543 FC 6 BB 0 CF 21227 A 11 B 7 B 45

REVIEW ARTICLE
Mechanisms regulating skeletal muscle growth and atrophy

Stefano Schiaffino1,2, Kenneth A. Dyar1, Stefano Ciciliot1, Bert Blaauw1,3 and Marco Sandri1,3
1 Venetian Institute of Molecular Medicine, Padova, Italy
2 Consiglio Nazionale delle Ricerche, Institute of Neuroscience, Padova, Italy
3 Department of Biomedical Sciences, University of Padova, Italy
Keywords
FoxO; IGF1; mTOR; myostatin; muscle
atrophy; muscle hypertrophy; protein
degradation; protein synthesis; satellite cells
Correspondence
S. Schiaffino; M. Sandri, Venetian Institute
of Molecular Medicine, Via Orus 2, 35129
Padova, Italy
Fax: +39 49 7923 250
Tel: +39 49 7923 232; +39 49 7923 258
E-mail: stefano.schiaffino@unipd.it; marco.
sandri@unipd.it
Website: www.vimm.it
(Received 25 January 2013, revised 13
March 2013, accepted 14 March 2013)
doi:10.1111/febs.12253
Skeletal muscle mass increases during postnatal development through a

process of hypertrophy, i.e. enlargement of individual muscle fibers, and a
similar process may be induced in adult skeletal muscle in response to contractile activity, such as strength exercise, and specific hormones, such as
androgens and b-adrenergic agonists. Muscle hypertrophy occurs when the
overall rates of protein synthesis exceed the rates of protein degradation.
Two major signaling pathways control protein synthesis, the IGF1Akt
mTOR pathway, acting as a positive regulator, and the myostatinSmad2/
3 pathway, acting as a negative regulator, and additional pathways have
recently been identified. Proliferation and fusion of satellite cells, leading to
an increase in the number of myonuclei, may also contribute to muscle
growth during early but not late stages of postnatal development and in
some forms of muscle hypertrophy in the adult. Muscle atrophy occurs
when protein degradation rates exceed protein synthesis, and may be
induced in adult skeletal muscle in a variety of conditions, including starvation, denervation, cancer cachexia, heart failure and aging. Two major protein degradation pathways, the proteasomal and the autophagiclysosomal
pathways, are activated during muscle atrophy and variably contribute to
the loss of muscle mass. These pathways involve a variety of atrophyrelated genes or atrogenes, which are controlled by specific transcription
factors, such as FoxO3, which is negatively regulated by Akt, and NF-jB,
which is activated by inflammatory cytokines.
Introduction
Skeletal muscle mass and muscle fiber size vary according to physiological and pathological conditions. An
increase in muscle mass and fiber size, i.e. muscle growth
or hypertrophy, occurs during development and in

response to mechanical overload (incapacitation or
ablation of synergistic muscles, strength training,
Abbreviations
4E-BP1, eukaryotic translation initiation factor 4E-binding protein 1; ACVR2, activin receptor 2; ALK4/5, activin receptor-like kinase 4/5;
AMPK, AMP-activated protein kinase; BNIP3, BCL2/adenovirus E1B 19 kDa protein-interacting protein 3; Fbxo, F-box only protein; Fn14,
fibroblast growth factor-inducible 14; FoxO, Forkhead box O; HDAC, histone deacetylase; IGF1, insulin-like growth factor 1; IKKb, IjB
ppel-like factor 15; MAFbx, muscle atrophy F-box; mTOR, mammalian target of rapamycin; mTORC1/2,
kinase b; IL, interleukin; KLF15, Kru
mTOR complex 1/2; MuRF1, muscle RING finger 1; NF-jB, nuclear factor j light-chain enhancer of activated B cells; nNOS, neuronal nitric
oxide synthase; PPAR, peroxisome proliferator-activated receptor; PGC-1a, PPAR-c co-activator-1a; PI3K, phosphatidylinositide-3-kinase;
PINK1, phosphatase and tensin homolog-induced putative kinase 1; REDD1, regulated in development and DNA damage responses 1; SRF,
serum response factor; TGF, transforming growth factor; TNFa, tumor necrosis factor a; TRAF, TNF receptor-associated factor; Trim32,
tripartite motif-containing protein 32; TWEAK, TNF-like weak inducer of apoptosis; VPS34, vacuolar protein sorting 34; YY1, Yin Yang 1.
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FEBS Journal 280 (2013) 42944314 2013 The Authors Journal compilation 2013 FEBS
S. Schiaffino et al.
reloading after unloading) or anabolic hormonal stimulation (testosterone or b2-adrenergic agonists). A

decrease in muscle mass and fiber size, i.e. muscle atrophy, results from aging, starvation, cancer, diabetes,
bed rest, loss of neural input (denervation, motor neuron disease) or catabolic hormonal stimulation (corticosteroids). The regulation of muscle mass and fiber size
essentially reflects protein turnover, i.e. the balance
between protein synthesis and degradation within the
muscle fibers. However, skeletal muscle fibers are multinucleated structures, thus protein turnover may also be
affected by cell or nuclear turnover, i.e. addition of new
myonuclei, due to fusion of satellite cells, or loss of
myonuclei, due to nuclear apoptosis. Before separately
considering conditions of muscle growth and muscle
atrophy, it is useful to make some general points. First,
skeletal muscles and muscle fiber types vary, often drastically, in their response to the same stimulus. This point
is evident in many experimental models used in muscle
research, without considering extreme cases such as the
differential response to testosterone in sexually dimorphic, androgen-sensitive muscles. For example, denervation in the rat diaphragm muscle causes atrophy of type
2X and 2B fibers, no change in type 2A fibers and slight
hypertrophy of type 1 fibers [1]. Similar changes are
found in other fast rat muscles (S. Schiaffino and
S. Ciciliot, unpublished data); however, the type 1 fibers
of the slow soleus show marked atrophy after denervation, thus the same fiber type may undergo opposite
changes in different muscles. With regard to nutrient
deprivation, slow muscles, such as the soleus, are less
sensitive to starvation compared to fast muscles [2]. This
response is presumably related to the different sensitivity of fast and slow muscles to corticosteroids [3]. Even
within the same muscle, for example the rat diaphragm,
corticosteroid treatment causes atrophy of type 2B and
2X fibers but not type 2A and 1 fibers [4]. This differential response probably reflects the fact that contractile
activity, which is greater in the continuously active
type 1 and 2A fibers, opposes the atrophic process,
possibly via the transcriptional co-activator PPAR-c
co-activator-1a (PGC-1a) [5].
Second, changes in protein turnover leading to
muscle hypertrophy or atrophy do not always proceed according to the simplistic equations suggested
by the balance analogy, i.e. muscle hypertrophy
results from increased protein synthesis and decreased
protein degradation, while muscle atrophy results
from decreased protein synthesis and increased protein degradation. Goldbergs analyses of muscle
growth in hypophysectomized rats showed that, during hypertrophy of the soleus muscle induced by tenotomy of the gastrocnemius, there is decreased
Mechanisms regulating muscle growth and atrophy
protein catabolism as well as increased synthesis of

new proteins, while during hypertrophy of the soleus
induced by growth hormone, there is increased protein synthesis without any change in protein degradation rates [6]. Starvation causes decreased protein
synthesis and increased protein degradation in both
fast and slow rat muscles [2]. However, muscle denervation is accompanied by increased protein degradation and increased rather than decreased protein
synthesis [7,8]. One must also consider that fast and
slow muscles differ in their protein turnover rates,
with slow muscles showing higher rates of both protein synthesis and degradation [2].
Third, changes in protein turnover and cell/nuclear
turnover in skeletal muscle do not always proceed in
parallel, thus myonuclear domains may vary. The myonuclear domain size, defined as the cytoplasmic volume
per myonucleus, varies among fiber types, being larger
in type 2B and 2X fibers compared to type 2A and 1
fibers, and, in contrast to initial reports, is not constant
in various conditions [8a]. For example, during muscle
atrophy caused by denervation or corticosteroids, there
is no loss of myonuclei; therefore the myonuclear
domain decreases in proportion to the decrease in
cross-sectional area [1,4,9,10]. Conversely, myonuclear
domains may increase during postnatal muscle growth
and in different hypertrophy models (see below).
Muscle growth
In this section, we focus on muscle growth processes
that take place after birth, including muscle growth
during postnatal development and the process of muscle hypertrophy induced in adult muscle by functional
overload. We do not deal specifically with muscle
growth during regeneration, which has been discussed
previously [11].
Major signaling pathways controlling muscle
growth
Two major signaling pathways control skeletal muscle
growth: the insulin-like growth factor 1 phosphoinositide-3-kinaseAkt/protein kinase Bmammalian target
of rapamycin (IGF1PI3KAkt/PKBmTOR) pathway acts as a positive regulator of muscle growth, and
the myostatinSmad3 pathway acts as a negative regulator (Fig. 1A). The role of the IGF1 pathway has
been supported by a variety of gain- and loss-of-function genetic approaches [12]. For example, muscle-specific inactivation of the IGF1 receptor impairs muscle
growth due to reduced muscle fiber number and size
[13]. Conversely, muscle-specific over-expression of
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Fig. 1. Signaling modules responsible for skeletal muscle growth during development, regeneration and overload-induced hypertrophy in the
adult. We postulate that all these modules converge to a final common pathway centered on mTOR and its effectors that control protein
synthesis. (A) Major signaling pathways. IGF1 stimulates mTOR activity and muscle growth via PI3KAkt. Follistatin induces muscle growth by
inhibiting myostatin and activin A. The two pathways cross-talk by direct interaction between Smad3 and Akt. In addition, transcriptional regulation
by Smad3/Smad4 heterodimers may repress mTOR and protein synthesis through mechanisms that have not yet been defined. The arrow
connecting mTOR with a myonucleus indicates transcriptional roles of mTOR. (b) Additional pathways controlling mTOR activity and protein
synthesis. The SRF (serum response factor), PA (phosphatidic acid) and nNOS (neuronal nitric oxide synthase) pathways may be activated by
mechanical overload. The dotted arrow connecting newly fused myonuclei (new mn) to the mTOR pathway indicates the postulated increase in
protein synthesis and myotube/myofiber growth associated with myoblast/satellite cell fusion. SC, satellite cell; SSC, satellite stem cell.
IGF1 causes muscle hypertrophy [14]. In vivo transfection studies in adult mouse and rat muscles have
helped to elucidate the pathways downstream of the
IGF1 receptor. IGF1 is known to activate both the
mitogen-activated protein kinase/extracellular signalregulated kinase (MAPK/ERK) and the PI3KAkt
pathways. However, only a Ras mutant that selectively
activates the PI3KAkt pathway was able to induce
hypertrophy of transfected fibers, whereas a Ras
mutant acting specifically on the ERK pathway did
not [15]. Accordingly, constitutively active Akt results
in a striking hypertrophy of transfected muscle fibers
[16,17], with a similar effect being seen using inducible
muscle-specific transgenic models [1820].
Akt stimulates protein synthesis by activating
mTOR and its downstream effectors. The kinase
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mTOR interacts with several proteins to form two

complexes: mTOR complex 1 (mTORC1) containing
raptor and mTOR complex 2 (mTORC2) containing
rictor. Here, we focus on mTOR signaling as it relates
to skeletal muscle growth, as a detailed general discussion of mTOR function and regulation has been published previously [21]. It should be stressed that
mTOR responds to multiple upstream signals in addition to Akt, including amino acids, and it controls several cellular processes in addition to protein synthesis,
including autophagy. The crucial role of mTOR in
mediating muscle growth is supported by genetic and
pharmacological evidence. Muscle-specific mTOR
knockout causes reduced postnatal growth, due to the
reduced size of fast but not slow muscle fibers, and
severe myopathy [22]. A similar phenotype is found in
mice lacking raptor in skeletal muscle, whereas those

lacking rictor have a normal phenotype, supporting a
major role of mTORC1 in mediating the effect of
mTOR on protein synthesis [23]. Rapamycin, a specific
mTOR inhibitor, acts especially on mTORC1,
although mTORC2 is also affected during chronic
treatment [21]. Rapamycin inhibits muscle growth during postnatal development [24], muscle regeneration
[17] (Fig. 2) and compensatory muscle hypertrophy
induced by synergist elimination [16]. Muscle growth
during reloading of unloaded muscles is only partially
inhibited by rapamycin [24]. Muscle fiber hypertrophy
induced by transfection of adult muscles with a constitutively active Akt construct is also blunted by rapamycin [16,17].
Two major effectors of mTORC1 that promote protein synthesis are eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) and S6 kinase 1.
Muscle growth is apparently unaffected by 4E-BP1
knockout [25]. In contrast, deletion of S6 kinase 1
causes muscle atrophy and partially prevents the
response to constitutively active Akt [26]. However,
the control of protein synthesis by mTOR is still
incompletely characterized [21]. The growth-promoting
effect of mTORC1 is repressed by AMP-activated protein kinase (AMPK), and hypertrophy of soleus muscle has been described in AMPK-deficient mice [26].
Another aspect of mTOR function that is incompletely understood is the role of mTOR in transcriptional regulation. In both yeast and mammalian cells,
TOR/mTOR controls cell growth by coordinately regulating the synthesis of ribosomes and tRNAs and
activating transcription by all three nuclear RNA
polymerases (I, II and III). However, ribosomal RNA
accumulation induced in overloaded muscles after synergist ablation is only partially inhibited by rapamycin
[27]. On the other hand, blockade of mTOR by
rapamycin in cultured myotubes is sufficient to block

most IGF1-induced changes in transcription [28].
What are the downstream effectors of mTOR that regulate
transcription?
The
transcription
factor
Yin Yang 1 (YY1) physically interacts with mTORC1
and mediates mTOR-dependent regulation of mitochondrial gene expression via a YY1PGC-1a complex
[29]. More recently, active mTORC1 was found to
induce YY1 phosphorylation, resulting in displacement
of the polycomb repressor complex, thereby activating
transcription of many genes of the insulin/IGF1Akt
pathway, including Igf1, Irs1, Irs2, Akt1 and Akt2.
Conversely, mTORC1 inactivation induced by rapamycin results in YY1 dephosphorylation and recruitment of the polycomb repressor complex to the
promoter of these genes, with a consequent block of
transcription [30]. Muscle-specific inactivation of the
Yy1 gene leads to up-regulation of genes of the insulin/IGF1Akt pathway [30]; however, the effect of this
knockout on muscle growth has not been described.
The second major signaling pathway that controls
skeletal muscle growth involves myostatin, a member
of the transforming growth factor b (TGFb) superfamily. Myostatin is produced by skeletal muscle and acts
as a negative regulator of muscle growth, as shown by
the finding that myostatin mutations in various mammalian species cause muscle hypertrophy [31]. Purified
myostatin inhibits protein synthesis and reduces myotube size when added to differentiated myotubes in
culture [32]. Furthermore, muscle atrophy is induced
in mice by systemically administered myostatin [31].
Muscle hypertrophy may also be induced by inhibitory
extracellular binding proteins, such as follistatin,
whose effect is even greater than the lack of myostatin,
because it binds to other TGFb superfamily members,
such as activin A, that act as negative regulators of
muscle growth like myostatin does (Fig. 1A). Myosta-
Fig. 2. Muscle growth in regenerating

skeletal muscle is dependent on mTOR
activity. Rapamycin, a specific mTOR
inhibitor, inhibits growth of regenerating
muscle. The section was stained with an
antibody specific for embryonic myosin
heavy chain [177]. Modified from [17].
Scale bar = 50 lm.
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tin and activin A interact and activate a heterodimeric

receptor complex with serinethreonine kinase activity,
comprising a type II receptor, activin receptor 2
(ACVR2 and ACVR2B), and a type I receptor, activin
receptor-like kinase 4 and 5 (ALK4 and ALK5). A
soluble form of ACVR2B acts as a myostatin/activin A inhibitor that is capable of inducing muscle
hypertrophy in adult mice. Myostatin/activin A signaling in myofibers is mediated by phosphorylation and
nuclear translocation of Smad2 or Smad3 transcription
factors, and formation of heterodimers with Smad4.
Although the transcriptional targets of the Smad2/
Smad4 and Smad3/Smad4 complexes that mediate the
inhibitory effect on growth are not known, it is possible that myostatin/activin A signaling interferes with
the AktmTOR pathway [33,34]. For example, muscle
hypertrophy induced by transfection of dominant-negative ACVR2B is partially prevented by mTOR-specific siRNAs or by rapamycin [33]. Likewise,
follistatin-induced muscle hypertrophy is blunted by
blocking the IGF1AktmTOR pathway at the level
of the IGF1 receptor, via a dominant-negative IGF1
receptor, at the level of Akt, via dominant-negative
Akt, or at the level of mTOR, via rapamycin. However, follistatin-induced muscle hypertrophy was
unchanged in S6 kinase 1/2 knockout mice [35].
Another recent study showed that virus-mediated
over-expression of a form of follistatin that remains
localized within the injected muscle stimulates Akt
phosphorylation, mTOR signaling and protein synthesis, leading to a striking muscle hypertrophy that is
inhibited by rapamycin [36]. Inhibition of Smad3 activity by follistatin is critical for activation of Akt
mTOR signaling, as constitutively active Smad3 was
found to suppress follistatin-induced muscle growth
and mTOR activation. It is also possible that a direct
interaction between Smad3 and Akt, as demonstrated
in other cell systems [37,38], may be involved in crosstalk between the myostatin/activin A and IGF1 pathways in skeletal muscle.
Additional signaling pathways controlling muscle
growth
As shown in Fig. 1B, other important signaling pathways are also known to control skeletal muscle growth.
The transcription factor SRF (serum response factor) is
required for muscle growth during development, as
shown by muscle-specific SRF knockout [39,40]. Using
an inducible, muscle-specific knockout model, SRF was
also found to be required for muscle hypertrophy
induced by synergist elimination [41]. In this model, the
effect of SRF is apparently mediated via release of
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interleukins 4 and 6 (IL-4 and IL-6), which act in a

paracrine manner to induce satellite cell proliferation
and fusion [41] (see below). Akt phosphorylation is
apparently unchanged in control and SRF mutant muscles at various time points after synergist ablation.
However, a previous study reported that SRF is able
to activate the Akt pathway via a muscle-enriched
microRNA, miR-486, that targets the phosphatase and
tensin homolog PTEN, which negatively affects PI3K
Akt signaling [42]. In addition, as activation of mTOR
and its downstream effectors were not examined in the
previous study [41], it is possible that mTOR activity
and protein synthesis are increased by SRF in muscles
undergoing overload-induced hypertrophy, either via a
transcriptional mechanism mediated by SRF itself or as
a secondary consequence of incorporation of new
myonuclei resulting from satellite cell activation and
fusion. Finally, it should be stressed that SRF is known
to control the transcription of several cytoskeletal and
sarcomeric protein genes, including those for a-actin,
by binding to CArG box regulatory elements.
The AktmTOR pathway is also a point of convergence for additional signaling pathways that are
known to promote muscle growth. This appears to be
the case for androgens and b2-adrenergic agents, which
both have well-known anabolic effects on skeletal muscles. Androgens potently stimulate muscle growth: testosterone loss in male mice decreases muscle Igf1
mRNA, Akt phosphorylation and the rate of myofibrillar protein synthesis; these changes are all reversed
by nandrolone treatment [43]. Muscle hypertrophy
induced by b2-adrenergic agents, such as clenbuterol
or formoterol, is accompanied by a significant increase
in Akt phosphorylation [44] and is completely blocked
by rapamycin [45]. Another signaling pathway that
controls muscle growth involves Wnt7a, an extracellular protein that acts both on satellite stem cells,
increasing their numbers, and on myofibers by activating the PI3KAkt pathway via its receptor Fzd7
[46,47]. A pathway linked to mTOR activation
involves neuronal nitric oxide synthase (nNOS). When
activated in myofibers by functional overload, nNOS
generates nitric oxide (NO) and causes peroxynitritedependent activation of the cation channel Trpv1,
located in the sarcoplasmic reticulum. The resulting
increase in intracellular Ca2+ induced by Trpv1-mediated Ca2+ release triggers activation of mTOR [48].
Furthermore, mTOR is also activated by mechanical
stimulation via an Akt-independent pathway involving
phosphatidic acid and activated phospholipase D [49].
A novel form of PGC-1a (PGC-1a4), which results
from alternative promoter usage and splicing of the
primary transcript, is involved in muscle growth, as
shown by the finding that mice with skeletal musclespecific transgenic expression of PGC-1a4 show
increased muscle mass and strength [50]. PGC-1a4,
which is expressed at significant levels in skeletal muscle, is a shorter, truncated form of the previously
described PGC-1a [50a], now referred to as PGC-1a1,
which is involved in mitochondrial biogenesis and not
in muscle growth. In cultured muscle cells, PGC-1a4
was found to induce IGF1 and repress myostatin, thus
promoting myotube hypertrophy, which was blocked
by an IGF1 receptor inhibitor. Myotube growth
induced by treatment with clenbuterol was also
blunted by PGC-1a4 knockdown.
Satellite cell fusion and increase of myonuclei
during muscle growth
The issue of whether satellite cell proliferation and
fusion contributes to muscle growth has been the subject of debate [51]. There is no doubt that myoblast
fusion is essential for muscle growth during early stages
of muscle differentiation. For example, myotube
growth in culture is impaired when myoblast fusion is
inhibited, either during formation of the nascent myotube or during the transition from nascent to mature
myotube [52]. IL-6 and IL-4 released by the myotubes
act on myoblasts, promoting their proliferation and
fusion, respectively [53,54]. Muscle cells lacking IL-4 or
the IL-4a receptor subunit form smaller myotubes with
fewer myonuclei [53]. Muscle growth during early postnatal development (from P0 to approximately P21 in
mice and rats) is also accompanied by, and presumably
dependent on, a continuous increase in the number of
myonuclei resulting from satellite cell fusion [55] (an
approximately fivefold increase from P3 to P21 in
mouse extensor digitorum longus muscle [56]). Muscle
regeneration recapitulates many aspects of embryonic
and neonatal myogenesis, with satellite cells acting as a
major myogenic stem cell, and undergoing active proliferation and fusion during formation of new myofibers
[11]. A distinct feature of muscle regeneration, which is
missing in normal muscle development, is the central
role of inflammation and of various macrophage populations in the muscle growth process [57].
On the other hand, muscle hypertrophy at late postnatal stages takes place without a significant contribution of satellite cell fusion. For example, the
approximately twofold increase in myofiber cross-sectional area from P21 to P56 in mouse extensor digitorum longus muscle occurs with a negligible change in
myonuclear number [56]. In adult skeletal muscle, clenbuterol-induced hypertrophy does not involve satellite
cell fusion [58], although satellite cell activation is
induced by androgens [59]. Similarly, myonuclear

number is not increased during muscle growth upon
reloading of unloaded muscles [9,60]. Satellite cell proliferation and fusion were not detected during muscle
hypertrophy induced by a muscle-specific, inducible
and constitutively active Akt1 transgene [18], or by
over-expression of JunB [61]. The contribution of
satellite cells to muscle hypertrophy induced by blockade of the myostatin/activin A pathway is controversial. In two studies, satellite cell activation was not
detected after injection of vectors encoding the myostatin propeptide, which binds non-covalently to myostatin and inhibits its activity [62], or in hypertrophic
muscles expressing dominant-negative ACVR2B [33].
In contrast, another study reported an increase in
BrdU-positive myonuclei and increased numbers of
satellite cells when using a soluble ACVR2B to block
this pathway [63]. A recent detailed study concluded
that satellite cells play little or no role in myostatin/
activin A signaling in vivo, based on the finding that
satellite cell and myonuclear number were unchanged
in hypertrophic muscles after injection of soluble
ACVR2B, and that muscle hypertrophy induced by
over-expressing follistatin also occurs in mice lacking
syndecan4 or Pax7, which have compromised satellite
cell function or number, respectively [64].
A widely used model of muscle hypertrophy in adult
mice or rats is compensatory hypertrophy induced by
ablation of synergist muscles: for example hypertrophy
of the plantaris or soleus muscle after removal of the
gastrocnemius, or hypertrophy of the extensor digitorum longus after removal of the tibialis anterior muscle. This model of acute functional overload causes
immediate satellite cell proliferation and fusion [65,66],
with a consequent increase in the number of myonuclei
[54,67]. A similarly dramatic increase in mechanical
load may be induced in human skeletal muscle by
high-intensity eccentric contractions, which also cause
proliferation of satellite cells [68] and, when repeated,
are known to induce muscle hypertrophy. Depending
on the intensity of the exercise and the trained/
untrained state of the host, eccentric contractions may
cause a spectrum of responses, ranging from severe
muscle damage and local inflammation to mild muscle
damage (myofibrillar disruptions) without inflammation, to remodeling of the extracellular matrix without
obvious damage to the muscle fibers. Similar changes
have been reported in rat or mouse muscles after elimination of synergists, and it is possible that the satellite
cell activation seen in each of these conditions may
reflect a response that is similar to that observed in
muscle regeneration. A role of satellite cells in IGF1induced muscle hypertrophy was suggested by the
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inhibitory effect of gamma radiation [69]; however,

exposure to radiation may affect protein synthesis
within the myofibers, thus complicating interpretation
of this experiment [70].
IL-6 produced by myofibers and satellite cells is
increased in overloaded muscles, suggesting a role for
IL-6 and downstream signal transducer and activator
of transcription 3 (STAT3) signaling in satellite cell
proliferation, myonuclear accretion and hypertrophy
[54]. IL-4 was found to control myoblast fusion, thus
promoting the transition from nascent to mature myotubes in cultured muscle cells and during postnatal
growth [53]. A recent study indicated that satellite cell
proliferation and fusion during overload-dependent
hypertrophy are induced by IL-6 and IL-4, respectively, and that both cytokines are released by overloaded myofibers under the control of SRF [41]. IL-4
expression is decreased by muscle-specific SRF knockout, which causes reduced postnatal muscle growth
and reduced hypertrophy after synergist ablation [40],
with both defects being rescued by IL-4 but not IL-6
over-expression [41]. However, another recent study
reported that recruitment of satellite cells is not
required for muscle hypertrophy, because hypertrophy
was unchanged in mice in which more than 90% of
satellite cells were ablated by diphtheria toxin A using
an inducible Pax7diphtheria toxin A transgene [71].
How may these opposite conclusions about the mechanism of muscle hypertrophy induced by functional
overload be reconciled?
It is clear that skeletal muscle has the capacity to
activate two modes of hypertrophy, either with or
without satellite cell involvement, as clearly shown by
the two stages of muscle growth during postnatal
development. These two modes of hypertrophy are
also observed at later stages, and may be activated in
the adult in response to various stimuli. It is likely that
satellite cells are activated and contribute to hypertrophy when an acute stimulus is involved, such as after
elimination of synergistic muscles, or after strong exercise with eccentric contractions, i.e. under conditions
when some form of muscle damage occurs. In contrast, more gradual exercise, or reloading of unloaded
muscles, does not trigger satellite cell activation and
fusion. It may be envisaged that, when one of the two
available modes of response is artificially impaired, as
is the case in gene or cell ablation models, the muscle
will use the remaining available mode. Thus, in the
absence of satellite cells, a growth response is still
induced by functional overload, but via increased protein synthesis alone. Loss-of-function approaches,
involving either genes or cells, should thus be interpreted with caution, because compensatory adapta4300
tions may occur, not only when the perturbation is

produced during development, as in traditional knockout models, but also when it is produced in the adult
using inducible systems.
Muscle atrophy
Muscle atrophy involves the shrinkage of myofibers
due to a net loss of proteins, organelles and cytoplasm.
Acute muscle atrophy, as occurs in many pathological
conditions, is due to hyperactivation of the cells main
degradation pathways, including the ubiquitinproteasome system and the autophagylysosome pathway.
Recent studies have highlighted a complex scenario
whereby these catabolic pathways modulate one
another at different levels, and are also coupled at various points to biosynthetic pathways. The result is a
coordinated balance between protein degradation and
synthesis that reflects the physiological state of the
muscle fiber. As muscle accounts for such a large proportion of total body mass, particularly total body
protein, this local balance has a significant effect on
general protein homeostasis.
The ubiquitinproteasome and autophagy
lysosome machinery are activated in atrophying
muscles
Activation of the cells proteolytic systems is transcriptionally regulated, and a subset of genes that are commonly up- or down-regulated has been identified in
atrophying skeletal muscle, regardless of the catabolic
condition [7275]. These common genes are thought to
regulate the loss of muscle components, and were thus
designated atrophy-related genes or atrogenes [75
77]. Among the up-regulated atrophy-related genes are
transcripts belonging to the ubiquitinproteasome and
autophagylysosome systems. The up-regulation of
several ubiquitinproteasome and autophagy-related
genes is normally blocked by Akt through negative
regulation of Forkhead box O (FoxO) transcription
factors [7779].
In muscle, the ubiquitinproteasome system is
required to remove sarcomeric proteins in response to
changes in muscle activity. The rate-limiting step of
the ubiquitination process, which affects subsequent
proteasome-dependent degradation, is catalysed by the
E3 enzyme, which is a ubiquitin ligase. Among the
known E3s, only a few are both muscle-specific and
up-regulated during muscle loss. The first to be
identified were atrogin-1/MAFbx (muscle atrophy Fbox) and muscle RING finger 1 (MuRF1). Mice lacking atrogin-1/MAFbx and MuRF1 are resistant to
muscle atrophy induced by denervation [72]. Moreover, knockdown of atrogin-1 prevents muscle loss
during fasting [80], whereas MuRF1 knockout mice
(but not atrogin-1 knockout mice) are also resistant to
dexamethasone-induced muscle atrophy [81]. So far,
very few muscle proteins have been identified as substrates for atrogin-1, and those that have been identified appear to be involved in growth-related processes
or survival pathways. For example, atrogin-1 promotes
degradation of MyoD, a key muscle transcription factor, and of eukaryotic translation initiation factor 3
subunit F (eIF3-f), an important activator of protein
synthesis [82,83]. In the heart, atrogin-1 ubiquitinates
and reduces the levels of calcineurin A, an important
factor triggering cardiac hypertrophy in response to
pressure overload [84]. Interestingly, immunoprecipitation experiments in C2C12 myoblasts and myotubes
have found that atrogin-1 interacts with sarcomeric
proteins, including myosins, desmin and vimentin, as
well as transcription factors, components of the translational machinery, enzymes involved in glycolysis and
gluconeogenesis, and mitochondrial proteins [85].
Whether atrogin-1 ubiquitinates these proteins has yet
to be proven. Conversely, MuRF1 was reported to
interact with and control the half-life of many important muscle structural proteins, including troponin I
[86], myosin heavy chains [87,88], actin [89], myosin
binding protein C and myosin light chains 1 and 2
[90]. Presumably, additional E3s that have not yet
been identified are also activated during atrophy to
promote the clearance of soluble cellular proteins and
to limit/regulate anabolic processes. A recent paper
reported that Trim32 (tripartite motif-containing protein 32) is a crucial E3 ligase for the degradation of
thin filaments (actin, tropomyosin and troponins),
a-actinin and desmin [91]. However, Trim32 knockout
mice are not protected from atrophy, but instead show
impaired recovery of muscle mass after atrophy [92].
Another E3 ubiquitin ligase that has been found to
play a critical role in atrophy is TRAF6 (TNF receptor-associated factor) [93], which mediates the conjugation of Lys63-linked polyubiquitin chains to target
proteins. Lys48-linked polyubiquitin chains are a signal for proteasome-dependent degradation, but Lys63linked polyubiquitin chains play other roles, such as
regulating autophagy-dependent cargo recognition by
interacting with the scaffold protein p62 (also known
as SQSTM1) [9496]. Muscle-specific TRAF6 knockout mice have a decreased amount of polyubiquitinated proteins, almost no Lys63-polyubiquitinated
proteins in starved muscles [97], and are resistant to
muscle loss induced by denervation, cancer or starvation [93,97,98]. The mechanism of this protection
involves both direct and indirect effects of TRAF6 on

protein breakdown. In fact, TRAF6-mediated ubiquitination is required for the optimal activation of c-Jun
N-terminal kinase, AMPK, FoxO3 and NF-jB [97].
All of these factors are crucial regulators of atrogin-1
and MuRF1 expression and of several autophagyrelated genes. Inhibition of TRAF6 reduces the
induction of atrogin-1 and MuRF1, thereby preserving
muscle mass under catabolic conditions.
Specific ubiquitin ligases may be involved in different models of muscle wasting and at different stages of
the atrophy process. For instance, the HECT domain
ubiquitin ligase Nedd4-1 has been reported to be upregulated mainly during muscle disuse. Indeed, deletion of the Nedd4-1 gene specifically in skeletal muscle
results in partial protection from muscle atrophy in
denervated type II fibers. However, Nedd4-1 knockout
mice have smaller muscles, suggesting that this E3 may
play additional roles during myogenesis or in the control of protein synthesis [99].
Mul1 is a mitochondrial ubiquitin ligase that plays
an important role in mitochondrial network remodeling. Mul1 is up-regulated by the FoxO family of transcription factors under catabolic conditions, such as
fasting or denervation, and causes mitochondrial fragmentation and removal via autophagy (mitophagy)
[100]. Importantly, knocking down Mul1 spares muscle
mass during fasting. Mul1 ubiquitinates the mitochondrial pro-fusion protein mitofusin 2, causing its degradation via the proteasome system. The exact
mechanism that triggers Mul1-dependent mitochondrial dysfunction and mitophagy is unclear, but it has
been reported that mitofusin degradation is permissive
for mitochondrial fission and mitophagy [101].
Carboxy terminus of Hsc70 interacting protein
(CHIP) is another ubiquitin ligase, which regulates
ubiquitination and lysosomal-dependent degradation
of filamin C, a muscle protein found in the Z-line
[102]. Filamins undergo unfolding and refolding cycles
during muscle contraction, and are therefore prone to
irreversible damage [102]. Alterations to filamin structure trigger binding of the co-chaperone BAG3, which
is a complex comprising the chaperones Hsc70 and
HspB8, as well as the ubiquitin ligase CHIP. CHIP
ubiquitinates BAG3 and filamin, which are recognized
and delivered to the autophagy system by p62 [102].
Interestingly, filamin B half life is controlled, at least
during myogenesis, by another ubiquitin ligase,
ASB2b, which is mainly expressed in muscle cells. In
this case, ubiquitination of filamin B by ASB2b leads
to proteasome-dependent degradation [103].
In skeletal muscle, E3 ligases also have important
regulatory functions in signaling pathways. For
4301
example, it was recently found that the ubiquitin ligase

Fbxo40 (F-box only protein) regulates anabolic signals
[104]. Fbxo40 ubiquitinates and affects the degradation
of insulin receptor substrate 1, a downstream effector
of insulin receptor-mediated signaling. Inhibition of
Fbxo40 by RNAi induces hypertrophy in myotubes,
and Fbxo40 knockout mice display bigger muscle
fibers [104].
Although some E3 ligases involved in muscle protein
ubiquitination and breakdown have been identified,
very little is known about how ubiquitinated proteins
are recognized and delivered to the proteasome.
ZNF216 has been identified as an important player in
the recognition and delivery of ubiquitinated proteins
to the proteasome during muscle atrophy. Interestingly, ZNF216 is up-regulated by FoxO transcription
factors in atrophying muscles, and ZNF216-deficient
mice are partially resistant to muscle loss during denervation. The absence of ZNF216 in muscle leads to
accumulation of polyubiquitinated proteins [105].
Another important system for extraction and degradation of ubiquitinated proteins from larger structures
is the p97/valosin containing protein (VCP) ATPase
complex. p97/VCP is induced during denervation, and
over-expression of a dominant-negative p97/VCP
reduces overall proteolysis by the proteasome and
lysosome pathways, and blocks the accelerated protein
breakdown induced by FoxO3. Interestingly, p97 and
its co-factors, Ufd1 and p47, have been found to be
associated with specific myofibrillar proteins, suggesting a role for p97 in extracting ubiquitinated proteins
from myofibrils [106].
Although a great body of research has focused on
the ubiquitination process, little is known about the
role of deubiquitination and its contribution to muscle
atrophy. The largest class of deubiquitinating enzymes
are ubiquitin-specific proteases. So far, only two
ubiquitin-specific proteases (USP14 and USP19) have
been found to be up-regulated in atrophying muscles
[73,107]. Knockdown of USP19 in myotubes results in
decreased protein degradation and reverts dexamethasone-induced loss of myosin heavy chain [108].
Macroautophagy, hereafter referred to as autophagy, is the other proteolytic system that is activated in catabolic conditions and that is under FoxO
regulation [109]. The various types of autophagy,
including their regulation and involvement in muscle
homeostasis, have been reviewed recently [110].
Briefly, autophagy is a highly conserved homeostatic
mechanism that is used for the degradation and recycling, through the lysosomal machinery, of bulk cytoplasm, long-lived proteins and organelles [111].
Although autophagy was initially considered a
4302
non-selective degradation pathway, the presence of

more selective forms of autophagy is becoming
increasingly evident. Indeed, autophagy may trigger
the selective removal of specific organelles, such as
mitochondria, via mitophagy. In mammals, parkin,
PINK1 (phosphatase and tensin homolog-induced
putative kinase 1), and BCL2/adenovirus E1B 19 kDa
protein-interacting protein 3 (Bnip3 and Bnip3L) have
been shown to regulate mitophagy, and inactivation
of the genes encoding these proteins leads to mitochondrial abnormalities [112,113]. PINK1 is normally
absent in healthy mitochondria because it is constitutively degraded by mitochondrial proteases. However,
once mitochondria are damaged, PINK1 is no longer
degraded and accumulates. PINK1 induces parkin
recruitment to mitochondria, promoting mitophagy
through ubiquitination of outer mitochondrial membrane proteins that are recognized by p62, which then
brings autophagic vesicles to ubiquitinated mitochondrial proteins [114,115]. Bnip3 and Bnip3L are
BH3-only proteins that are localized at the outer
membrane of the mitochondria after cellular stress,
and reportedly bind directly to LC3 (MAP1LC3A
microtubule-associated protein 1 light chain 3 alpha),
thereby recruiting the autophagosome to damaged
mitochondria [116,117]. In atrophying muscle, the
mitochondrial network is dramatically remodeled following fasting or denervation, and autophagy via
Bnip3 contributes to mitochondrial remodeling
[101,118120]. Expression of the fission machinery is
sufficient to cause muscle wasting in mice, whereas
inhibition of mitochondrial fission prevents muscle
loss during denervation, indicating that disruption of
the mitochondrial network is a crucial amplificatory
loop of the muscle atrophy program [101,118]. Conversely, impairment of basal mitophagy is deleterious
to muscle homeostasis, and leads to the accumulation
of damaged and dysfunctional mitochondria [121].
Accordingly, the phenotype of mice with muscle-specific inactivation of various genes coding for autophagy-related proteins, such as Atg7, Atg5 or
nutrient-deprivation autophagy factor-1 (NAF-1), a
Bcl-2-associated autophagy regulator, results in atrophy, weakness and various myopathic features
[122124]. In addition, altered regulation of autophagy-related genes leads to muscle dysfunction. Histone deacetylases 1 and 2 (HDACs) were found to
regulate muscle autophagy by controlling the expression of autophagy genes. Muscle-specific ablation of
both HDAC1 and HDAC2 results in partial perinatal
lethality, and the HDAC1/2 knockout mice that do
survive develop a progressive myopathy characterized
by impaired autophagy [125,126].
IGF1AKTFoxO signaling
Several studies have shown that the IGF1 and/or insulin signaling suppress protein breakdown while promoting muscle growth [127129]. Additional data
supporting the role of the IGF1 pathway in regulating
muscle atrophy have been obtained from studies of
Akt. Electroporation of constitutively active Akt in
adult myofibers completely blocks muscle atrophy
induced by denervation [16]. Akt transgenic mice display muscle hypertrophy and protection from denervation-induced atrophy [19,20,130], showing that the Akt
pathway promotes muscle growth and simultaneously
blocks protein degradation [20,33]. In particular, Akt
regulates both the ubiquitinproteasome system and
the autophagylysosome pathway, and this action is
mediated by FoxO transcription factors. The FoxO
family members that are important for skeletal muscle
include three isoforms: FoxO1, FoxO3 and FoxO4.
Akt phosphorylates all FoxOs, promoting their export
from the nucleus to the cytoplasm. As predicted, the
reduced activity of the Akt pathway observed in various models of muscle atrophy leads to decreased levels
of phosphorylated FoxO in the cytoplasm and a
marked increase in nuclear FoxO [131] (Fig. 3). The
translocation and transcriptional activity of FoxO
members is sufficient to promote atrogin-1 and
MuRF1 expression, and muscle atrophy. Studies utilizing FoxO3 over-expression in adult muscle or musclespecific FoxO1 transgenic mice showed markedly
reduced muscle mass and fiber atrophy [77,132,133]. In
contrast, FoxO knockdown by RNAi blocks the upregulation of atrogin-1 expression during atrophy and
prevents muscle loss [77,134].
Cross-talk between protein breakdown and protein
synthesis is not limited to Akt, but also involves
FoxO. Activation of FoxO in Drosophila muscle upregulates 4E-BP1 [135] and represses mTOR via sestrin
[136]. Consistently, in mammals, FoxO3 reduces total
protein synthesis in adult muscle [137]. Thus, when
Akt is active, protein breakdown is suppressed, and
when FoxO is induced, protein synthesis is further
suppressed. This is not trivial, as FoxO activity is regulated by several post-translational modifications,
including phosphorylation, acetylation and mono- and
polyubiquitination [138]. Adding an additional level of
complexity, the regulatory consequences of these
changes appear to be specific for individual FoxO
members. For example, recent evidence suggests that
acetylation negatively regulates FoxO3 activity, but
has no effect on FoxO1 [139]. Mutants of FoxO3 that
mimic the effect of acetylation have cytosolic localization and a reduced capacity to induce transcription of
the gene encoding atrogin-1, and cause muscle atrophy
[140]. Most of these regulatory mechanisms are Aktindependent, and may play a role in muscle atrophy
induced by oxidative or energy stress.
Other studies have revealed a connection between
AMPK and FoxO3. AMPK phosphorylates several
Akt-independent sites on FoxO3, thereby stimulating
its transcriptional activity [141,142]. Indeed, treatment
Fig. 3. Protein degradation regulates

protein synthesis. In the presence of
growth factors, the PI3KAkt/protein
kinase B pathway sequesters FoxO1/3/4
transcription factors in the cytoplasm. In
the absence of growth factors, Akt is
inactive, and therefore, FoxOs are
translocated into the nucleus and induce
the transcription of target genes that
regulate the ubiquitinproteasome and
autophagylysosome systems. mTOR
senses the amino acids derived from the
proteasome, or, when localized on
lysosomes, the amino acid flux derived
from lysosomal protein breakdown, and is
therefore activated.
4303
of muscle cultures with 5-aminoimidazole-4-carboxamide riboside (AICAR), an activator of AMPK,

increases protein breakdown and atrogin-1 expression
via the FoxO family [143]. It has recently been shown
that FoxO3 is activated via AMPK in myofibers to
induce expression of atrogin-1 and MuRF1 under conditions of energy stress [101,144]. Activation of AMPK
also leads to induction of some autophagy-related
genes encoding proteins such as LC3 and Bnip3.
Increased oxidative stress occurs during denervation
and hindlimb suspension. During these disuse conditions, nNOS moves from the sarcolemma, where it is
bound to the dystrophinglycoprotein complex, to the
cytosol. Free cytosolic nNOS induces oxidative stress
and enhances FoxO3-mediated transcription of atrogin-1 and MuRF1, thereby causing muscle loss [145].
Interestingly, the NF-jB pathway is not involved in
nNOS-mediated muscle atrophy [145]. Similarly, when
dihydropyridine receptor (DHPR) is reduced in adult
muscle by RNAi, muscle atrophy is triggered via
nNOS relocalization and FoxO3 activation [146].
However, in this latter setting, the genes up-regulated
by FoxO3 are those encoding the autophagy regulators
LC3, vacuolar protein sorting 34 (VPS34) and Bnip3
as well as the lysosomal enzyme cathepsin L. In
humans, the diaphragm of patients that are mechanically ventilated undergoes rapid atrophy caused by
activation of proteolytic systems, including autophagy,
through Akt inhibition and FoxO1 induction [147].
Interestingly, oxidative stress is increased and therefore
contributes to FoxO activation in this example of disuse-mediated atrophy.
FoxO activity is also modulated by direct or indirect
actions of co-factors and by interaction with other
transcription factors. FoxOs have been found to interact with PGC-1a, a critical co-factor for mitochondrial
biogenesis [148,149]. Maintaining high levels of PGC1a under catabolic conditions (either in transgenic
mice or by transfecting adult myofibers) spares muscle
mass during denervation, fasting, heart failure, aging
and sarcopenia similar to the effect observed for
expression of constitutively active FoxO3 [5,150,151].
Similar beneficial effects were recently obtained by
over-expression of PGC-1b, a homolog of PGC-1a
[152]. The positive action on muscle mass of these cofactors is due to inhibition of autophagylysosome
and ubiquitinproteasome degradation. PGC-1a and
PGC-1b reduce protein breakdown by inhibiting the
transcriptional activity of FoxO3 and NF-jB, but do
not affect protein synthesis. Thus, these co-factors prevent the excessive activation of proteolytic systems by
inhibiting the action of the pro-atrophy transcription
factors without perturbing the translational machinery.
4304
We recently reported that the transcription factor

JunB blocks atrophy and promotes hypertrophy in
adult muscles [61]. Indeed, JunB blocks myofiber atrophy of denervated tibialis anterior muscles and cultured myotubes induced by FoxO3 over-expression,
dexamethasone treatment or starvation. Under these
conditions, JunB prevents activation of atrogin-1 and
partially prevents activation of MuRF1, thereby reducing the increase in overall protein degradation induced
by activated FoxO3. Further analysis revealed that
JunB does not inhibit FoxO3-mediated activation of
the autophagylysosome system, but only ubiquitin
proteasome degradation, by inhibiting atrogin-1 and
MuRF1 induction under catabolic conditions. In fact,
JunB directly binds FoxO3, thereby preventing its
recruitment to the promoters of key atrogenes. Moreover, JunB over-expression is sufficient to induce dramatic hypertrophy of myotubes and adult muscle.
These hypertrophic changes depend on increased protein synthesis, without affecting the basal rate of protein degradation. The growth-promoting effects
mediated by JunB in muscle resemble the effects of
inhibiting the TGFb pathway [33,34]. Indeed, JunB
over-expression markedly suppresses myostatin expression in transfected myotubes and decreases the phosphorylation of Smad3, the transcription factor
downstream of the myostatinTGFb signaling pathway [61].
Inflammatory cytokines and NF-jB signaling
NF-jB transcription factors are expressed in skeletal
muscle and are activated by inflammatory cytokines,
particularly tumor necrosis factor a (TNFa). Indeed,
inflammation is a potent trigger of muscle wasting and
cachexia [153]. NF-jB is maintained in the inactive
state by binding of a family of inhibitory proteins
called IjB. The increase in the TNFa level induces
activation of an IjB kinase (IKKb) complex that
phosphorylates IjB, resulting in its ubiquitination and
proteasomal degradation. This leads to nuclear translocation of NF-jB and activation of NF-jB-mediated
gene transcription [153].
Transgenic mice that over-express IKKb specifically
in muscle show severe muscle wasting that is mediated,
at least in part, by the ubiquitin ligase MuRF1, but
not by atrogin-1 [154]. In contrast, muscle-specific
inhibition of NF-jB by transgenic expression of a constitutively active IjB mutant does not induce an overt
phenotype, but denervation atrophy is substantially
reduced [155]. Mice deficient for the p105/p50 subunit
of NF-jB are partially resistant to muscle atrophy
induced by hindlimb unloading [156]. However, one of
the effects of TNFa and pro-inflammatory cytokines is

to induce insulin resistance and suppression of the
IGF1Akt pathway [157159]. Therefore, Akt phosphorylation should always be monitored when NF-jB
signaling is altered, as Akt inhibition may substantially
contribute to muscle wasting. Indeed IKKb conditional knockout mice are resistant to muscle atrophy
but show activation of Akt [160]. The significance of
decreased muscle atrophy following IKKb ablation
and the degree to which this effect is Akt-dependent
remains unclear. Nevertheless, these findings highlight
the relevance of the cross-talk between the two pathways, and future studies are required to elucidate the
respective contributions of the IKKbNF-jB and
AktFoxO pathways to muscle atrophy.
A recent study revealed an unexpected connection
between TNFa signaling and myogenin on MuRF1 and
atrogin-1 expression: TNFa treatment causes up-regulation of myogenin, MuRF1 and atrogin-1. Interestingly,
a G protein-coupled receptor blocks TNFa-mediated
myogenin up-regulation by activating Gai2 [161] and
expression of muscle-specific ubiquitin ligases. However,
the precise mechanisms of TNFa-mediated myogenin
regulation, the interplay with Gai2 and the implications
for muscle wasting are still far from fully understood.
TNF-like weak inducer of apoptosis (TWEAK) is a
member of the TNF superfamily that was recently
found to induce muscle atrophy [158,162]. TWEAK
acts on responsive cells by binding to fibroblast growth
factor-inducible 14 (Fn14), a small cell-surface receptor. Fn14 is up-regulated in denervated muscle, allowing NF-jB activation and consequently MuRF1 (but
not atrogin-1) expression [162]. TWEAK knockout
mice display reduced atrophy after denervation, as well
as reduced NF-jB activation and MuRF1 expression.
However, Fn14 does not increase under all conditions
of muscle atrophy; for instance, it is not induced by
dexamethasone treatment. Another important player
in NF-jB signaling is the ubiquitin ligase TRAF6,
which is required for Fn14 up-regulation during fasting [97]. As noted earlier, TRAF6 is also required for
activation of FoxO3 and AMPK in starved muscles
and for induction of the ubiquitinproteasome and
autophagylysosome systems [97].
The pro-inflammatory cytokines TNFa, IL-6 and
IL-1 also activate the Janus kinase/signal transducer
and activator of transcription (JAK/STAT) pathway.
Interestingly, sepsis and cancer induce STAT3 phosphorylation in muscles, and STAT3 inhibition spares
muscle mass in tumor-bearing mice [163]. Moreover,
over-expression of Stat3 is sufficient to induce muscle
atrophy and to up-regulate atrogin-1. However,
another recent study identified an unexpected role of
Stat3 in autophagy regulation. Stat3 has been reported

to block VPS34 expression, resulting in alteration of
assembly of the Vps34Beclin1Vps15Atg14 complex,
and therefore autophagy inhibition and muscle degeneration [164]. This Stat3-dependent regulation of autophagy occurs downstream of Fyn tyrosine kinase.
Other signaling pathways
Myostatin inhibition and its role in muscle growth has
been described above; however, the mechanism of myostatin activation and its role and capacity to trigger
muscle atrophy remain unclear. Myostatin activation
has been reported to induce massive [165], mild or no
atrophy at all [166,167]. However, in muscle cell cultures, myostatin was reported to up-regulate essential
atrophy-related ubiquitin ligases. This regulation was
found to be FoxO-dependent and NF-jB-independent
[168]. Importantly, myostatin expression is controlled
by FoxO1, supporting the concept that the myostatin
pathway synergizes with AktFoxO signaling [169]. A
recent study showed that inhibition of myostatin by soluble ACVR2B prevents and fully reverses skeletal muscle loss and atrophy of the heart in tumor-bearing
animals [63]. Such treatment dramatically prolongs the
survival of these animals, suggesting potential therapeutic efficacy in patients with cancer cachexia. Reports
attempting to dissect the downstream signaling have
shown that Smad2 and Smad3 are the principle transcription factors that mediate myostatins effects on
muscle mass [33,34,36,100]. However, as mentioned
above, specific transcriptional targets of Smad2 and
Smad3 are still unknown, and mechanisms of Smaddependent atrophy remain to be established.
Glucocorticoid levels are increased in many pathological conditions associated with muscle loss. Glucocorticoid treatment induces atrogin-1 and MuRF1
expression and muscle wasting in cell culture and in vivo
[16,77,88,127,170]. In contrast, adrenalectomy or treatment with a glucocorticoid receptor antagonist attenuate muscle loss in some diseases [170,171]. The
mechanisms of glucocorticoid-mediated muscle atrophy
were recently unraveled. Once in the nucleus, the glucocorticoid receptor activates expression of two target
genes, encoding REDD1 (regulated in development and
DNA damage responses 1) and KLF15 (Kr
uppel-like
factor 15) [172]. REDD1 inhibits mTOR activity by
sequestering 14-3-3 and increasing TSC1/2 activity.
Inhibition of mTOR is permissive for activation of an
atrophy program via KLF15. Indeed, mTOR activation
attenuates glucocorticoid-induced muscle atrophy.
KLF15 is a transcription factor that is involved in several metabolic processes in skeletal muscle, for instance
4305
up-regulation of branched-chain aminotransferase 2.

KLF15 participates in muscle catabolism via transcriptional regulation of FoxO1, atrogin-1 and MuRF1.
Moreover, KLF15 negatively affects mTOR through
up-regulation of branched-chain aminotransferase 2,
which in turn induces branched-chain amino acid degradation. Interestingly, FoxO1 and glucocorticoid receptor cooperate to up-regulate MuRF1 expression [173].
Proteolysis-dependent regulation of
protein synthesis
Synthesis and degradation of proteins are two processes that are intimately connected. Indeed, most of
the above-mentioned pathways concomitantly regulate
both synthesis and degradation, such that when protein synthesis is induced, degradation is suppressed
and vice versa. However, this control appears to be a
compensatory mechanism to limit energy expenditure
for the production of novel proteins under catabolic
conditions. As mentioned above, in denervated muscles, net protein synthesis is increased rather than
decreased compared to innervated muscles [8]. This is
because a proportion of the amino acids released from
protein breakdown stimulate protein synthesis via
mTOR, and, if this mechanism is blocked, muscle loss
is exacerbated [8]. The direct action of amino acids on
translation plays an important role in the rewiring of
protein synthesis during catabolic conditions, changing
the metabolism and expression of sarcomeric proteins
in order to optimize muscle homeostasis and performance. An important example of amino acid-dependent regulation of gene transcription during a
catabolic state has recently been described [174] for
lysosomal-dependent protein degradation. Nutrients,
especially free amino acids, are sensed by the mTOR
kinase, which then inhibits autophagy by blocking formation of the Atg1/unc-51-like kinase 1 complex, an
important regulatory step for autophagy initiation.
The mTORC1 complex is therefore at the center of a
variety of cellular process such as protein synthesis,
autophagy, aging, mitochondrial function and energy
production. These various actions of mTORC1 are
exploited by its localization/recruitment to various cellular compartments. For instance, the Rag GTPase
complex, which senses lysosomal amino acids, promotes localization of mTORC1 to the lysosomal surface. Accumulation of amino acids within the
lysosomal lumen generates an activating signal that is
transmitted to the Rag GTPases via vacuolar H+adenosine triphosphatase ATPase (v-ATPase), recruiting mTORC1 to the lysosomes. This mTOR localization initiates amino acid signaling and protein
4306
synthesis [174] (Fig. 3). Concomitantly, mTOR also

inhibits transcription factor EB, a master regulator of
lysosome biogenesis [175]. Activation of mTORC1
induces phosphorylation and localization of transcription factor EB at the lysosomal membrane, thus inhibiting its transcriptional activity [176]. These data
indicate that the content/activity of the lysosome
directly regulates lysosome biogenesis via an mTOR
transcription factor EB axis. The implication of this
signaling as it relates specifically to muscle homeostasis
has yet to be investigated.
Conclusions and perspectives

Our understanding of the mechanisms that control
muscle growth and atrophy has greatly advanced during the last ten years. Major milestones in this progress
have been identification of the transduction pathways
that mediate myostatin and IGF1 signals, in particular
the crucial role of Akt and its main downstream effectors, mTOR, which controls protein synthesis, and
FoxO3, which controls protein degradation via the proteasomal and autophagic/lysosomal systems. In addition, other pathways, such as SRF, have emerged as
potential players in regulation of muscle fiber size, and
the contribution of satellite cells has been the object of
intensive investigation. It is clear that there is no common mechanism that applies to all models of muscle
growth or wasting, and an important objective for
future studies will be to define the pathways that are
operative in the various situations. For example, autophagy is highly up-regulated in skeletal muscles during
starvation, but its induction after denervation, when
the ubiquitinproteasome pathway is strongly activated, is much less important. Satellite cell activation
may likewise vary in different models of muscle hypertrophy, and its contribution to the increase in muscle
fiber size remains to be established.
Dissection of the pathways that control muscle mass
and function will provide useful indications for the
development of drugs that are able to boost muscle
growth and prevent muscle wasting, a target that is now
being actively pursued in both academic and biotechnology/pharmaceutical research, and may have great
therapeutic importance for treatment of neuromuscular
diseases, systemic disorders, muscle disuse and aging.
Acknowledgements
Original work reported here is supported by the EC
FP7 Project MYOAGE (grant number 223576 to S.S.
and M.S.) and the European Research Council (grant
number 282310-MyoPHAGY to M.S.).
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Mechanisms regulating skeletal muscle growth and atrophy

Skeletal muscle mass increases during postnatal development through a

or hypertrophy, occurs during development and in

reloading after unloading) or anabolic hormonal stimulation (testosterone or b2-adrenergic agonists). A

Mechanisms regulating muscle growth and atrophy

protein catabolism as well as increased synthesis of

Mechanisms regulating muscle growth and atrophy

mTOR interacts with several proteins to form two

mice lacking raptor in skeletal muscle, whereas those

Mechanisms regulating muscle growth and atrophy

rapamycin in cultured myotubes is sufficient to block

Fig. 2. Muscle growth in regenerating

Mechanisms regulating muscle growth and atrophy

tin and activin A interact and activate a heterodimeric

interleukins 4 and 6 (IL-4 and IL-6), which act in a

Mechanisms regulating muscle growth and atrophy

induced by androgens [59]. Similarly, myonuclear

Mechanisms regulating muscle growth and atrophy

inhibitory effect of gamma radiation [69]; however,

tions may occur, not only when the perturbation is

Mechanisms regulating muscle growth and atrophy

involves both direct and indirect effects of TRAF6 on

Mechanisms regulating muscle growth and atrophy

example, it was recently found that the ubiquitin ligase

non-selective degradation pathway, the presence of

Mechanisms regulating muscle growth and atrophy

Fig. 3. Protein degradation regulates

Mechanisms regulating muscle growth and atrophy

of muscle cultures with 5-aminoimidazole-4-carboxamide riboside (AICAR), an activator of AMPK,

We recently reported that the transcription factor

the effects of TNFa and pro-inflammatory cytokines is

Mechanisms regulating muscle growth and atrophy

Stat3 in autophagy regulation. Stat3 has been reported

Mechanisms regulating muscle growth and atrophy

up-regulation of branched-chain aminotransferase 2.

synthesis [174] (Fig. 3). Concomitantly, mTOR also

Conclusions and perspectives

Mechanisms regulating muscle growth and atrophy

hormone receptor signaling modes regulate skeletal

Mechanisms regulating muscle growth and atrophy

25 Le Bacquer O, Petroulakis E, Paglialunga S, Poulin F,

36 Winbanks CE, Weeks KL, Thomson RE, Sepulveda

47 von Maltzahn J, Renaud JM, Parise G & Rudnicki

Mechanisms regulating muscle growth and atrophy

Dupont-Versteegden EE (2012) Satellite cell depletion

Mechanisms regulating muscle growth and atrophy

72 Bodine SC, Latres E, Baumhueter S, Lai VK, Nunez

84 Li HH, Kedar V, Zhang C, McDonough H, Arya R,

95 Komatsu M, Waguri S, Koike M, Sou YS, Ueno T,

Mechanisms regulating muscle growth and atrophy

accelerated degradation of muscle proteins. EMBO J

Mechanisms regulating muscle growth and atrophy

Autophagy and skeletal muscles in sepsis. PLoS One

(FKHR) transgenic mice have less skeletal muscle

forkhead FoxO3a and interaction with Ulk1. J Cell

Mechanisms regulating muscle growth and atrophy

157 de Alvaro C, Teruel T, Hernandez R & Lorenzo M

Mechanisms regulating muscle growth and atrophy

overexpression of myostatin. Am J Physiol Endocrinol

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