused
by muscle-specific activation of an inducible Akt transgene
is not accompanied by satellite cell proliferation, as
assessed by BrdU incorporation [26]. Over-expression of the
transcription factor JunB likewise causes muscle fiber
hypertrophy without satellite cell proliferation [27]. Myostatin, a transforming growth factor-b (TGF-b) family
member acting via activin receptors and Smad transcription
factors, is a negative regulator of muscle growth, as
absence or blockade of myostatin causes muscle hypertrophy. The hypertrophic muscle fibers of the myostatin
null mice were reported to contain fewer myonuclei per
fiber than their controls and satellite cell-independent
muscle hypertrophy was seen in adult muscle following
myostatin blockade induced by local injection of vectors
coding for the myostatin propeptide, which binds noncovalently to myostatin and inhibits its activity [28].
However, inhibition of myostatin signaling in adult mice
using soluble ActRIIB, an activin type 2 receptor specific for
myostatin and a subset of TGF-b family ligands, was found
to induce an increased incorporation of BrdU, indicating
DNA synthesis, in muscle nuclei and increased proportion of
satellite cells labeled by Pax7 and M-cadherin [29]. The
discrepancy between these results might be due to the fact
that signaling of multiple TGF-b ligands, and not only of
myostatin, is inhibited using soluble ActRIIB [30]. Other
experiments suggest that satellite cell activation contributes to the increase in muscle mass induced by local viralmediated gene transfer of IGF-1, since muscle hypertrophy
in this model is partially prevented by gamma radiation to
destroy the proliferative capacity of satellite cells [31]. As
pointed out before, radiation experiments are difficult to
interpret, and only a genetic approach to block satellite
cell activation in an inducible way in adult muscle, could
provide direct evidence for an obligatory role of satellite
cells in muscle hypertrophy. Indeed, conditional ablation of
>90% of satellite cells was recently obtained in mature
skeletal muscle using tamoxifen inducible expression of
diphtheria toxin A-chain in Pax7 expressing cells [32].
Overload hypertrophy and increase in force of the plantaris
muscle after removal of the synergist gastrocnemius was
unchanged in these mice supporting the notion that satellite cells are not necessary for functional muscle hypertrophy [32]. However, in a physiological context, satellite
cells do undergo proliferation and fusion during overload
hypertrophy and it remains possible that they do contribute
to functional hypertrophy: adaptive changes in the protein
synthesis/protein degradation balance within the myofibers
might occur in the absence of satellite cells thus leading to
an apparently normal hypertrophy process [11]. Indeed,
a complex cross-talk between myofibers and satellite cells
take place during muscle hypertrophy, a shown by the
finding that deletion of serum response factor (SRF)
specifically in myofibers and not in satellite cells blunts
overload-induced hypertrophy and impairs satellite cell
proliferation and recruitment to pre-existing fibers [33]. It
will be important to establish whether functional hypertrophy can be maintained for long periods without myonuclear accretion.

S15

Signaling pathways involved in satellite cell

activation
Satellite cell activation is controlled by several growth
factors, intracellular signaling pathways and transcription
factors (see [34] for a review). In addition to systemic factors,
e.g. hormones such as testosterone, local factors released
by myofibers, fibroblasts or macrophages may act on satellite cells. Cytokines, such as interleukin-4 (IL-4) [35] and
interleukin-6 (IL-6) [36], as well as prostaglandins [18,37] have
been implicated in satellite cell proliferation. The Notch and
Wnt signaling pathways appear to have a major role in
controlling the balance between satellite cell proliferation
and differentiation [38]. Notch, a membrane receptor activated by the ligand Delta, is involved in the initial proliferation
of activated satellite cells. On the other hand, Wnt signaling
(Wnt being the ligand of the membrane receptor Frizzled)
decreases the proliferative capacity and promotes the
differentiation of satellite cells to become fusion-competent
myoblasts. However, in aging muscle an increased Wnt
signaling in the myogenic progenitors, possibly resulting from
increased amounts of Wnt or Wnt-like molecules present in
the serum of aged animals and binding to Frizzled receptors,
has been implicated in the conversion of satellite cells to
a fibrogenic fate [39]. Other factors, including hepatocyte
growth factor (HGF), the ligand of the c-Met tyrosine kinase
receptor, promote satellite cells proliferation and inhibit
differentiation [40]. Magic-Factor 1, an HGF-derived engineered protein that contains two Met-binding domains and
activates the Akt pathway, was recently shown to promote
myogenic precursor cell survival and differentiation and
induce muscle hypertrophy in vivo [41].
In contrast, as discussed above, satellite cell proliferation
is impaired by inhibitory factors, such as myostatin and other
TGF-b family members. Bone morphogenetic proteins (BMPs)
permit satellite cell proliferation but prevent their differentiation [42]. IGF-1 is unique, in that it promotes both
proliferation and differentiation of satellite cells. All these
factors should be viewed as components of a complex
signaling network with multiple interactions between the
various factors. For example, myostatin inhibits activation of
Akt, but IGF-1 can dominantly block the effects of myostatin
[43,44]. Blockade of the Notch pathway likewise relieves
myostatin repression of myoblast proliferation and differentiation, and myostatin upregulates Notch downstream
target genes [45]. The intersections between the various
pathways and their relative role in satellite cells and in
myofibers have been incompletely characterized. A major
open issue here is the nature of the interactions between
satellite cells and associated myofibers, with particular
reference to the signals that satellite cells may receive from
the myofibers in an in vivo setting. IL-6 and IL-4 produced by
myofibers were recently shown to enhance satellite cell
proliferation and fusion, respectively [33].

Satellite cells in muscle atrophy and aging

Satellite cells, like muscle interstitial cells, undergo transient proliferation during the early stages after denervation
of adult skeletal muscle, possibly as a result of the inflammatory reaction induced by the degeneration of the distal

S16
stump of the transected axons [4]. However, muscle satellite
cells decrease in number at later stages after denervation
probably by apoptosis [46]. Satellite cell apoptosis has been
reported in different pathological conditions, including
unloading, muscular dystrophy, cancer cachexia and
ischemia, and can occur even in the absence of pathological
changes of the associated muscle fibers (Fig. 3). However,
systematic quantitative studies on apoptosis of satellite cells
and myonuclei in muscle pathology are missing. It is even
debated whether myonuclear loss occurs in atrophying
muscle, and recent studies indicate that denervationinduced atrophy is not accompanied by a reduction in the
number of myonuclei per fiber except in old animals [47,48].
Muscle atrophy occurs in a variety of very different conditions, including starvation, disuse, weightlessness in space
flights, cancer cachexia, renal or cardiac failure, but the
response of satellite cells and myonuclei to these conditions
has been poorly investigated.
A unique form of slowly progressive muscle atrophy,
called sarcopenia, occurs during aging. It is controversial
whether satellite cells decrease in number in aging skeletal
muscle [48,49]. On the other hand, most studies indicate
that during aging satellite cells display reduced proliferative response after damage and reduced regenerative
capacity. In aging muscle, satellite cells may also display
a tendency to adopt alternate lineages, showing fibrogenic
potential that could contribute to muscle fibrosis [39]. The

Figure 3 Apoptotic satellite cell in ischemic rat soleus

muscle. Serial, non consecutive sections of the same field. The
satellite cell shows chromatin compaction, nuclear fragmentation and condensation of the cytoplasm typical of apoptotic
cells. Note also vacuole formation (lower panel) in the
apoptotic satellite cell. In contrast, the associated muscle fiber
has a normal ultrastructure. Hanzlikova & Schiaffino, unpublished observation (see [52] for the muscle ischemia model
used in this experiment).

G. Pallafacchina et al.
age-dependent decline in satellite cell activation is not
the result of an intrinsic deficiency, but is probably due to
the environment, as shown by muscle transplantation and
parabiosis studies. Rat muscles, from either young or old
animals, autografted in young rats regenerated significantly
greater mass and developed greater maximum contractile
force than muscles autografted in old rats, suggesting that
the poor regeneration of muscles in old animals is a function of the environment provided by the old host, which is
not appropriate to promote efficient muscle regeneration
[50]. Parabiosis has been used to generate animals sharing
a common blood circulation to test the presence of circulating factors that promote or impair satellite cell activation. Heterochronic parabiosis experiments showed that
the proliferation and differentiation capacity of aged
satellite cells is restored in old mice surgically joined to
young partners [51]. Conversely, satellite cells in young
mice that had been paired with old mice showed a decline
in functionality. Thus, satellite cell function appears to be
positively influenced by the young systemic environment
and negatively affected by the old systemic environment.

Conclusions
Muscle wasting is a serious complication of a variety of
disorders, ranging from aging sarcopenia to cancer cachexia,
renal failure, cardiac failure, and neuromuscular diseases.
The development of interventions aimed at preventing the
loss of muscle tissue requires a full understanding of the
mechanisms that control muscle growth and the maintenance of muscle mass. These mechanisms have been traditionally investigated by biochemical techniques aimed at
evaluating the relative role of anabolic and catabolic phases
of protein turnover. However, muscle mass regulation may
also be controlled by cell turnover involving satellite cells
and changes in the number of myonuclei. Ongoing research
aims at exploring whether muscle growth can be promoted
and muscle atrophy can be prevented by boosting satellite
cell activation either by blocking the effect of negative
growth regulators, such as myostatin, or promoting or
mimicking the effect of growth factors, such as IGF-1.
A recent study supports the notion that addition of
myonuclei is a prerequisite for maintaining specific force in
hypertrophic muscle fibers of the mouse fast-twitch
extensor digitorum longus [53]. Myonuclear number and
force were analyzed in single fibers from two muscle
hypertrophy models, myostatin knockout and musclespecific IGF-1 overexpression. In the IGF-1 overexpression
model, muscle fiber hypertrophy is accompanied by new
myonuclear incorporation, thus the myonuclear domain
size remains unchanged, and specific force is maintained.
In contrast, a loss of specific force is seen in the fast fibers
from myostatin knockout mice, in which fiber hypertrophy
occurs without addition of myonuclei, thus leading to
expansion of the myonuclear domains.
Two recent reviews deals with the muscle stem cell
niche [54] and the role of satellite cells in muscle growth
and in different muscle hypertrophy models [55]. Agedependent changes in the stem cell niche, involving robust
expression of sprouty1 (Spry1), an inhibitor of fibroblast
growth factor (FGF) signalling, were shown to influence

Satellite cells and muscle growth

stem cell quiescence and function [56]. Aging has been
associated with diminished muscle re-growth and satellite
cell proliferation in the early recovery phase after immobility-induced atrophy in human skeletal muscle [57].
Another study shows that satellite cells appear to play little
or no role in myostatin/activin A signaling in vivo, since i)
myostatin/activin A inhibition can cause muscle hypertrophy in mice lacking either syndecan4 or Pax7, both of
which are essential for satellite cell function, and ii) muscle
hypertrophy after pharmacological blockade of this
pathway occurs without significant satellite cell proliferation and fusion to myofibers and without an increase in the
number of myonuclei per myofiber [58].

Conflict of interest
The authors have no conflict of interest to report.

Acknowledgments
This work was supported by grants from the European
Commission (FP7 Integrated Project MYOAGE to S.S.) and
the Italian Space Agency (ASI, project OSMA to S.S.). We
thank Chen-Ming Fan and Peter Zammit for critical reading
of the manuscript and Chen-Ming Fan for communicating
results prior to publication. We apologize to all those
authors whose work could not be cited in this short overview due to space restrictions.

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