REVIEW
Molecular and Cellular Determinants of Skeletal
Muscle Atrophy and Hypertrophy
Vittorio Sartorelli* and Marcella Fulco
(Published 3 August 2004)
Introduction
Two opposing phenomena—muscle growth and muscle atro-
phy—are mechanistically linked, in that either the activity or in-
activity of a common set of molecules controlling a few cellular
pathways determines whether the skeletal muscle tissue will re-
spond to defined stimuli with increased protein synthesis and
stimulation of cell growth (muscle hypertrophy) or with in-
creased protein breakdown and reduced cell proliferation
(muscle atrophy). Among these molecules, insulin-like growth
factor– 1 (IGF-1) occupies a nodal point.
The IGF-1 Pathway
Pertinent to the discussion of the mechanisms regulating both
muscle atrophy and muscle hypertrophy is the description of
pathways regulated by IGF-1 [Fig. 1; for a detailed review of
the IGF-1 pathway in skeletal muscle, see (1)]. IGF-1 is a se-
creted growth factor that regulates several cellular biochemical
pathways after binding to its membrane receptor, the IGF-1
receptor (IGFR). Upon binding of IGF-1, the IGFR, which is a
receptor tyrosine kinase, becomes phosphorylated and recruits
the insulin receptor substrate 1 (IRS1), leading to the activation
of the lipid kinase phosphatidylinositol 3-kinase (PI3K). PI3K
catalyzes the transfer of a phosphate group to the membrane-
bound phosphatidylinositol 4,5-bisphosphate (PIP2). Phospho-
rylation of PIP2 generates phosphatidylinositol 3,4,5-trisphos-
phate (PIP3), which recruits two additional kinases, Akt1 and
phosphoinositide-dependent protein kinase-1 (PDK-1) (2). Atk1
is bound, phosphorylated, and activated by PDK-1 (3). Once
Akt1 is activated, it initiates a cascade of phosphorylation
events targeting mammalian target of rapamycin (mTOR) (4)—
which in turn phosphorylates the p70 S6 kinase (p70S6K)—and
glycogen synthase kinase 3β (GSK-3β) (5). Phosphorylated
IRS1 also stimulates the Ras-Raf-MEK-ERK pathway, a mito-
gen-activated protein kinase (MAPK) pathway. Activation of
this pathway may actually prevent hypertrophy because Ras-
Raf-MEK-ERK inactivation, rather than its activation, appears
to characterize skeletal muscle hypertrophy (6). Phosphoryla-
tion of mTOR represses, through an adaptor protein known as
Raptor, eukaryotic initiation factor 4E (eIF-4E)–binding protein
1 [4EBP1, also known as phosphorylated heat- and acid-stable
protein (PHAS-1)], an inhibitor of eIF-4E (7). Thus, mTOR-
mediated inhibition of 4EBP1 results in activation of eIF-4E
and subsequent increased protein synthesis. An additional level
of regulation on mTOR is provided by glucose and amino acids,
which influence the interaction between Raptor and mTOR (8).
Therefore, mTOR phosphorylation activates both eIF-4E and
p70S6K, two positive regulators of protein synthesis. Similarly,
Muscle Gene Expression Group Laboratory of Muscle Biology,
National Institute of Arthritis, Musculoskeletal and Skin Diseases,
National Institutes of Health, Bethesda, MD 20892, USA.
*Corresponding author. E-mail: sartorev@mail.nih.gov
www.stke.org/cgi/content/full/sigtrans;2004/244/re11
the eukaryotic translation initiation factor 2B (eIF-2B) is activated
through Akt-mediated phosphorylation and inactivation of GSK-3β.
In summary, activation of the IGF-1 pathway leads to a series of
phosphorylation events culminating in the activation of molecules
that regulate protein synthesis and that are likely involved in the
genesis of muscle hypertrophy.
Molecular Determinants of Muscle Atrophy
Skeletal muscle atrophy is characterized by a decrease in the
size of preexisting muscle fibers and is observed in several
physiological and pathological settings. Atrophy has been inter-
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preted as the result of a passive adaptation of the muscle to a
lack of electrical or mechanical stimuli. Recently, this view has
been challenged by several findings indicating that the estab-
lishment of an active transcriptional program is necessary for
the induction of muscle atrophy.
The ubiquitin protein ligases MuRF1 and MAFbx. Using dif-
ferential display and complementary DNA (cDNA) microarray
approaches, the messenger RNAs (mRNAs) obtained from
muscles of either rats or mice in which atrophy was induced by
immobilization, denervation, hind-limb suspension, or food de-
privation were compared with controls, and the expression of
two genes was consistently found to be increased. The two
genes encode muscle RING finger 1 (MuRF1) (9) and muscle
atrophy F-box (MAFbx; also known as atrogin-1) (9, 10), two
ubiquitin protein ligases expressed solely in skeletal and cardiac
muscles. Ubiquitin ligases are enzymes involved in catalyzing
the ubiquitination of proteins fated to be degraded by the pro-
teasome. During atrophy, there is extensive muscle remodeling
characterized by increased proteolysis, and MuRF1 and MAFbx
might mediate such a process. A role for the ubiquitination-
mediated proteolysis of muscle proteins by MuRF1 is suggested
by experiments in which MuRF1 interacts with titin, a giant
myofibrillar protein located at the M line of the sarcomere and
mediates titin’s degradation (11).
An active role for both MuRF1 and MAFbx in mediating
muscle atrophy can be inferred from experiments conducted
with mice in which both alleles for either MAFbx or MuRF1
have been deleted. MAFbx−/− and MuRF1−/− animals are partial-
ly refractory to denervation-induced atrophy (9). It should be
possible, in principle, to cross the MAFbx−/− and MuRF1−/− ani-
mals to obtain double-knockout MAFbx−/−:MuRF1−/− and to de-
termine whether these animals are viable and whether MAFbx
and MuRF1 act cooperatively to mediate atrophy. A comple-
mentary approach for evaluating the functional role of these two
ubiquitin ligases could be pursued by generating mice that over-
express either MAFbx or MuRF1, because they may develop
spontaneous muscle atrophy, have an exacerbated response to
atrophic stimuli, or fail to respond to hypertrophic stimuli.
Finally, because both MAFbx and MuRF1 are expressed in the
heart, it will be important to determine their role in pathological
conditions characterized by cardiac remodeling (for example,
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heart failure, acute myocardial infarction, and IGFR IGFR

cardiomyopathies that accompany several
muscular dystrophies). It appears that neither
MuRF1 nor MAFbx plays a role in physio- IGF-1
logical muscle homeostasis, because both
MuRF1- and MAFbx-knockout animals have
normal skeletal muscles (9).
Nonetheless, the PI3K-Akt-mTOR and
ubiquitin-protein ligase pathways seem to be
linked, in that IGF-1-dependent activation of PIP2 PIP3
P
the PI3K-Akt-mTOR pathway blocks accu-
mulation of MAFbx mRNA and prevents P P PI3K P P P
muscle proteolysis in a cellular model of dex- P P
amethasone (DEX)-induced atrophy (12). P
From a mechanistic and therapeutic point of IRS1 Akt PDK-1
view, several models of atrophy—including P P

denervation, immobilization, and atrophies

accompanying chemically induced diabetes,
treatment with dexamethasone or interleukin-
1 (IL-1; a cachexia-inducing cytokine), and

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P
experimental sepsis—all result in increased
P Raptor
P
GSK-3β mTOR 14-3-3
transcription, mRNA stabilization, or both, of 4EBP1
MuRF1 and MAFbx (9, 13, 14). This sug- P P P
P
gests the possibility that a common set of P P
transcriptional regulators are stimulated by FOXO
diverse atrophic stimuli and that pharmaco- p70S6K
logical modulators targeting these regulators
may be effective in preventing atrophy ob- eIF2B eIF4E
served in disparate pathological conditions.
The FOXO transcription factors and mus-
cle atrophy. Two studies have advanced our
knowledge of the molecular modulators of
muscle atrophy (15, 16). In these studies, the
FOXO family of transcription factors was re-
ported to regulate MAFbx and MuRF1 tran-
scription and to influence muscle atrophy. Akt Fig. 1. The IGF-1 pathway is involved in muscle atrophy and hypertrophy. Upon IGF-
negatively regulates FOXO transcription fac- 1 binding, the IGFR is phosphorylated. The phosphorylated receptor recruits and
tors by phosphorylating them and promoting phosphorylates the IRS1, which activates PI3K. PI3K transfers a phosphate group to
the membrane-bound PIP2 to generate PIP3. PIP3 serves as a nucleation site for
their nuclear export into the cytoplasm, where
Akt1 and PDK-1. PDK-1 phosphorylates and activates Akt1, which, in turn, catalyzes
they are retained through association with the the transfer of phosphate groups to several substrates. Akt-mediated phosphoryla-
14-3-3 proteins (17). Muscle atrophy is mim- tion of the FOXO transcription factors promotes their cytoplasmic retention and func-
icked in cultured myotubes—that is, terminal- tional inactivation through interaction with the 14-3-3 proteins. Because the FOXO
ly differentiated, postmitotic syncytial cells proteins stimulate the transcription of the atrophy-promoting factor MAFbx, FOXO in-
forming the muscle fiber—by exposing them activation prevents muscle atrophy. Akt phosphorylates and inhibits GSK-3β, which
to either DEX or starvation (removal of activates the eukaryotic translation factor eIF-2B and increases protein synthesis.
growth factors, glucose, and amino acids for 6 The mTOR is also a phosphorylation substrate for Akt. With the assistance of the in-
hours). In these situations, transcription of teracting protein Raptor, phosphorylated mTOR promotes phosphorylation and inhibi-
both MAFbx and MuRF1 is increased. Con- tion of 4EBP1. Also, mTOR promotes protein synthesis by relieving 4EBP1-mediated
comitantly, phosphorylation of Akt and of inhibition of eIF-4B. When phosphorylated by mTOR, the ribosomal p70S6K be-
FOXO1 and FOXO3 is reduced. Animals with comes activated and increases protein synthesis. Green arrows indicate phosphory-
denervation atrophy treated with intramuscular lation events that activate the substrate, whereas red arrows point at phosphoryla-
injection of IGF-1, which promotes Akt phos- tions that result in substrate inactivation.
phorylation, do not increase expression of
MAFbx and MuRF1 and, most importantly, are spared from mus- of blocking the increase in MAFbx and MuRF1. These findings
cle loss. FOXO3 dephosphorylation allows transcriptional activa- indicate that the effects of activating the IGF-1-PI3K-Akt path-
tion of the MAFbx promoter and consequently increases MAFbx way that prevents atrophy operate through the FOXO proteins.
mRNA production. Through Akt-mediated phosphorylation of Nonetheless, it is likely that additional targets besides MAFbx are
FOXO1, 3, and 4, IGF-1 counteracts the ability of DEX to acti- affected by the FOXO proteins. In fact, although overexpression
vate MAFbx and MuRF1 transcription. When cultured myotubes of MAFbx alone does not cause muscle atrophy, muscle fibers
exposed to DEX are infected with an adenovirus expressing a expressing a constitutively active form of FOXO3 display a much
constitutively active form of FOXO1, IGF-1 becomes incapable reduced diameter (16). Furthermore, in the same study, FOXO3

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 REVIEW
overexpression resulted in increased MAFbx transcription, where-
as in another study (15), MAFbx expression was not affected by
FOXO1. These findings raise the possibility that FOXO3 and
FOXO1 may regulate different targets. Alternatively, the differ-
ences intrinsic to the two experimental settings may be responsi-
ble for the different results. Indeed, reduced expression of
FOXO1 achieved with RNA interference reduced activation of
the MAFbx promoter (16). The identification of additional FOXO
targets is expected to shed light on the molecules and mecha-
nisms regulating muscle atrophy.
Another transcription factor, nuclear factor κB (NF-κB),
mediates the effects of tumor necrosis factor–α (TNF-α) and
interferon-γ (IFN-γ) (18) in promoting the muscle wasting that
accompanies several pathological conditions (19). However,
forced activation of the NF-κB pathway does not increase
MAFbx expression (16), suggesting that muscle atrophy can be
elicited through processes that do not involve FOXO proteins,
for example, NF-κB-mediated degradation of the master
regulatory protein MyoD (18). The possibility exists that
different mediators of muscle atrophy may act at distinct stages
and may indeed cross-talk to ensure initiation and completion
of the atrophic program.
Exercise and Muscle Growth
Postnatal skeletal muscle growth in response to chronic physical
exercise is characterized by cell hypertrophy. Skeletal muscle
hypertrophy is defined as an increase in fiber diameter without
an apparent increase in the number of muscle fibers, accompa-
nied by enhanced protein synthesis and augmented contractile
force. Microtraumas resulting from chronic exercise also lead to
satellite cell activation and proliferation, which contribute to the
increased muscle mass that ensues from extensive physical
activity. The molecular determinants of muscle growth are be-
ginning to be characterized.
IGF-1 in muscle growth. Increased muscle loading, such as
that resulting from chronic exercise, results in augmented ex-
pression of the gene encoding IGF-1 in both animal models
(20) and humans (21). More specifically, two IGF-1 isoforms,
IGF-1E and mechanogrowth factor (MGF), seem to be selec-
tively expressed in skeletal muscle and to be regulated by me-
chanical load (22). These observations, along with the findings
that the circulating IGF-1 produced by the liver is not necessary
for postnatal body growth (23), suggest that specific isoforms
of IGF-1 act in an autocrine or paracrine manner to regulate
skeletal muscle biology. Availability of IGF-1 for muscle IGFR
is controlled by the combination of IGF-1, IGFR, and IGF-1
binding proteins (IGFBPs). Binding of IGF-1 to certain IGFBPs
results in opposing biological effects. For instance, binding of
IGF-1 to IGFBP-4 appears to inhibit cell proliferation and dif-
ferentiation, whereas binding to IGFBP-5 has a dual effect (that
is, either inhibition or stimulation of IGF-1 effects), depending
on the culture conditions (24, 25). The analysis of the physio-
logical contribution of the individual IGFBPs in the animal has
been hampered by the redundancy in the IGFBP system (26).
Nonetheless, muscle overloading is associated with increased
abundance of IGFBP-4 and decreased abundance of IGFBP-5,
suggesting that these two isoforms may be involved in regulat-
ing muscle adaptation to mechanical forces (27). Thus, whether
IGF-1 acts as an extracellular cue in muscle biology depends on
a finely tuned and regulated series of events leading to either
the stimulation or the inactivity of the IGF-1–IGFR axis.
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Animals overexpressing IGF-1 under the control of muscle-
specific regulatory elements display muscle hypertrophy and in-
creased muscle regeneration during senescence (28, 29). These
findings, along with the observation that IGF-1 overexpression
improves the phenotype of the mdx mouse model for Duchenne
muscular dystrophy, suggest that IGF-1 may positively influ-
ence satellite cell proliferation, activation, or both (30). Consis-
tent with the existence of a linear pathway proceeding from
IGF-1 to Akt, deliberate activation of the Akt-mTOR pathway
can stimulate fiber hypertrophy both in control and denervated
muscles (31). Together, these results suggest a potential thera-
peutic value of manipulating the IGF-1–Akt-mTOR pathway in
the treatment of muscle atrophy. In contrast, acute physical ex-
ercise is associated with increased levels of total and phospho-
rylated Akt, increased phosphorylation and reduced activity of
GSK-3β, and reduced levels of phosphorylated β-catenin (32).
Thus, the Akt to GSK-3β pathway may also be involved in mus-
cle hypertrophy and in the initial phases of muscle activity that
contribute to hypertrophy.
Although there is little doubt that IGF-1 is involved in medi-
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ating experimental muscle hypertrophy, additional molecules
and stimuli may be required to assist IGF-1 in this process.
Transgenic mice in which IGF-1 expression is driven by the
muscle-specific regulatory regions of the gene encoding myosin
light chain 1/3 (MLC1/3) display pronounced muscle hypertro-
phy (33). Expression of the endogenous MLC1/3 gene and acti-
vation of the IGF-1 transgene occurred early during develop-
ment. Nonetheless, muscle hypertrophy in MLC1/3–IGF-1 mice
first becomes detectable only 10 days after birth (33). It is pos-
sible that moderate physical exercise may be required for the
overexpressed IGF-1 to induce hypertrophy or that molecules
expressed or activated after birth may be necessary for the hy-
pertrophic effects of IGF-1. Alternatively, the rapid postnatal
muscle growth in both the transgenic and the wild-type animals
may mask the effects of IGF-1, which become evident in
transgenic animals only after muscle growth slows in the con-
trol animals. The physiological role of the Akt-mTOR pathway
in ensuring muscle trophism also remains to be fully clarified,
because pharmacological treatment with the mTOR-specific
inhibitor rapamycin fails to induce muscle atrophy in control
animals (31).
Myostatin. Myostatin is a transforming growth factor–β
(TGF-β) family member expressed in the myotome compart-
ment of developing somites and in the skeletal muscles of adult
animals (34). Naturally occurring mutations in the myostatin
[Mstn, also known as growth and differentiation factor 8
(GDF-8)] gene are responsible for the “double-muscling” phe-
notype, which is characterized by a dramatic increase in mus-
cle mass of certain breeds of cattle (35). Mstn-null mice show
an increase in muscle mass due to muscle hyperplasia (in-
creased number of muscle fibers) and hypertrophy (increased
muscle fiber diameter) (34). Recently, a child with muscle hy-
pertrophy was found to have a loss-of-function mutation in the
Mstn gene (36), although whether the child’s muscles have an
increased number of fibers or a normal number of enlarged
myofibers remains to be established. These findings indicate
that inactivation of myostatin has similar effects in humans,
mice, and cattle.
After an enzymatic cleavage, the active myostatin peptide in-
teracts with the membrane-bound type IIB activin receptor,
initiating a signaling cascade (likely mediated by the Smad tran-
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scription factors) that ultimately blocks muscle differentiation,
possibly by inhibiting the master regulatory genes MyoD (37)
and Pax-3 (38), which encode proteins controlling skeletal myo-
genesis (39, 40). These findings raise the possibility that phar-
macological inhibition of myostatin may be of therapeutic value
to promote muscle growth and differentiation in human diseases
(41). Accordingly, antibody-mediated myostatin blockade effec-
tively ameliorates anatomical and physiological muscle parame-
ters in the mdx mouse (42). Consistent with these findings,
knockout of the Mstn gene in the mdx mouse improves its dys-
trophic muscle phenotype (43). Whether down-regulation of
Mstn gene expression is involved in exercise-induced muscle
hypertrophy remains to be firmly determined (44). Interestingly,
Mstn-null mice have a substantial reduction in fat accumulation
despite normal food intake. Furthermore, when Mstn-null mice
were bred with two different models of obesity, agouti lethal
yellow [A(y)] and obese [Lep(ob/ob)], the double-mutant mice
exhibited partly corrected glucose metabolism (45). Therefore,
pharmacological inactivation of myostatin may have the double
benefit of increasing muscle mass and retarding or preventing
the development of obesity and type II diabetes.
Follistatin and deacetylase inhibitors. Follistatin is a secret-
ed protein that interacts with and inhibits the activity of several
TGF-β family members, including GDF-11 [also known as
bone morphogenetic protein 11 (BMP-11)] (46), a protein with
high sequence similarity to myostatin (47). Furthermore, myo-
statin circulates as a part of a latent complex containing myo-
statin propeptide and either follistatin-related gene (FLRG) or
GDF-associated serum protein-1 (GASP-1), two molecules
closely related to follistatin (48, 49). Finally, follistatin interacts process of muscle regeneration. Increased muscle regeneration
with myostatin and reverses the inhibition exerted by the latter
on muscle differentiation of primary chick cells (38). Biochemi-
cal experiments indicate that follistatin can block the binding of
myostatin to the activin IIB receptor by interacting with the C-
terminal region of a myostatin dimer
(50). Mice overexpressing follistatin
under the control of muscle-specific
regulatory elements display a muscle
phenotype that recapitulates that ob-
served in the absence of myostatin
(50). Thus, follistatin counteracts the
biological activity of myostatin and
possibly of other TGF-β family mem-
bers.
Follistatin (Fst) gene expression is
activated by exposure of skeletal mus-
cle cells to deacetylase inhibitors (51),
a class of small, membrane-permeable
molecules that block the activity of Fig. 2. The deacetylase inhibitor trichostatin A induces an increase in both the diameter of
class I-II histone deacetylases differentiated myotubes and the number of myonuclei. Undifferentiated C2C12 skeletal my-
oblasts were either mock-treated (control) or exposed to 50 nM trichostatin A and allowed
(HDACs). Some of these molecules, in-
to differentiate in low growth factor–containing medium for 2 days before immunostaining
cluding valproic acid, are currently em- with an antibody to MHC.
ployed to treat various clinical condi-
tions such as epilepsy (52) and mood
disorders (53). Exposure of cultured skeletal muscle cells to
HDAC inhibitors results in the formation of myotubes with in-
creased diameter, increased number of myonuclei (Fig. 2), and
enhanced abundance of muscle structural proteins such as
myosins (54). Similarly, mouse embryos exposed to HDAC in-
hibitors display a premature formation of caudal somites and
augmented muscle gene expression when compared to control
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animals (54, 55). At the doses employed in those studies, val-
proic acid (a known teratogen) did not cause apparent toxicity
or malformations. In cultured cells, the effects of HDAC in-
hibitors on follistatin are restricted to skeletal muscle cells, be-
cause treatment with these inhibitors of mouse primary ker-
atinocytes and of other cell lines fated to differentiate toward
the adipose, bone, or pituitary phenotypes fails to activate Fst
gene expression (51). These findings are relevant because they
suggest that systemic delivery of HDAC inhibitors may activate
follistatin expression selectively in skeletal muscles. Iezzi et al.
(51) found that the effects exerted by HDAC inhibitors on
skeletal muscle are due to an increased ability of undifferentiat-
ed myoblasts to be recruited and to fuse with already formed
myotubes, and appear not to be mediated by either IGF-1 or
IL-4 (56), two molecules involved in myoblast fusion and
growth. Follistatin overexpression in skeletal muscle cells can
fully recapitulate the morphological and biochemical modifica-
tions induced by the HDAC inhibitors, indicating the pivotal
role of follistatin in promoting myoblast accretion. Consistent
with these observations, blockade of follistatin, by either
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functional inactivation with recombinant myostatin or RNA
interference-meditated “knock-down” of follistatin, render
HDAC inhibitors incapable of promoting myoblast accretion. A
role for follistatin during skeletal muscle regeneration is indi-
cated by its expression in activated satellite cells during both
initial (51, 57) and later (51) stages of muscle regeneration.
Systemic delivery of HDAC inhibitors in a mouse model of
muscle degeneration and regeneration results in the activation
of markers, suggesting the existence of an active and sustained
promoted by HDAC inhibitors requires the presence of activat-
ed satellite cells, indicating that the activity of HDAC inhibitors
may be not only cell-type specific, but also limited to damaged
muscles (51).
In conclusion, an alternative method to blocking myostatin
activity to promote muscle growth may be by inducing Fst gene
expression with HDAC inhibitors. Although it is not known
whether exercise-induced muscle hypertrophy is associated with
an increase of Fst expression, it is tempting to speculate that
this might be the case, because Fst expression is observed in ac-
tivated satellite cells (57).
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Cell Determinants of Muscle Growth
Satellite cells. Satellite cells are lineage-committed adult stem
cells (58), located between the basal lamina and the sarcolemma
of myofibers, that contribute to postnatal muscle growth (59)
and muscle regeneration after injury (60). Upon myotrauma,
quiescent satellite cells become activated, proliferate, and ulti-
mately fuse to existing damaged muscle fibers or among them-
selves to form new myofibers (61). Satellite cells are activated
in response to hypertrophic stimuli, such as those occurring
during muscle mechanical overload (59, 62, 63). In several
animal models of compensatory hypertrophy (64–66) or after
resistance training in humans (67–69), the total number of
activated satellite cells is substantially increased. In most of
these early works, activation, proliferation, and incorporation of
satellite cells into myofibers was documented by electron mi-
croscopy. Quiescent satellite cells are recognizable for their dis-
tinct location and morphological features, such as a very high
nuclear-to-cytoplasm ratio with few organelles and a smaller
nuclear size with increased amounts of heterochromatin com-
pared to fiber myonuclei (70). When activated, satellite cells are
easily identified, because they appear as swellings on the my-
ofiber, have an increased cytoplasmic-to-nuclear ratio, and have
increased numbers of intracellular organelles (61). Satellite
cells have been the object of extensive studies aimed at the
identification of specific molecular markers. Among the specif-
ic satellite cell markers so far identified are Pax7, a paired-box-
containing transcription factor essential for the specification of
satellite cells (71); myocyte nuclear factor (MNF, also called
Foxk1), a winged-helix transcription factor; c-Met, the receptor
for hepatocyte growth factor (HGF); M-cadherin, a calcium-de-
pendent cell adhesion molecule that is expressed only in a small
subset of quiescent satellite cells; neural cell adhesion molecule
(NCAM) and vascular adhesion molecule-1 (VCAM-1); and
syndecan-3 and syndecan-4 [reviewed in (72)]. All these mark-
ers are present in either quiescent or proliferating satellite cells.
Upon exposure to signals emanating from the damaged area,
quiescent satellite cells become activated and start proliferating
(73). Once satellite cells are activated, they express the genes
encoding the two myogenic regulatory factors Myf 5 and
MyoD, which are not detectable in quiescent cells (74). The ap-
pearance of MyoD temporally precedes any signs of cellular di-
vision, such as the expression of proliferative cell nuclear anti-
gen (PCNA) (75). After proliferation, satellite cells initiate ex-
pression of the genes encoding myogenin, muscle regulatory
factor 4 (MRF4), cyclin-dependent kinase inhibitor p21, and,
after a permanent exit from the cell cycle, they fuse with dam-
aged myofibers or give rise to new myofibers (76, 77). Newly
formed myofibers can be identified by the central location of
myonuclei and expression of embryonic or developmental
forms of myosin heavy chain (MHC) (78). In a process called
self-renewal, a small proportion of satellite cells return to the
quiescent state to replenish the satellite cell pool.
Because satellite cells in their mitotic phase are sensitive to
DNA damage, γ-irradiation has been used to impair their activa-
tion and proliferation and to test for their functional relevance
in the development of skeletal muscle hypertrophy. Compen-
satory hypertrophy can be largely prevented by muscle irradia-
tion, providing compelling evidence that the presence of activat-
ed and proliferating satellite cells is indeed necessary for this
process (79–81). However, compensatory hypertrophy is not
completely prevented by muscle irradiation, suggesting the pos-
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sibility that some satellite cells could enter terminal differentia-
tion and fuse with damaged muscle fibers after one cell division
at most, thus evading the antiproliferative effect of radiation
damage (82). Alternatively, some satellite cells may have sur-
vived, given the existence of cell subpopulations resistant to ra-
diation (83). It should also be possible to address the satellite
cell requirement for the genesis of muscle hypertrophy in Pax7-
deficent mice subjected to compensatory hypertrophy. In fact,
because Pax7-deficient mice lack satellite cells, any increase in
muscle mass would have to be ascribed either to the expansion
of other nonsatellite adult stem cells (see Nonsatellite Adult
Stem Cells, below) or to increased protein synthesis in existing
myofibers.
Satellite cell activation. The mechanisms leading to satellite
cell activation during muscle hypertrophy are not entirely un-
derstood. It is postulated that extensive physical activity, such as
resistance training or muscle overloading (chronic stretch, ago-
nist muscle ablation, tenotomy), inflicts muscle injury (84, 85)
that, similar to more severe muscle damage, may initiate a pro-
cess of regeneration. An indirect proof of muscle damage after
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mechanical stress is given by an increase of serum markers such
as muscle creatine kinase, an enzyme that is usually restricted
to the myofiber cytosol (86). Muscle injury initiates an inflam-
matory response with the attraction of nonmuscle mononucleat-
ed cells, such as neutrophils and macrophages, into the dam-
aged zone (87, 88), with consequent release of several growth
factors (by either the infiltrating cells or the damaged myofibers
themselves). These growth factors may ultimately regulate
satellite cell proliferation and differentiation (89). Indeed, sever-
al cytokines have been described that modulate proliferation
and differentiation of satellite cells in vitro or during regenera-
tion after muscle injury (72, 90). HGF, which was initially de-
tected in hepatic tissue, is considered to be a key regulator of
satellite cell activity during muscle regeneration (91, 92). HGF
is secreted by damaged tissue during the early phase of muscle
regeneration in amounts proportional to the extent of muscle
injury (93, 94). It seems that HGF directly regulates satellite
cell activation, as suggested by the presence of its receptor c-
Met in quiescent and activated satellite cells. Upon HGF bind-
ing, the c-Met receptor tyrosine kinase transmits intracellular
signals through a unique multidocking site at its C terminus that
is generated by autophosphorylation of two tyrosine residues.
The multisubstrate docking site mediates the binding of several
adaptor proteins, such as Grb2, SHC, Crk (also known as
CRKL), PI3K, and the large adaptor protein Gab1. These adap-
tor proteins then participate in transducing extracellular signals
elicited by HGF to downstream targets (95). The PI3K-Akt
pathway, for instance, mediates HGF-induced survival and pro-
tection from apoptosis (96).
Other secreted factors may also participate in satellite cell
activation. For example, fibroblast growth factor 6 (FGF-6) is
another potential regulator of satellite cell activity (97, 98).
However, FGF-6-deficient mice generated by two different lab-
oratories display different phenotypes during muscle regenera-
tion. In one case, FGF-6-null animals have impaired satellite
cell proliferation and defects in muscle regeneration in response
to a crush injury (99), whereas another study found no evidence
of regenerative defects in response to several kinds of muscle
damage (100). IL-4 is secreted by both myotubes and
macrophages present in the regenerating muscles. By promot-
ing fusion of myoblasts with preformed myotubes (56), IL-4
Page 5
 REVIEW
may actively participate in the regenerative process. Leukemia
inhibitory factor (LIF), IL-6, IL-15, TNF-α, and several other
factors have been described as potentially involved in the mus-
cle remodeling response after injury (101). However, a defini-
tive role for all these factors in regulating regeneration, hyper-
trophy, or both remains to be further elucidated.
As already described, a large body of evidence supports the
importance of IGF-1 in the genesis of skeletal muscle hypertro-
phy. The expression of genes encoding two IGF-1 muscle-
specific isoforms, IGF-1E and MGF, is stimulated by mechani-
cal overload (102) with apparently different kinetics. MGF
seems to be expressed early after mechanical damage and to
temporally precede the activation of satellite cells, whereas
IGF-1E expression peaks later and is likely to be involved in
maintaining protein synthesis required to complete the muscle
repair (103). IGF-1 can promote both proliferation (104, 105)
and differentiation of cultured satellite cells (106, 107), and
these findings have been confirmed in animal models. For in-
stance, both IGF-1–mediated muscle hypertrophy and compen-
satory hypertrophy are halved by γ-irradiation (108). Further-
more, IGF-1–induced muscle hypertrophy is accompanied by
increased DNA content of myofibers (109, 110), appearance of
centrally located nuclei, and appearance of developmental
forms of myosin (29, 111). All these findings support the in-
volvement of satellite cells in IGF-1–mediated muscle hypertro-
phy. Further evidence for a role of satellite cells is suggested by
experiments in which muscle-localized expression of IGF-1
prevented, through an increase of the regenerative potential of
satellite cells, the aging-related loss of muscle mass (29). Final-
ly, satellite cells derived from mice overexpressing IGF-1 dis-
play an increased proliferative potential (112), which seems to
be mediated by activation of the PI3K-Akt pathway and down-
regulation of the activity of cyclin-dependent inhibitor p27kip1
(113), which results from an inhibitory effect on FOXO1 (114).
Therefore, the molecular pathways activated by IGF-1 in the
muscle fibers to promote increased protein translation appear to
also be activated in satellite cells.
Satellite cells and aging. Aging is accompanied by a decline
in muscle mass and strength, a phenomenon referred as to sar-
copenia (115). It is clear that fitness is greater at any age in in-
dividuals who exercise regularly versus those who do not and
that sarcopenia is reduced—albeit not abolished—in physically
active elderly people. A decline in the number of satellite cells,
their proliferative capacity, or both may contribute to sarcope-
nia. One of the mechanisms responsible for the reduced regen-
erative potential of old muscle seems to be the decline in Notch
signaling (116), a pathway involved in the formation of several
tissues during embryogenesis. Notch signaling also contributes
to satellite cell activation, proliferation, and cell lineage deter-
mination (117). The regenerative potential of old muscle can be
experimentally restored either by forced activation of Notch sig-
naling or, as mentioned, by IGF-1. Whether physical exercise
activates the Notch signaling pathway is not known. However,
manipulations involving the Notch and IGF-1 pathways may re-
sult in the activation and proliferation of satellite cells and may
be useful in retarding age-related loss of muscle mass and
strength.
Nonsatellite adult stem cells. In recent years, there have been
several reports indicating that cells deriving from bone marrow
can contribute to the regeneration of injured muscle (118, 119).
The ontology and effectiveness of these cells in promoting mus-
www.stke.org/cgi/content/full/sigtrans;2004/244/re11
cle regeneration are currently being intensively pursued. In one
study, multipotent progenitors of mesodermal tissues [termed
“mesoangioblasts” (120)] that express Flk1 (vascular
endothelial growth factor–receptor 2), the key marker of
angiopoietic progenitors, were intraarterially delivered into
α-sarcoglycan–null dystrophic mice. This resulted in restora-
tion of the α-sarcoglycan–dystrophin complex and, most impor-
tantly, in complete functional muscle recovery of the dystrophic
animals (121). Although of extreme biological and clinical rele-
vance, the discussion of these nonmuscle resident stem cells is
beyond the scope of this review. Novel populations of adult
stem cells have been isolated from uninjured skeletal muscle
that express the CD45 and Sca1 (122, 123), two surface mark-
ers expressed on hematopoietic stem cells. When cultured in
vitro, these stem cells form hematopoietic colonies but do not
differentiate into muscle, with the exception of a small percent-
age that can adopt the myogenic phenotype when cocultured
with satellite cell-derived myoblasts (124). This population of
cells is clearly distinct from satellite cells, because they contain
the CD45 and Sca1 markers, which are not present on satellite
Downloaded from http://stke.sciencemag.org/ on June 21, 2015
cells (124). Upon muscle injury, the number of cells in the
CD45+:Sca1+ population increases approximately 10-fold and
gives rise to myogenic cells (125). This suggests that a factor, or
factors, released by the injured or regenerating muscle may
switch the fate of the CD45+:Sca1+ population and redirect it
from the hematopoietic to the myogenic phenotype. Indeed,
Polesskaya et al. (125) demonstrated that the expression of
genes encoding selected members of the secreted Wnt protein
family are induced in regenerating muscles. Consistent with
this, ectopic expression of Wnts causes muscle commitment of
CD45+:Sca1+ cells. The results of this study indicate that resi-
dent, nonsatellite-derived progenitors can, in response to Wnt
signaling, participate in muscle repair. Because mesoan-
gioblasts contain both Sca1 and Wnts (120), it should be infor-
mative to compare the expression profiles of mesoangioblasts
and of muscle resident CD45+:Sca1+ cells to establish whether
these cells have a common origin. Although these findings are
important in suggesting a potential clinical use of Wnt modula-
tors to influence muscle regeneration, whether muscle-resident
adult stem cells may participate in muscle hypertrophy remains
to be experimentally tested. Finally, it is interesting to note that
IGF-1 has been reported to enhance the proliferation potential
of a subpopulation of bone marrow stem cells, and their recruit-
ment to sites of muscle damage, in lethally irradiated mice that
received bone marrow transplants (126). Thus, it is possible that
also adult stem cells may respond to IGF-1 signaling.
Conclusions and Future Directions
It has been known for some time that muscle hypertrophy is the
result of the activity both of molecules that stimulate growth of
existing myofibers and of fiber accretion obtained through re-
cruitment of activated satellite cells. Nonetheless, only recently
has a detailed description of the molecular and cellular mecha-
nisms underlying postnatal muscle growth become available. It
is now clear that the IGF-1 pathway is central to both increased
protein synthesis and satellite cell activation. Similarly, the IGF-
1 pathway controls the activity of the FOXO transcription
factors. Under physiological conditions, IGF-1 prevents FOXOs
from activating the gene expression program leading to muscle
atrophy. It does not seem likely that the IGF-1 pathway is dedi-
cated to controlling cell growth exclusively in skeletal muscle,
Page 6
 REVIEW
because overexpression of the Drosophila IRS, Akt, or p70S6K
can cause hypertrophy in disparate cell lineages (127), includ-
ing those giving rise to the eye and wing (128). Rather, the au-
tocrine or paracrine activity of locally produced IGF-1 may en-
sure skeletal muscle specificity.
In several pathological settings, it would be desirable to ei-
ther prevent muscle atrophy or activate pathways that lead to in-
creased muscle growth and that promote muscle hypertrophy. In
this respect, it is of interest to discuss the experimental use of
small molecules—whose therapeutic efficacy is currently being
evaluated in clinical trials (129, 130)—that modulate the activi-
ty of nuclear deacetylases. The transcriptional activity of FOXO
proteins is regulated by Sir2, an NAD+-dependent deacetylase,
with the expression of several FOXO targets being reduced by
Sir2 overexpression (131, 132). Because inhibition of
FOXO-transcriptional activity is associated with reduced ex-
pression of MAFbx, it will be important to determine whether
the Sir2 agonist resveratrol (133) is of therapeutic value in re-
ducing FOXO-dependent activation of the muscle atrophy pro-
gram. Similarly, the use of class I-II deacetylase inhibitors has
given encouraging results in promoting muscle regeneration in
an animal model of muscle injury through activation of
follistatin gene expression (51). Future experiments will deter-
mine whether these agents are effective in modulating the pro-
gression of muscle wasting in animal models of cancer, sepsis,
and degenerative diseases.
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Citation: V. Sartorelli, M. Fulco, Molecular and cellular determinants of
skeletal muscle atrophy and hypertrophy. Sci. STKE 2004, re11 (2004).
Page 9
 Molecular and Cellular Determinants of Skeletal Muscle Atrophy
and Hypertrophy
Vittorio Sartorelli and Marcella Fulco (July 27, 2004)
Science Signaling 2004 (244), re11. [doi: 10.1126/stke.2442004re11]

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