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DEVELOPMENTAL DYNAMICS 243:201–215, 2014

REVIEWS–A PEER REVIEWED FORUM

Mechanisms of Muscle Growth and Atrophy in


Mammals and Drosophila
Rosanna Piccirillo,1,2 Fabio Demontis,3,4* Norbert Perrimon,3,5 and Alfred L. Goldberg1

Background: The loss of skeletal muscle mass (atrophy) that accompanies disuse and systemic diseases is
highly debilitating. Although the pathogenesis of this condition has been primarily studied in mammals,
Drosophila is emerging as an attractive system to investigate some of the mechanisms involved in muscle
growth and atrophy. Results: In this review, we highlight the outstanding unsolved questions that may
benefit from a combination of studies in both flies and mammals. In particular, we discuss how different
environmental stimuli and signaling pathways influence muscle mass and strength and how a variety of
disease states can cause muscle wasting. Conclusions: Studies in Drosophila and mammals should help
identify molecular targets for the treatment of muscle wasting in humans. Developmental Dynamics
243:201–215, 2014. V
C 2013 Wiley Periodicals, Inc.
Developmental Dynamics

Key words: skeletal muscle growth; muscle atrophy; animal models of muscle wasting; proteostasis

Key Findings:
 Modulation of muscle mass by environmental stimuli and transcription factors during disease states
 Role of protein synthesis and degradation pathways in muscle atrophy
 Mammals and Drosophila are useful model organisms to identify the molecular and cellular mechanisms
responsible for muscle growth and atrophy in humans

Submitted 11 April 2013; First Decision 1 August 2013; Accepted 1 August 2013

INTRODUCTION ety of systemic diseases, as well as eases, injury, and death (Demontis et
inadequate nutrition, all lead to fiber al., 2013b). General wasting of all
Skeletal muscle accounts for approxi- atrophy (i.e., loss of cell proteins), and muscles occurs with fasting and dis-
mately 40–50% of the body mass in consequently, a decrease in functional use and is an integral feature of a
humans. Maintenance of muscle mass capacity. In addition, there is a pro- number of systemic diseases, includ-
and strength through proper nutri- gressive loss of muscle mass and ing many cancers, cardiac failure,
tion and exercise is critical to main- strength in the aged, often termed renal failure, sepsis, AIDS, as well as
tain full activity, prevent obesity, and “sarcopenia” (Nair, 2005; Demontis et burns and traumatic injury, and mus-
decrease the risk of heart disease, dia- al., 2013a), which is a major contribu- cle loss correlates with a poor progno-
betes, and cancer (Pate et al., 1995). tor to the frailty in the elderly and sis. In these conditions, the skeletal
Lack of contractile activity and a vari- increases the risk of age-related dis- muscles are inherently normal, and

1
Department of Cell Biology, Harvard Medical School, Boston, Massachusetts
2
Department of Oncology, IRCCS, Mario Negri Institute for Pharmacological Research, Milano, Italy
3
Department of Genetics, Harvard Medical School, Boston, Massachusetts
4
Department of Developmental Neurobiology, Division of Developmental Biology, St. Jude Children’s Research Hospital, Memphis,
Tennessee
5
Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts
Grant sponsor: Muscular Dystrophy Association; Grant sponsor: NIH; Grant numbers: AR055255; R01AR057352; Grant sponsor: Italian
Association for Cancer Research AIRC-Start Up; Grant number: 11423; Grant sponsor: St. Jude Children’s Hospital/ALSAC; Grant spon-
sor: The Ellison Medical Foundation - New Scholar in Aging Award; Grant sponsor: HHMI.
*Correspondence to: Dr. Fabio Demontis, St. Jude Children’s Research Hospital, Memphis, TN 38105. E-mail:
Fabio.Demontis@stjude.org
DOI: 10.1002/dvdy.24036
Published online 29 August 2013 in Wiley Online Library (wileyonlinelibrary.com).

C 2013 Wiley Periodicals, Inc.


V
202 PICCIRILLO ET AL.
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Fig. 1. Environmental stimuli and signaling pathways increasing proteolysis and depressing protein synthesis and leading to muscle atrophy.
Representative fields of a transverse section of muscle fibers from fed mice or weight-matched mice deprived of food for 48 hr are shown. Nuclei
and membranes are indicated in blue (Hoechst) and green, respectively. Scale bar ¼ 50 mm.

the loss of mass is a response to physi- factors with alterations in fiber compo- response to calcium release from the
ological or pathological stimuli (e.g., sition and size (Fig. 1). Similar observa- sarcoplasmic reticulum (SR, the speci-
fasting or cancer), rather than to any tions have been made in Drosophila alized endoplasmic reticulum [ER] of
intrinsic genetic defect. By contrast, where muscles account for 40 to 50% of muscles), resulting in force genera-
there are a variety of primary muscle the body mass, and muscle growth tion (Taylor, 2006). In addition, in
diseases (termed myopathies) that depends on nutrient supply sensed via both insects and mammals, muscle
result from inherent structural or the Insulin/Akt/TOR pathway (as in fibers can be either glycolytic or oxi-
enzymatic defects (e.g., muscular dys- mammals). For example, under normal dative. For example, Drosophila
trophies) or from inflammatory dis- nutrient conditions, Drosophila muscles direct and indirect flight muscles,
eases (e.g., myosites) (Askanas and undergo a striking 50-fold increase in which promote wing motion indirectly
Engel, 2002). Many mutations that fiber size in only 5 days during larval by compressing the thorax, can func-
perturb muscle function by affecting development (Demontis and Perrimon, tion for extended periods during flight
the contractile apparatus, energy 2009; Fig. 2A). and are primarily oxidative. By con-
metabolism, or membrane integrity Similarities between vertebrate trast, body wall muscles of the larva
can lead to skeletal and cardiac and Drosophila muscles are both and leg muscles of adult flies, which
myopathies. structural and functional. Both are are used only intermittently, rely
Extensive studies in vertebrates composed of tandem arrays of sarco- mainly on glycolysis (Taylor, 2006).
have shown that skeletal muscle is a meres containing the thin and thick These distinct patterns of energy
highly adaptive tissue that responds to filaments, which, in a typical muscle metabolism resemble the differences
exercise, nutrient supply, and endocrine twitch, slide past each other in between type I and type IIb fibers in
MECHANISMS OF MUSCLE GROWTH AND ATROPHY 203
Developmental Dynamics

Fig. 2. Developmental growth of skeletal muscles in Drosophila larvae is inhibited by FOXO overexpression. A: Skeletal muscle size dramatically
increases by 50-fold in the larval stage of development, which lasts 5 days. Muscle growth results from enhanced protein synthesis without any
addition of muscle nuclei. Larvae expressing a GFP-tagged Myosin Heavy Chain (Mhc) protein in body wall muscles are shown. B: The size
increase of body wall muscles is inhibited by overexpressing the transcription factor FOXO in muscles (C: Dmef2-Gal4 UAS-foxo vs. Dmef2-Gal4
in B). Ventral Longitudinal muscles 3 and 4 (VL3 and VL4) from animals at the end of larval development are outlined for comparison in B and C.
The dramatic increase in muscle mass observed during Drosophila larval development provides a sensitive setup for the identification of evolutio-
narily conserved genes regulating muscle mass. B0 –B00 , C0 –C00 : Micrographs outline sarcomeres and nuclei within muscle fibers (F-actin, red;
Nuclei, blue). Scale bar ¼ 40 mm in B,C and 10 mm in B0 ,B00 and C0 ,C00 . See Demontis and Perrimon (2009) for more information.

mammalian muscles. Type I slow ordered fashion, but overall fiber com- Here in this review, we discuss how
fibers are non-fatiguing, primarily position is adapted to the specific Drosophila with its extensive genetic
burn fatty acids and glucose oxida- functions of the muscle. For example, toolkit and short life cycle provides a
tively, and are dark in color because in rodents the antigravity soleus mus- powerful experimental system to
they are rich in mitochondria, myo- cle, which is continually used in address some of the outstanding
globin, and blood supply. By contrast, standing, is composed primarily of unsolved questions about muscle atro-
the easily fatigued, fast type IIb fibers oxidative fibers and is quite resistant phy. Specifically, we review the mecha-
are primarily glycolytic, and have a to fatigue. In typical mixed muscles, nisms of skeletal muscle atrophy and
low mitochondrial content and capil- the slower oxidative fibers are used in hypertrophy that may be similar in
larity density (Taylor, 2006). Most all contractions, but the easily Drosophila and mammals, and discuss
mammalian muscles, especially in fatigued larger glycolytic fibers are emerging insights and outstanding
humans, are composed of mixtures of recruited only with maximal efforts questions that may benefit from stud-
fiber types that are recruited in an (Brooke and Kaiser, 1970). ies in both species (see Tables 1 and 2).
204 PICCIRILLO ET AL.

TABLE 1. A List of Prominent Yet Unsolved Questions for Future Research on Muscle Atrophy in Drosophila and
Mammals

In Drosophila
 Which are the mechanisms of developmental muscle growth, atrophy, and segmental apoptosis in Drosophila?
 What determines the distinct sensitivity to histolysis of different insect muscles during pupal metamorphosis?
 Are Drosophila muscle precursor cells similarly regulated as mammalian satellite cells?
 Is there turnover of the contractile apparatus in normal muscles?
In mammals
 What is the basis for the differential response of different mammalian fiber types to catabolic stimuli?
 How are components of the myofibril assembled and degraded both normally and at increased rates during atrophy,
while preserving contractile function?
 In atrophying muscles, how are the increases in proteolysis by the ubiquitin proteasome pathway and by autophagy and
the decreases in protein synthesis coordinated?
 Do syncytial apoptosis and necroptosis contribute to muscle wasting?
 What is the precise contribution, if any, of satellite stem cells to muscle atrophy and hypertrophy?
In both
 How do various signaling pathways and transcription factors (NF-kB, JunB, etc.) interact with FoxO transcription fac-
tors to cause (or combat) muscle atrophy in mammals and Drosophila?

MODULATION OF MUSCLE ily (Sandri et al., 2004; Zhao et al., Fig. 3). Similarly, upon fasting when
Developmental Dynamics

MASS BY ENVIRONMENTAL 2007) and NF-kB (Cai et al., 2004; circulating insulin and IGF-1 levels
Hunter et al., 2002). fall, autocrine production of IGF-1 by
STIMULI AND
In mammals, systemic muscle wast- muscle also decreases. As a result, the
TRANSCRIPTION FACTORS ing is induced in response to fasting IGF-1/Akt pathway is markedly
In mammals, muscles are the major or diseases (i.e., untreated diabetes, depressed leading to rapid protein
protein reservoir in the body, and dur- AIDS, cancer, and heart failure) and loss. Furthermore, in fasting and
ing fasting, amino acids generated by by various circulating hormones, cyto- other catabolic states, the release of
net protein degradation are released kines, and excess of glucocorticoids glucocorticoids by the adrenal glands
into the venous blood to provide sub- (Fig. 1). In addition, atrophy of spe- increases and further promotes prote-
strates for hepatic gluconeogenesis. cific muscles occurs upon decreased olysis and inhibits muscle protein
Thus, under starvation conditions, usage (e.g., with nerve injury or synthesis.
muscle proteolysis is critical for main- immobilization in a cast). These very In addition to FoxOs, other tran-
taining the supply of glucose, in par- different physiological stimuli may scription factors (i.e., Smad 2 and 3,
ticular to the brain, and of amino involve some common signaling mech- NF-kB, JunB, Runx1, and Myogenin)
acids essential for continued protein anisms. Contractile activity causes have been shown to influence muscle
synthesis. Myofibrillar proteins com- release of IGF-1 (Insulin-like Growth mass. For example, the Smad tran-
prise about two-thirds of muscle dry Factor 1), which functions as an scription factors mediate the catabolic
weight, and changes in muscle size important autocrine growth factor. effects of myostatin, a circulating
are due primarily to changes in the IGF-1 is also a circulating hormone TGF-family member that inhibits nor-
content of the contractile apparatus released from the liver in response to mal muscle growth (Lee, 2004). Myo-
(Cohen et al., 2009; Solomon and pituitary growth hormone. The auto- statin binds to the Activin RIIB
Goldberg, 1996). In most types of crine production of IGF-1 by muscle (ActRIIB) receptors and activates
muscle atrophy, the loss of mass is falls with disuse and following loss of transcription by Smad 2 and 3. Con-
driven by an increase in protein deg- innervation (Zeman et al., 2009), in versely, inhibition of ActRIIB recep-
radation and to a lesser extent by a animals lacking pituitary growth hor- tors or of Smad 2 and 3 causes muscle
decrease in protein synthesis (Fig. 1). mone or during chronic heart failure hypertrophy (Sartori et al., 2009; Fig.
Protein degradation occurs via both (Schulze and Spate, 2005). So the loss 4). NF-kB has also been shown to be
the ubiquitin proteasome system of IGF-1, through both endocrine and an important factor in muscle atrophy
(UPS) and the autophagy/lysosome autocrine mechanisms, contributes to (Bonetto et al., 2011; Cai et al., 2004),
pathway, while protein synthesis is the atrophy process mainly by attenu- although its exact mechanism
regulated primarily by Insulin/IGF-1 ating signaling by the IGF-1/Akt appears unclear (Mourkioti et al.,
(Insulin-like Growth Factor 1) acting pathway in both systemic catabolic 2006). Endurance exercise induces
through the Akt/TOR/FoxO pathway states and locally with disuse. the production of the transcriptional
(Glass, 2010; Fig. 3). During atrophy, Reduced Akt signaling decreases pro- co-activator PGC-1a, which promotes
both UPS and autophagy/lysosome tein synthesis in muscle as in other mitochondrial gene expression lead-
degradative systems are activated, cells and leads to enhanced muscle ing to oxidative phosphorylation and
and key components are induced by proteolysis via activation of FoxO subsequently differentiation of oxida-
transcription factors of the FoxO fam- transcription factors (Glass, 2010; tive muscle fibers (Handschin and
MECHANISMS OF MUSCLE GROWTH AND ATROPHY 205

TABLE 2. Similarities and Differences in Muscle Atrophy and Hypertrophy in Insects and Mammals.

Similarities Major differences


 Fiber composition differs in muscles with distinct  Fiber atrophy and hypertrophy occur in adult mammals
physiological roles (continually active oxidative but muscle growth appears to occur only during development
vs. glycolytic muscles) in Drosophila
 Distinct muscles differ in sensitivity to  Muscle stem cells have not been
atrophic/histolytic stimuli (i.e. steroids) observed in flies
 FoxOs cause muscle atrophy in mammals and  Drosophila lacks a major ubiquitin ligase implicated
inhibit growth of larval muscles in flies in myofibrillar turnover (MuRF1)
 The UPS plays a role in muscle atrophy in mammals as
well as in muscle mass loss during insect metamorphosis

Advantages for Studying Muscle Atrophy and Hypertrophy


In Drosophila In mammals
 Flies have a shorter life cycle than mice  Rodents loose muscle mass similar to humans during
different kinds of atrophy
 Flies are easily amenable to various genetic  Muscles are accessible for physiological and
manipulations (e.g. genome-wide RNAi screens) biochemical studies
 Large groups of flies can be analyzed for any  Endocrine signals regulating atrophy have been
given intervention characterized in mammals
 The 50-fold increase in muscle mass observed during  Energy metabolism and physiological regulation of
larval development is valuable for identifying genes muscle mass are well defined
Developmental Dynamics

involved in myofibrillar assembly and muscle growth

Spiegelman, 2008). In addition, JunB, of muscle fibers in adult mammals, et al., 2006) by inhibiting FoxO3, and
which has long been known as a which are postmitotic cells. JunB perhaps other catabolic processes.
rapid-response gene that triggers cell overproduction can both promote Interestingly, the transcription factor
proliferation, is also important in hypertrophy and inhibit muscle atro- Runx1 is induced by denervation and
determining the size and growth rate phy (Raffaello et al., 2010; Sandri limits denervation-induced muscle
wasting by regulating the expression
of muscle structural proteins and ion
channels (Wang et al., 2005).
A number of other transcription
factors (e.g., Myogenin, MyoD and
MEF2) are important in embryonic
differentiation of muscle, but are not
critical in post-natal muscle growth.
However, in the adult Myogenin par-
ticipates in the induction of atrophy
following denervation (Moresi et al.,
2010). While multiple transcription
factors can promote or inhibit muscle
atrophy, their specific roles, modes of
activation, and functional interac-
tions occurring during different types
of muscle atrophy remain unclear.
This area represents an important
gap in our knowledge and possibly
could lead to the development of
rational interventions to combat mus-
cle wasting.
The powerful genetic toolkit available in
Drosophila may be of particular advantage
to analyze the genetic interactions among
transcription factors inducing muscle atro-
Fig. 3. Signaling pathways increasing proteolysis, depressing protein synthesis, and leading to phy or hypertrophy and to identify novel
muscle atrophy. A comparison of the molecular players in Drosophila (indicated in italics) and
mammals is shown.
regulators of muscle mass. In Drosophila,
206 PICCIRILLO ET AL.

muscles (Porter et al., 1989). Differen-


ces in fiber-type composition and inner-
vation pattern may explain the
resistance of extraocular muscles to
wasting following denervation.
Whether denervation influences
muscle mass in the adult fly, and
whether it can be counteracted by
Insulin/Akt signaling has not yet been
studied, probably because of the diffi-
culties in altering physiological load
and measuring the sizes of specific
muscles in this organism. However,
muscle-nerve interactions have been
thoroughly examined during the
developmental phase of metamorpho-
sis in Drosophila, when these interac-
tions are important to define proper
muscle size and patterning. In partic-
ular, surgical severing of the meso-
Fig. 4. Myostatin signaling pathway as a basis to counteract muscle wasting. Molecules to
inhibit this pathway are currently in human clinical trials to cure the muscle wasting associated
thoracic nerve with microbeam lasers
with Duchenne Muscular Dystrophy. leads to denervation that can retard
the formation of some muscle fibers,
Developmental Dynamics

like the dorso-longitudinal flight


muscles undergo dramatic size increase cular diseases, such as amyotrophic lat- muscles, by regulating the rate of pro-
during larval development, where fiber eral sclerosis (ALS), cause profound liferation of the pool of myoblasts, the
growth also relies heavily on nutrient sens- muscle atrophy in mammals (Fig. 1). muscle stem cells that are precursors
ing via the Insulin/Akt/TOR pathway Different muscle fiber types have dis- of the adult musculature (Fernandes
(Demontis and Perrimon, 2009). In the tinct propensities to atrophy upon and Keshishian, 1998). Similarly,
larval muscles, the activities of the tran- denervation, with type I oxidative nerve–muscle interactions are neces-
scription factors FOXO, Myc and Mnt are fibers being more sensitive to sary for achieving proper muscle size
integrated to achieve normal muscle denervation-induced atrophy than type in the moth Manduca sexta, where
growth. In particular, FOXO inhibits mus- II (Herbison et al., 1979), even though denervation during development also
cle growth at least in part by decreasing type II fibers are lost preferentially in decreases the number of proliferating
Myc (diminutive) gene expression and its various systemic wasting states, e.g., myoblasts (Bayline et al., 2001). In
transcriptional activity (Demontis and Per- glucocorticoids treatment (Goldberg addition, denervation results in mus-
rimon, 2009). Conversely, overexpression of and Goodman, 1969), fasting (Li and cle patterning defects in Drosophila,
the Insulin receptor results in increased Goldberg, 1976), sepsis (Tiao et al., with a failure to form dorsal ventral
Myc gene expression, which promotes 1997) or cancer (Acharyya et al., 2004; muscles, indicating that the differen-
nucleolar biogenesis and primes muscle Baracos et al., 1995). Importantly, acti- tiation of specific muscle fibers is per-
growth. In addition, RNAi-mediated knock- vation of the Insulin/Akt pathway is turbed (Fernandes and Keshishian,
down of Myc inhibits muscle growth, as sufficient to counteract the loss of mus- 1998). The interconnection between
does overexpression of Mnt (Demontis and cle mass associated with denervation neuronal activity and muscle pattern-
Perrimon, 2009), which antagonizes Myc (Bodine et al., 2001b). Acutely, the ing has also been extensively studied
activity by binding to the common interac- weight loss and transcriptional in adult mammals, where motoneur-
tion partner Max (Bellosta and Gallant, response to denervation and pure dis- ons influence fiber type differentiation
2010). Finally, genome-wide RNAi analy- use (e.g., with spinal isolation) are very (Grinnell, 1995) even in the adult.
ses, as recently applied to the study of mus- similar, but with time, denervated Moreover, prolonged electrical stimu-
cle morphogenesis (Schnorrer et al., 2010), muscles show a more profound atrophy lation of type II fibers causes the mus-
may uncover new regulators of fiber size in (Sacheck et al., 2007). So although the cle to acquire many characteristics of
Drosophila. Orthologs of these genes may post-natal maintenance of muscle mass type I fibers (Goldspink, 1985).
also be important for muscle atrophy and is clearly dependent on continual neu- Despite these observations, the tran-
hypertrophy in human and thus represent ronal activity, which causes contractile scriptional mechanisms underlying
new therapeutic targets. activity, it remains possible that trophic muscle–nerve interactions remain to
factors released by innervating motor be clarified. Knowledge gained from
neurons may also be important in studies in Drosophila should help
DENERVATION determining muscle properties. Inter- define the nature of muscle–nerve
Like nutrient deprivation, loss of mus- estingly, some muscles, such as the interactions, which are presumably
cle stimulation by nerves, as occurs extraocular muscles of primates, are related to the mechanisms function-
during inactivity, immobilization, extremely resistant to denervation ing in mammalian adult differenti-
paralysis, nerve injury, and neuromus- atrophy when compared to limb ated muscles.
MECHANISMS OF MUSCLE GROWTH AND ATROPHY 207

GLUCOCORTICOIDS, Although no hormones are known group of indirect flight muscles


INFLAMMATION, AND that function similarly to glucocorti- (IFMs) of the adult (Farrell et al.,
coids upon stress in insects, a class of 1996; Roy and VijayRaghavan, 1998;
OXIDATIVE STRESS
steroid hormones called ecdysteroids Dutta et al., 2004). Subsequently,
Among the major stimuli that can (including ecdysone) has been impli- most larval muscles in the abdomen
trigger muscle atrophy in mammals cated in the complete breakdown and undergo histolysis. For example, the
are the glucocorticoids (e.g., cortisol) death of muscle cells (also termed his- dorsal external oblique muscles
or its synthetic analogs (e.g., dexa- tolysis) during pupal metamorphosis. (DEOMs) degenerate in the late pre-
methasone), which at high pharmaco- Throughout this process, most larval pupal stage (Wasser et al., 2007).
logical doses cause atrophy muscles degenerate completely in However, some other abdominal
preferentially of type IIb glycolytic response to ecdysone and presumably muscles initially persist, undergo
fibers (Dahlmann et al., 1986; Gold- provide amino acids for the develop- atrophy (day 1 and 2 of pupal stage),
berg and Goodman, 1969). These ste- ment of the adult tissues. Although and subsequently increase in mass
roids are released from the adrenal glucocorticoids do not cause death of (hypertrophy; late pupal stage) to
gland in stressful states and are muscles in mammals, the rapid loss of form the temporary dorsal internal
essential for muscle wasting during muscle mass and breakdown of myofi- oblique muscles (DIOMs) of the adult.
fasting, renal failure, diabetes, and brils in response to structurally DIOMs are needed for eclosion and
sepsis (Menconi et al., 2007; Schak- related molecules (glucocorticoids and degenerate only after the adult has
man et al., 2008). Glucocorticoids act ecdysteroids) suggests some similar emerged (Kimura and Truman, 1990).
to reduce muscle size by inhibiting mechanisms of action. Accordingly, Interestingly, the nuclear proteins
amino acid transport into muscle, pro- larval muscles undergo marked atro- EAST and Chromator have antagonis-
tein synthesis, and enhancing proteol- phy before apoptosis is evident in tic functions and, respectively, accel-
ysis. Consequently, they promote the response to ecdysone (Bayline et al., erate and delay the atrophy of DIOMs
Developmental Dynamics

release from muscles of amino acids 1998; Hegstrom and Truman, 1996). during pupal metamorphosis. In addi-
that can be burned directly or serve However, not all insect muscles tion, Chromator partially blocks the
as substrates in the liver for glucose undergo histolysis in response to breakdown of DEOMs muscles
production. Although not normally ecdysteroids. An example of such (Wasser et al., 2007).
catabolic, normal or slightly increased diverse responses to ecdysteroids The mechanisms by which distinct
levels of glucocorticoids can induce comes from pioneering studies in the insect muscles respond differently to
muscle wasting when there is a fall in moth Manduca sexta. During pupal ecdysone are still not understood, and
Insulin/IGF-1 signaling, as occurs metamorphosis, the larval muscles thus this may represent a valuable
during fasting, diabetes, and insulin- are either maintained, modified, or model to better understand the speci-
resistant states (most diseases; Hu degenerate (Bayline et al., 1998; Heg- alized responses of distinct muscles to
et al., 2009). Because of their ability strom and Truman, 1996). In particu- catabolic stimuli. Algorithms recently
to also reduce inflammation, prolifer- lar, the large intersegmental muscles became available to facilitate the
ation of white cells, and immune (ISMs) from Manduca initially atro- analysis of images from high-
responses, glucocorticoids are widely phy and lose approximately 40% of throughput RNAi screens for muscle
used to treat rheumatoid arthritis, their mass starting 3 days before histolysis (Chinta et al., 2012). In
allergic reactions, asthma, transplant adult eclosion, while at the same mammals, there are several sexually
rejection, lupus, and some forms of time, the flight muscles of the adult dimorphic muscles (e.g., the levator
cancer. The induction of muscle (and musculature are actively growing in anus that is also involved in the con-
bone) wasting is a serious adverse mass. Subsequently, ISMs undergo trol of the penis) that show much
effect of high doses of these drugs and cell death and are completely lost greater sensitivity to the anabolic
often limits their use in the clinic. within 30 hr of adult life, while actions of testosterone than typical
Interestingly, lack of contractile activ- newly-formed flight muscles do not muscles (Herbst and Bhasin, 2004).
ity enhances the tendency of muscles (Schwartz, 1992). The precise basis for their greater
to atrophy in response to glucocorti- Studies in Manduca have benefited sensitivity to these steroids is largely
coids (Goldberg and Goodman, 1969). from the large sizes of these muscles, unknown.
For example, although the dark oxi- but the genetic analysis of this pro- In addition to glucocorticoids, pro-
dative soleus is relatively resistant to cess is easier in Drosophila, where inflammatory cytokines including
these agents, the denervated soleus is different muscles also respond in dis- TNF-a (Tumor Necrosis Factor a), IL-
highly susceptible to cortisone- tinct fashion to ecdysone. By 8 hr 1 (Interleukin 1), IL-6, activin, and
induced atrophy, which helps explain after puparium formation, most myostatin have all been reported to
the marked loss of body mass in the muscles in the head and thoracic seg- contribute to muscle wasting
bed-ridden patients. Thus, an out- ments undergo histolysis while the (cachexia) in mammals during sepsis
standing question is how the sensitiv- abdominal muscles are preserved and in cancer-bearing animals at
ity of different muscles to (Fernandes et al., 1991). Among the least in part by activating the NF-kB,
glucocorticoids or other catabolic thoracic muscles, the larval oblique STAT3, and/or the Smad transcription
stimuli is modulated at the molecular muscles escape histolysis and serve as factors (Bonetto et al., 2011). Some of
level by contractile work or other ana- template for the formation of the dor- these cytokines and the pathways
bolic stimuli. sal longitudinal muscles (DLMs), a they activate are conserved in
208 PICCIRILLO ET AL.

Drosophila. For example, Drosophila including NF-kB and FoxO (Dodd aerobic fibers are relatively resistant
eiger (CG12919) is a TNF superfamily et al., 2010), but other modes of acti- to atrophy induced by various circu-
ligand that activates a canonical TNF vation have also been demonstrated. lating catabolic factors, including
signaling cascade (Moreno et al., Genetic manipulations that enhance fasting, glucocorticoids, cancer, and
2002). In addition, the JAK/STAT muscle ROS levels, such as knock-out sepsis, apparently due to the presence
pathway, which is activated in mam- of the cytoplasmic anti-oxidant of PGC-1a. Its expression is decreased
mals by various members of the Inter- enzyme Sod1 (superoxide dismutase in many, perhaps all, types of atrophy
leukin family, is conserved in 1) in mice leads to oxidative damage (Sacheck et al., 2007; Sandri et al.,
Drosophila where it is activated by to proteins and muscle wasting (Jang 2006), and PGC-1a and its homolog
the Unpaired family of cytokine-like and Van Remmen, 2011; Muller et al., PGC-1b, directly antagonize the
ligands (outstretched, unpaired 2, and 2006). On the other hand, mice devoid induction of the atrophy gene pro-
unpaired 3). Studies on the effects of of the mitochondrial superoxide dis- gram by both FoxO3 (Sandri et al.,
these signaling pathways on Drosoph- mutase 2 in muscle have elevated oxi- 2006) and NF-kB, and thus suppress
ila muscle growth and remodeling dative stress, but do not exhibit the acceleration of protein degrada-
may provide useful models of muscle wasting (Kuwahara et al., tion (Brault et al., 2010; Fig. 3). Pre-
inflammation-induced atrophy. 2010; Lustgarten et al., 2009). Thus, sumably, these effects help account
Another type of circulating factor oxidative stress does not appear to be for the ability of exercise to retard
that can increase muscle size or coun- sufficient to induce atrophy, and it atrophy. Following disuse and upon
teract atrophy are cathecolamines remains unclear if these signs of oxi- restoration of activity, the increased
and their synthetic analogs, clenbu- dative stress are a key factor in the PGC-1a levels and IGF-1/PI3K-Akt
terol or b2 agonists, which activate b2 atrophy process or an incidental signaling inactivate FoxO leading to
adrenergic receptors (whose Drosoph- factor. decreased expression of atrogenes.
ila homolog is octopamine receptor 2). These genes are induced or sup-
Developmental Dynamics

These agents cause production of PHYSICAL ACTIVITY AND pressed coordinately during various
cyclic-AMP and activation of PKA types of atrophy due to uremia, diabe-
that can ultimately cause cardiac and
INACTIVITY tes, cancer, denervation, disuse, and
skeletal muscle hypertrophy (Nave- Muscle wasting in adult mammals is fasting and include components of
gantes et al., 2001). In fact, clenbu- generally viewed as a reversible pro- both the UPS and autophagy/lyso-
terol has often been used illegally to cess, but this reversibility has not some pathways (Zhao et al., 2007).
induce growth of cattle and enhance been rigorously studied, e.g., at differ- Among these atrogenes, two
food production but, because residues ent ages. The loss of muscle on fasting muscle-specific ubiquitin ligases,
of cathecolamines are retained in the is rapidly reversed by refeeding and MuRF1 and atrogin-1, are dramati-
meat, this practice is dangerous and can even lead to “overshoot” growth. cally induced by FoxO3 (Sandri et al.,
is banned. Also, because of the side Similarly, the loss of body mass with 2004) and are essential for muscle
effects of cathecolamines (e.g., blood acute illness is rapidly reversed upon atrophy (Bodine et al., 2001a; Gomes
pressure and cardiac function), their recovery, especially in children where et al., 2001). In addition to a role for
ability to inhibit atrophy has not been it has been termed “catch-up” growth. PGC-1a in repressing FoxO activity,
exploited as a therapy for muscle In the elderly, this capacity to reverse PGC-1a4 (a PGC-1a splice variant
wasting. wasting seems to be more limited but preferentially produced after resist-
Increased production of reactive this impression and its possible cellu- ance exercise) protects muscles from
oxygen species (ROS) has been pro- lar basis has not been systematically atrophy by inducing IGF-1 while
posed to play a role in the muscle studied. The extent of muscle wasting repressing myostatin expression
degeneration of the queen fire ant, induced by food deprivation in mam- (Ruas et al., 2012).
Solenopsis spp., where histolysis fol- mals can be counteracted by physical The mechanisms linking contractile
lows the mating flight and insemina- activity, especially isometric exercise, activity to the action of these tran-
tion (Davis et al., 1993). Similarly, in which stimulates the IGF-1/Akt path- scription factors in atrophy is still not
mammals there are multiple observa- way and builds muscle mass and clear even though this area is critical
tions suggesting a possible role of oxi- strength. In fact, in starving rats and determines whether a cell grows
dative stress in triggering muscle where there is rapid muscle wasting, or atrophies. One well-studied excep-
atrophy. First, the transcription factor generally increased activity of the sol- tion is NFAT, a key transcription fac-
ATF4, which promotes the expression eus (e.g., induced by loss of a syner- tor that is activated by increases in
of oxidative stress responsive genes, gist) can induce hypertrophy Ca2þ levels. In skeletal muscle, it is
is upregulated in most types of atro- (Goldberg, 1968). Both strength and involved in fiber type specification
phy (Lecker et al., 2004) as are the endurance exercise increase the activ- and influences PGC-1a expression
metallothioneins, heavy metal- ity of the transcriptional co-activator (McCullagh et al., 2004) and in car-
binding components that can serve PGC-1a (Gibala et al., 2009; Terada diac muscle it can trigger hypertro-
antioxidant roles (Sacheck et al., et al., 2002), which in turn stimulates phy (van Rooij et al., 2002). An
2007). In addition, during disuse, mitochondrial biogenesis and oxida- additional potential link between
ROS have been proposed to activate tive metabolism characteristic of type physical activity and protein turnover
several transcription factors involved I fibers but not hypertrophy (Hand- is the dihydropyridine receptor
in muscle atrophy in mammals, schin and Spiegelman, 2008). Type I (DHPR) a1S subunit, which can serve
MECHANISMS OF MUSCLE GROWTH AND ATROPHY 209

as a molecular sensor of muscle activ- to disuse is important to define more sible for activating many atrophy-
ity (Pietri-Rouxel et al., 2010). DHPR rigorously since Drosophila muscles related signaling cascades (Paul et al.,
a1S knock-down induces muscle atro- may differ radically from mammals 2010); TRIM32, involved in the degra-
phy via FoxO3A activation, which and lack the capability to alter muscle dation of thin filaments and the des-
leads to upregulation of autophagy- mass in response to changes in con- min cytoskeleton (Cohen et al., 2012;
related genes and the induction of tractile activity. While such an appa- Kudryashova et al., 2005); and Cbl-b,
autophagy. However, the loss of rent difference may be due to which inhibits IGF-1 signaling by pro-
DHPR presumably represents a form insufficient studies, it is also possible moting the degradation of the Insulin
of disuse since it should reduce con- that because of their brief lifespan Receptor Substrate IRS-1 (Nakao
tractile activity (i.e., disrupt and very different lifestyle, Drosoph- et al., 2009). Homologs of atrogin-1
excitation-contraction coupling). ila may not have evolved similar reg- (Drosophila CG11658), TRIM32 (Dro-
Thus far, studies on the effects of ulatory mechanisms as mammals for sophila abba), TRAF6 (Drosophila
muscular contractions have been mobilizing amino acids from muscle CG10961), and Cbl-b (Drosophila Cbl)
lacking in insects. Although genetic proteins. So disuse may not result in are encoded in the Drosophila genome,
studies in Drosophila in principle obvious muscle atrophy in flies. suggesting possible similarities in the
might help elucidate the interconnec- pathways governing proteolysis and
tions between exercise and muscle muscle atrophy in fruit flies and mam-
mass, experimental approaches for ROLE OF PROTEIN mals. For example, CG11658 expres-
exercising this organism and methods SYNTHESIS AND sion levels increase in muscle wasted
for measuring changes in muscle DEGRADATION PATHWAYS (mute) mutants, lacking a component
mass or metabolic adaptations have of the histone locus body and charac-
not been described, in contrast to the
IN MUSCLE ATROPHY terized by a severe loss of muscle mass
extensive literature on mammals. Despite the greater diversity of possi- and integrity during development
Developmental Dynamics

Recently, a mechanized platform for ble regulatory factors in mammals (Bulchand et al., 2010). Moreover, Dro-
the physical training of flies has been (ranging from hormones to cytokines), sophila TRIM32 (abba) is required for
described (Piazza et al., 2009), in the final cellular mechanisms regulat- integrity of the costamere, a structure
which a repeated tapping of the con- ing muscle size appear similar in Dro- that connects the sarcomeres to the
tainer where the flies are housed acti- sophila and mammals (Figs. 1–3). In overlying sarcolemma providing stabil-
vates the innate instinct of the flies to Drosophila, the Insulin/Akt-respon- ity during muscle contraction, and its
climb (negative geotaxis). This prom- sive transcription factor FOXO medi- mutation results in unbundling of
ising system may be useful to dissect ates most of the gene expression myofibrils and progressive muscle
the genetic basis underlying the effect changes induced by nutrient starva- wasting (LaBeau-DiMenna et al.,
of physical exercise on muscles. For tion in larval muscles (Teleman et al., 2012).
example, an interaction between 2008) and its activation is sufficient to However, no homologs of MuRF1, a
physical exercise and spargel, the stunt developmental muscle growth E3 ligase that ubiquitinates myofibril-
PGC-1a homolog that promotes mito- (Demontis and Perrimon, 2009; Fig. lar proteins, are found in flies. Very
chondrial activity in Drosophila (Tie- 2B and C). Similarly, in mammals, recently, the p97/VCP ATPase com-
fenbock et al., 2010), has been found various types of muscle atrophy share plex, which forms distinct complexes
with this system, highlighting that a common transcriptional program involving different adaptors (e.g., p47
spargel is required for full exercise mainly driven by FoxO3 (Lecker and Ufd-1) and distinct components of
capacity in Drosophila and the induc- et al., 2004; Sandri et al., 2004) and the thick (i.e., Myosin Light chains)
tion of physiological effects deriving possibly other FoxO family members, and thin (i.e., actin) filaments, has
from exercise (Tinkerhess et al., like FoxO1. MuRF1 and atrogin-1 are been shown to have a major role in
2012). key atrogenes induced by FoxO3 multiple types of atrophy, where it
While endurance exercise clearly (Sandri et al., 2004) that are neces- seems to catalyze the extraction of
decreases the loss of muscle mass in sary for rapid muscle atrophy (Bodine ubiquitinated proteins from the myo-
mice and in humans, no morphologi- et al., 2001a; Gomes et al., 2001). fibrils prior to proteasomal degrada-
cal signs of muscle deterioration have While proteins comprising the thick tion (Piccirillo and Goldberg, 2012).
been observed in flightless Drosophila filaments of the myofibrils have been Thus, Drosophila homologs of p97
mutants or in response to transient clearly identified as MuRF1 sub- (Drosophila TER94) and Ufd-1 (Dro-
local paralysis of adult flies induced strates (Cohen et al., 2009), how sophila CG6233) could participate in
with the temperature-sensitive dyna- atrogin-1 causes muscle loss is less a conserved mechanism for muscle
min mutant shibire (which are clear, but probably involves the degra- protein degradation, although p97
depleted of synaptic vesicles; Deak, dation of growth-related proteins also functions in other disassociation
1976). Such studies did not identify including the transcription factor and degradative processes (e.g.,
decreases in muscle mass of the kinds MyoD, and the translation initiation destruction of misfolded proteins in
seen with disuse in small mammals factor eIF3-f, which in turn reduces the ER). Interestingly, human muta-
where fiber diameters decrease by protein synthesis (Lagirand-Canta- tions in p97 cause an inclusion body
10–40% within 1–2 weeks without loube et al., 2008; Fig. 3). Additional myopathy and all amino acid residues
any clear structural deterioration. E3s are also important in muscle size altered in the disease are perfectly
This apparent lack of clear responses control. These include TRAF6, respon- conserved in Drosophila TER94
210 PICCIRILLO ET AL.

(Ritson et al., 2010). It will clearly be through the disposal of mitochondria closely related FoxO genes and their
of interest to define the biochemical (Romanello et al., 2010), as well as respective roles are still uncertain.
mechanisms for disassembly and deg- soluble cell proteins. Importantly, FoxO1, 3, and 4 are coordinately acti-
radation of the sarcomeric apparatus Mul1 is an E3 ubiquitin ligase recently vated upon nutrient deprivation, but
during pupal metamorphosis and if implicated in FoxO induced-mitophagy may have distinct roles in specific cat-
they involve the p97 complex. (Lokireddy et al., 2012), the autophagic abolic states and may regulate dis-
Studies in Manduca have high- destruction of mitochondria, while the tinct genes (Moylan et al., 2008),
lighted the involvement of the UPS in ubiquitin ligase Parkin is needed for although FoxO1 and 3 both induce
ecdysone-induced muscle histolysis. In mitophagy of damaged mitochondria atrogin-1, MuRF1, and Mul1. FoxO3a
particular, levels of ubiquitin conju- (Yang and Yang, 2011). Both Mul1 and and FoxO4 knock-out mice (Hosaka
gates dramatically increase at eclosion, Parkin are conserved in Drosophila et al., 2004) are viable and analysis of
during which loss of muscle proteins is (CG1134 and parkin, respectively) and FoxOs-deficient mice (Paik et al.,
maximal. Histolysis is also character- may play a role in muscle wasting in 2007) may clarify whether specific
ized by the coordinated induction of this organism. FoxO transcription factors are neces-
ubiquitin-activating enzymes (E1), sev- The loss of mitochondria must con- sary for the induction of atrophy in
eral ubiquitin-conjugating enzymes tribute importantly to the decreased response to different stimuli. Thus
(E2s), ubiquitin ligases (E3s), and ubiq- endurance during atrophy. Neverthe- far, it is only known that overexpres-
uitin itself (Haas et al., 1995; Schwartz less, the changes in mitochondrial sion of FoxO-dominant negative
et al., 1990) together with heightened numbers and functional capacity dur- mutants, which block all FoxOs in
expression in the abdominal interseg- ing different types of atrophy have adult muscles, can prevent multiple
mental muscles (ISMs) of MS73/Rpt3 surprisingly not been studied exten- types of atrophy (Sandri et al., 2004).
and S10b/Rpt4, which encode ATPase sively. Because ubiquitination can also It would be interesting to test
subunits of the 26S proteasome (Daw- target larger structures to autophagic whether FOXO is able to alter the
Developmental Dynamics

son et al., 1995; Hastings et al., 1999; vacuoles, several ubiquitin-binding expression of the Drosophila homolog
Jones et al., 1995; Low et al., 1997). proteins (including p97, p62, NBR1, of atrogin-1 as in mammals.
Thus, activation of the UPS seems to NDP52, and parkin) exist in cells that
play a fundamental role in the loss of bind insoluble or organellar ubiquiti-
skeletal muscle mass during insect nated proteins and facilitate their
metamorphosis similar to that in atro- docking to the autophagic vacuole via
SYNCYTIAL APOPTOSIS
phy in mammals. These insect muscles LC3. Their functions in muscle merit Additional mechanisms responsible
shrink in size markedly (atrophy) further study to better understand the for modifying muscle mass during
before the onset of apoptosis, presum- coordination between different protein development and adulthood include
ably due to increased proteolysis. It degradation pathways during atrophy the poorly defined pathway of syncy-
should be noted that the UPS is also and their roles in clearing different tial apoptosis. In this process, loss of
required to maintain muscle mass and cellular constituents (reviewed in Kor- individual nuclei within a fiber is
integrity during larval development olchuk et al., 2010), especially since more commonly observed than the
(Haas et al., 2007) and for viability in certain components (p97 cofactors) are death of the entire fiber, possibly via
mammals, due to its many critical roles essential in proteolysis by both degra- caspase-independent mechanisms act-
in cellular quality control and regulat- dative systems. ing via endonuclease-G (Primeau
ing metabolism. In other words, differ- In addition to the activation of pro- et al., 2002; Sandri and Carraro,
ent degrees of protein breakdown have tein degradation pathways, muscle 1999) or nucleophagy, the selective
beneficial or detrimental effects on wasting upon fasting, glucocorticoid autophagic degradation of nuclear
muscle mass, depending on what pro- treatment, and other disease states components (Park et al., 2009). In
teins are digested. results from an inhibition of protein addition, segmental necrosis, the
In addition to the UPS, autophagy synthesis that is triggered by death of a portion of a fiber without
contributes to the histolysis of several decreased IGF-1/Akt/TOR signaling the overall loss of the fiber, is a char-
tissues during metamorphosis in Dro- and inhibited by glucocorticoids (Hu acteristic feature of many myopathies,
sophila (Baehrecke, 2003). Although et al., 2009). Interestingly, ecdyste- especially Duchenne muscular dystro-
a recent study indicated that autoph- roids inhibit Insulin signaling in Dro- phy (Wallace and McNally, 2009).
agy is not involved in muscle histoly- sophila (Colombani et al., 2005), The genetic regulation of syncytial
sis in response to ecdysone during suggesting that muscle histolysis dur- apoptosis, and whether it differs from
metamorphosis (Zirin et al., 2013), ing metamorphosis may also rely on segmental necrosis, is unclear and
other catabolic stimuli may activate inhibition of Akt signaling and the may benefit from genetic studies to
autophagy to induce muscle atrophy activation of FOXO. However, mutant elucidate the underlying regulatory
in other contexts in insects. flies lacking the only Drosophila foxo pathways. In insects, syncytial apopto-
Many atrogenes induced by FoxO3 gene are viable and have only minor sis occurs during metamorphosis,
encode for proteins of the autophagy/ developmental defects (Junger et al., when some nuclei within the same
lysosome system (e.g., Cathepsin L, 2003), suggesting that FOXO is not fiber degenerate and are lost, while
LC3, GabarapL1; Lecker et al., 2004; necessary for overall muscle histolysis those in proximity to the site of inner-
Zhao et al., 2007), which contributes to during metamorphosis. By contrast, vation are spared (Bayline et al., 1998;
muscle atrophy in mammals especially mammalian muscle contains three Hegstrom and Truman, 1996).
MECHANISMS OF MUSCLE GROWTH AND ATROPHY 211

Therefore, in insects the local induc- recapitulates myoblast fusion during information on the regulation of satel-
tion of syncytial apoptosis may vary development. Interestingly, apoptosis lite cell function in mammals.
even within a single fiber depending of satellite cells but not pre-existing
on the proximity to the site of fibers has been observed during rapid
innervation. atrophy (Bruusgaard and Gundersen, EFFECTS OF MUSCLE MASS
While apoptosis occurs upon muscle 2008). Unfortunately, since satellite ON BODY METABOLISM IN
histolysis during insect metamorpho- cells are heterogeneous, few in num-
DROSOPHILA AND
sis, fiber cell death has not been ber (less than 2% of the nuclear con-
observed upon inhibition of larval mus- tent of muscle), and much less MAMMALS
cle growth in Drosophila (Demontis susceptible to in vivo electroporation It is now clear that the skeletal mus-
and Perrimon, 2009) and during rapid than muscle fibers, their specific role cle has major effects on the metabo-
atrophy in mammals (Bruusgaard and in atrophy is still largely unknown. lism of the organism, its growth,
Gundersen, 2008). In animal models of Although satellite cells are not needed aging, and resistance to disease
uremia, fasting, diabetes, and cancer, for muscle re-growth following disuse- (Demontis and Perrimon, 2010;
the pro-apoptotic gene Bnip3 is induced atrophy (Jackson et al., Demontis et al., 2013bb). These
induced but it also functions in mitoph- 2012), further studies are necessary organismal effects involve muscle-
agy (Mammucari et al., 2007; Lecker to test whether satellite cells can pos- derived signaling factors but also
et al., 2004). However, segmental apo- sibly reverse or prevent muscle atro- arise from indirect effects of muscle
ptosis of fibers has been reported dur- phy in other contexts, as has been mass and its high metabolic demand.
ing aging in mammals and Drosophila recently suggested (Thornell, 2011). Skeletal muscle consumes a major
(Marzetti et al., 2012; Zheng et al. Important roles in hypertrophy fraction of nutrients, and with intense
2005). Future studies in Drosophila have often been postulated, especially exercise, its energetic demand
and mammals should elucidate the in providing additional nuclei to pre- increases dramatically. Consequently,
Developmental Dynamics

pathways governing muscle syncytial vent a fall in concentration of nuclei multiple physiological mechanisms
apoptosis, and how this poorly under- when fibers enlarge. However, it exist to provide glucose or fatty acids
stood process impacts on the loss of remains controversial whether stem to muscle. For example, when muscle
muscle mass and strength. cell proliferation is essential during growth was induced in adult mice by
Importantly, other pathways of pro- hypertrophy as it clearly is upon increasing the expression of the Akt1
grammed cell death including necrop- regeneration (Zammit et al., 2002). kinase in type IIb fibers, the trans-
tosis, which depends on the activity of New techniques have recently become genic mice displayed resistance to
the serine/threonine kinase RIP1, available to dissect their possible con- both diet-induced obesity and hepatic
have not been examined in muscles. tributions to muscle adaptations. steatosis, at least in part via a stimu-
Notably, TNF-a, which helps trigger These include the ex vivo transfection lation of fatty acid oxidation in the
muscle wasting in inflammatory of muscle stem cells followed by intra- liver (Izumiya et al., 2008). In addi-
states (Glass, 2010), although per- muscular injection and the in vivo tion, postnatal loss of the transcrip-
haps indirectly, is able to induce nec- administration of adenoviral vectors tion factor myogenin in muscles
roptosis in other cell types (Galluzzi where transgene expression is driven results in smaller body size of mice,
and Kroemer, 2008). The possible under muscle stem cell–specific pro- suggesting that Myogenin acts to
relevance of necroptosis during moters of the Pax3 and Pax7 genes influence the post-natal growth of
muscle wasting awaits further (Biressi and Rando, 2010). muscles and also other tissues via an
investigation. Currently, there is no evidence of unknown mechanism (Knapp et al.,
satellite cells in any Drosophila adult 2006). As in mammals, in developing
muscles, and it is not clear whether Drosophila larvae the extent of mus-
ROLE OF MUSCLE STEM they do not exist or simply have not cle growth influences whole-organism
yet been identified. If present they growth and metabolism. In particular,
CELLS may be related to the twist-expressing muscle-specific inhibition of the Insu-
In vertebrates, satellite cells are the adult muscle precursors (AMPs), lin receptor/Akt/TOR pathway and of
small mononucleated muscle stem muscle progenitor cells that escape Myc activity decreases not only mus-
cells localized between the sarco- histolysis and form all adult muscles cle growth, but also feeding behavior
lemma and the basal lamina of mus- in Drosophila (Figeac et al., 2007). and the growth of non-muscle tissues,
cle fibers. In the adult, most stem Interestingly, even if the Drosophila while muscle-specific activation of the
cells are in a quiescent state, but can homologs of the mammalian satellite Insulin receptor has the opposite
become dramatically activated upon cells markers Pax3 and Pax7, paired effects (Demontis and Perrimon,
injury or specific stimuli like IGF-1, and gooseberry, respectively, are not 2009).
which promotes their proliferation expressed in AMPs, these muscle- A remarkable and very promising
and differentiation during hypertro- committed stem-like cells, like quies- intervention to increase muscle mass
phy (Biressi and Rando, 2010). For cent satellite cells, have high levels of and reduce atrophy in mammals is
example, after damage, satellite cells Notch activation (Figeac et al., 2011). through inhibition of the TGF-b fam-
fuse to one another or to an undam- This finding suggests that studies on ily members, like Myostatin and Acti-
aged fiber, promoting muscle regener- twist-expressing muscle progenitors vin, all of which signal via the
ation, through a process that partially in Drosophila may provide useful ActRIIB complex (Fig. 4). Activin is
212 PICCIRILLO ET AL.

produced normally in multiple cell Future studies in both Drosophila Bodine SC, Stitt TN, Gonzalez M, Kline
types and also in cancerous cells and and mammals should further dissect WO, Stover GL, Bauerlein R,
Zlotchenko E, Scrimgeour A, Lawrence
plays an important role in reproduc- the pathways governing muscle JC, Glass DJ, Yancopoulos GD. 2001b.
tion (Xia and Schneyer, 2009), while growth and atrophy in health and dis- Akt/mTOR pathway is a crucial regula-
Myostatin is expressed predomi- ease to discover novel drugs and ther- tor of skeletal muscle hypertrophy and
nantly in skeletal muscles (Zhou apeutic interventions. can prevent muscle atrophy in vivo.
et al., 2010; Zimmers et al., 2002). Nat Cell Biol 3:1014–1019.
Bonetto A, Aydogdu T, Kunzevitzky N,
Myostatin normally acts to limit pre-
ACKNOWLEDGMENTS Guttridge DC, Khuri S, Koniaris LG,
natal and postnatal muscle growth Zimmers TA. 2011. STAT3 activation in
We are grateful to the Muscular Dys-
and mutations in the Myostatin gene skeletal muscle links muscle wasting
trophy Association and the NIH and the acute phase response in cancer
or its receptor result in increased
(AR055255) (to A.L.G.), the Italian cachexia. PLoS One 6:e22538.
muscle mass in mice, cattle, dogs, and Brault JJ, Jespersen JG, Goldberg AL.
Association for Cancer Research
humans (Lee, 2004). Developmental 2010. Peroxisome proliferator-activated
AIRC-Start Up (11423) (to R.P.), St.
inhibition of Myostatin results in both receptor gamma coactivator 1alpha or
Jude Children’s Research Hospital/ 1beta overexpression inhibits muscle
muscle hyperplasia and hypertrophy,
ALSAC and the Ellison Medical Foun- protein degradation, induction of ubiq-
while postnatal inhibition increases
dation (to F.D.), and the NIH uitin ligases, and disuse atrophy. J Biol
muscle mass via hypertrophy, with no Chem 285:19460–19471.
(R01AR057352) and HHMI (to N.P.).
accompanying hyperplasia in several Brooke MH, Kaiser KK. 1970. Muscle
species (McPherron 2010). Suppres- fiber types: how many and what kind?
sion of the Myostatin-based pathway Arch Neurol 23:369–379.
REFERENCES Bruusgaard JC, Gundersen K. 2008. In
(as in Fig. 4) has been also proven vivo time-lapse microscopy reveals no
effective in counteracting muscle Acharyya S, Ladner KJ, Nelsen LL,
Damrauer J, Reiser PJ, Swoap S, loss of murine myonuclei during weeks
wasting in mice with chronic kidney Guttridge DC. 2004. Cancer cachexia is of muscle atrophy. J Clin Invest 118:
Developmental Dynamics

disease (Zhou et al., 2010), following regulated by selective targeting of skel- 1450–1457.
treatment with glucocorticoids (Gil- etal muscle gene products. J Clin Invest Bulchand S, Menon SD, George SE, Chia
114:370–378. W. 2010. Muscle wasted: a novel compo-
son et al., 2007), as well as in cancer nent of the Drosophila histone locus
cachexia (Benny Klimek et al., 2010; Askanas V, Engel WK. 2002. Inclusion-body
myositis and myopathies: different etiolo- body required for muscle integrity. J
Zhou et al., 2010). This effect on mus- gies, possibly similar pathogenic mecha- Cell Sci 123:2697–2707.
cle size resulted at least in part from nisms. Curr Opin Neurol 15:525–531. Cai D, Frantz JD, Tawa NE Jr., Melendez
the inhibition of the FOXO-induced Baehrecke EH. 2003. Autophagic pro- PA, Oh BC, Lidov HG, Hasselgren PO,
grammed cell death in Drosophila. Cell Frontera WR, Lee J, Glass DJ,
activation of atrogenes and ubiquitin- Shoelson SE. 2004. IKKbeta/NF-kap-
Death Differ 10:940–945.
dependent proteolysis and perhaps Baracos VE, DeVivo C, Hoyle DH, paB activation causes severe muscle
also through the subsequent stimula- Goldberg AL. 1995. Activation of the wasting in mice. Cell 119:285–298.
tion of muscle stem cell proliferation. ATP-ubiquitin-proteasome pathway in Chinta R, Tan JH, Wasser M. 2012. The
skeletal muscle of cachectic rats bearing study of muscle remodeling in Drosoph-
Remarkably, inhibition of Activin and ila metamorphosis using in vivo micros-
Myostatin signaling via blockade of a hepatoma. Am J Physiol 268:E996–
1006. copy and bioimage informatics. BMC
the ActRIIB receptors not only dra- Bayline RJ, Duch C, Levine RB. 2001. Bioinform 13:S14.
matically reverses cancer-induced Nerve-muscle interactions regulate Cohen S, Brault JJ, Gygi SP, Glass DJ,
weight loss in certain cancer models, motor terminal growth and myoblast Valenzuela DM, Gartner C, Latres E,
distribution during muscle develop- Goldberg AL. 2009. During muscle atro-
but also improves the survival of mice phy, thick, but not thin, filament com-
ment. Dev Biol 231:348–363.
without slowing tumor growth (Zhou Bayline RJ, Khoo AB, Booker R. 1998. ponents are degraded by MuRF1-
et al., 2010). Thus, improving muscle Innervation regulates the metamorphic dependent ubiquitylation. J Cell Biol
mass aside from enhancing the qual- fates of larval abdominal muscles in the 185:1083–1095.
ity of life can strikingly influence moth, Manduca sexta. Dev Genes Evol Cohen S, Zhai B, Gygi SP, Goldberg AL.
208:369–381. 2012. Ubiquitylation by Trim32 causes
cancer-related mortality, at least in coupled loss of desmin, Z-bands, and
Bellosta P, Gallant P. 2010. Myc function
mice. in Drosophila. Genes Cancer 1:542–546. thin filaments in muscle atrophy. J Cell
Benny Klimek ME, Aydogdu T, Link MJ, Biol 198:575–589.
Pons M, Koniaris LG, Zimmers TA. Colombani J, Bianchini L, Layalle S,
PERSPECTIVES 2010. Acute inhibition of myostatin- Pondeville E, Dauphin-Villemant C,
family proteins preserves skeletal mus- Antoniewski C, Carre C, Noselli S,
In this review, we have highlighted a cle in mouse models of cancer cachexia. Leopold P. 2005. Antagonistic actions of
number of important similarities and Biochem Biophys Res Commun 391: ecdysone and insulins determine final
differences between developmental 1548–1554. size in Drosophila. Science 310:667–670.
and post-natal mechanisms regulat- Biressi S, Rando TA. 2010. Heterogeneity Dahlmann B, Rutschmann M, Reinauer H.
in the muscle satellite cell population. 1986. Effect of starvation or treatment
ing muscle size in Drosophila and with corticosterone on the amount of eas-
Semin Cell Dev Biol 21:845–854.
mammals. The emerging evidence Bodine SC, Latres E, Baumhueter S, Lai ily releasable myofilaments in rat skele-
that multiple signaling pathways VK, Nunez L, Clarke BA, Poueymirou tal muscles. Biochem J 234:659–664.
influence muscle size and are intri- WT, Panaro FJ, Na E, Dharmarajan K, Davis WL, Jacoby BH, Jones RG,
cately interconnected should have Pan ZQ, Valenzuela DM, DeChiara TM, Goodman DB. 1993. Superoxide forma-
Stitt TN, Yancopoulos GD, Glass DJ. tion preceding flight muscle histolysis
important implications in under- 2001a. Identification of ubiquitin ligases in Solenopsis: fine structural cytochem-
standing human diseases and applica- required for skeletal muscle atrophy. istry and biochemistry. Histochem J 25:
tions in combating muscle wasting. Science 294:1704–1708. 478–490.
MECHANISMS OF MUSCLE GROWTH AND ATROPHY 213

Dawson SP, Arnold JE, Mayer NJ, Gilson H, Schakman O, Combaret L, under pathophysiological conditions in
Reynolds SE, Billett MA, Gordon C, Lause P, Grobet L, Attaix D, mice. J Clin Invest 119:3059–3069.
Colleaux L, Kloetzel PM, Tanaka K, Ketelslegers JM, Thissen JP. 2007. Hunter RB, Stevenson E, Koncarevic A,
Mayer RJ. 1995. Developmental Myostatin gene deletion prevents Mitchell-Felton H, Essig DA,
changes of the 26 S proteasome in glucocorticoid-induced muscle atrophy. Kandarian SC. 2002. Activation of an
abdominal intersegmental muscles of Endocrinology 148:452–460. alternative NF-kappaB pathway in
Manduca sexta during programmed cell Glass DJ. 2010. Signaling pathways per- skeletal muscle during disuse atrophy.
death. J Biol Chem 270:1850–1858. turbing muscle mass. Curr Opin Clin Faseb J 16:529–538.
Deak II. 1976. Use of Drosophila mutants Nutr Metab Care 13:225–229. Izumiya Y, Hopkins T, Morris C, Sato K,
to investigate the effect of disuse on the Goldberg AL. 1968. Role of insulin in Zeng L, Viereck J, Hamilton JA, Ouchi
maintenance of muscle. J Insect Physiol work-induced growth of skeletal muscle. N, LeBrasseur NK, Walsh K. 2008.
22:1159–1165. Endocrinology 83:1071–1073. Fast/Glycolytic muscle fiber growth
Demontis F, Perrimon N. 2009. Integra- Goldberg AL, Goodman HM. 1969. Rela- reduces fat mass and improves meta-
tion of Insulin receptor/Foxo signaling tionship between cortisone and muscle bolic parameters in obese mice. Cell
and dMyc activity during muscle work in determining muscle size. J Metab 7:159–172.
growth regulates body size in Drosoph- Physiol 200:667–675. Jackson JR, Mula J, Kirby TJ, Fry CS,
ila. Development 136:983–993. Goldspink G. 1985. Malleability of the Lee JD, Ubele MF, Campbell KS,
Demontis F, Perrimon N. 2010. FOXO/4E- motor system: a comparative approach. McCarthy JJ, Peterson CA, Dupont-
BP signaling in Drosophila muscles reg- J Exp Biol 115:375–391. Versteegden EE. 2012. Satellite cell
ulates organism-wide proteostasis dur- Gomes MD, Lecker SH, Jagoe RT, Navon depletion does not inhibit adult skeletal
ing aging. Cell 143:813–825. A, Goldberg AL. 2001. Atrogin-1, a muscle regrowth following unloading-
Demontis F, Piccirillo R, Goldberg AL, muscle-specific F-box protein highly induced atrophy. Am J Physiol Cell
Perrimon N. 2013a. Mechanisms of expressed during muscle atrophy. Proc Physiol 303:C854–861.
skeletal muscle aging: insights from Natl Acad Sci USA 98:14440–14445. Jang YC, Van Remmen H. 2011. Age-asso-
Drosophila and mammalian models. Dis Grinnell AD. 1995. Dynamics of nerve- ciated alterations of the neuromuscular
Model Mech 6: doi:10.1242/dmm.012559 muscle interaction in developing and junction. Exp Gerontol 46:193–198.
(in press). mature neuromuscular junctions. Phys- Jones ME, Haire MF, Kloetzel PM,
Demontis F, Piccirillo R, Goldberg AL, iol Rev 75:789–834. Mykles DL, Schwartz LM. 1995.
Developmental Dynamics

Perrimon N. 2013b. The influence of Haas AL, Baboshina O, Williams B, Changes in the structure and function
skeletal muscle on systemic aging and Schwartz LM. 1995. Coordinated induc- of the multicatalytic proteinase (protea-
lifespan. Aging Cell, doi: 10.1111/ tion of the ubiquitin conjugation path- some) during programmed cell death in
acel.12126. way accompanies the developmentally the intersegmental muscles of the
Dodd SL, Gagnon BJ, Senf SM, Hain BA, programmed death of insect skeletal hawkmoth, Manduca sexta. Dev Biol
Judge AR. 2010. Ros-mediated activa- muscle. J Biol Chem 270:9407–9412. 169:436–447.
tion of NF-kappaB and Foxo during Haas KF, Woodruff E 3rd, Broadie K. Jones SW, Hill RJ, Krasney PA, O’Conner
muscle disuse. Muscle Nerve 41:110– 2007. Proteasome function is required B, Peirce N, Greenhaff PL. 2004. Dis-
113. to maintain muscle cellular architec- use atrophy and exercise rehabilitation
Dutta D, Anant S, Ruiz-Gomez M, Bate ture. Biol Cell 99:615–626. in humans profoundly affects the
M, VijayRaghavan K. 2004. Founder Handschin C, Spiegelman BM. 2008. The expression of genes associated with the
myoblasts and fibre number during role of exercise and PGC1alpha in regulation of skeletal muscle mass.
adult myogenesis in Drosophila. Devel- inflammation and chronic disease. Faseb J 18:1025–1027.
opment 131:3761–3772. Nature 454:463–469. Junger MA, Rintelen F, Stocker H,
Farrell ER, Fernandes J, Keshishian H. Hastings RA, Eyheralde I, Dawson SP, Wasserman JD, Vegh M, Radimerski T,
1996. Muscle organizers in Drosophila: Walker G, Reynolds SE, Billett MA, Greenberg ME, Hafen E. 2003. The
the role of persistent larval fibers in Mayer RJ. 1999. A 220-kDa activator Drosophila forkhead transcription fac-
adult flight muscle development. Dev complex of the 26 S proteasome in tor FOXO mediates the reduction in
Biol 176:220–229. insects and humans. A role in type II cell number associated with reduced
Fernandes JJ, Keshishian H. 1998. programmed insect muscle cell death insulin signaling. J Biol 2:20.
Nerve-muscle interactions during flight and cross-activation of proteasomes Kimura KI, Truman JW. 1990. Postmeta-
muscle development in Drosophila. from different species. J Biol Chem 274: morphic cell death in the nervous and
Development 125:1769–1779. 25691–25700. muscular systems of Drosophila mela-
Fernandes J, Bate M, Vijayraghavan K. Hegstrom CD, Truman, JW. 1996. Steroid nogaster. J Neurosci 10:403–401.
1991. Development of the indirect flight control of muscle remodeling during Knapp JR, Davie JK, Myer A, Meadows
muscles of Drosophila. Development metamorphosis in Manduca sexta. J E, Olson EN, Klein WH. 2006. Loss of
113:67–77. Neurobiol 29:535–550. myogenin in postnatal life leads to nor-
Figeac N, Daczewska M, Marcelle C, Herbison GJ, Jaweed MM, Ditunno JF. mal skeletal muscle but reduced body
Jagla K. 2007. Muscle stem cells and 1979. Muscle atrophy in rats following size. Development 133:601–610.
model systems for their investigation. denervation, casting, inflammation, and Korolchuk VI, Menzies FM, Rubinsztein
Dev Dyn 236:3332–3342. tenotomy. Arch Phys Med Rehabil 60: DC. 2010. Mechanisms of cross-talk
Figeac N, Jagla T, Aradhya R, Da Ponte 401–404. between the ubiquitin-proteasome and
JP, Jagla K. 2011. Specification and Herbst KL, Bhasin S. 2004. Testosterone autophagy-lysosome systems. FEBS
behavior of AMPs, muscle-committed action on skeletal muscle. Curr Opin Lett 584:1393–1398.
transient Drosophila stem cells. Fly Clin Nutr Metab Care 7:271–277. Kudryashova E, Kudryashov D,
(Austin) 5:7–9. Hosaka T, Biggs WH 3rd, Tieu D, Boyer Kramerova I, Spencer MJ. 2005.
Galluzzi L, Kroemer G. 2008. Necroptosis: AD, Varki NM, Cavenee WK, Arden Trim32 is a ubiquitin ligase mutated in
a specialized pathway of programmed KC. 2004. Disruption of forkhead tran- limb girdle muscular dystrophy type 2H
necrosis. Cell 135:1161–1163. scription factor (FOXO) family members that binds to skeletal muscle myosin
Gibala MJ, McGee SL, Garnham AP, in mice reveals their functional diversi- and ubiquitinates actin. J Mol Biol 354:
Howlett KF, Snow RJ, Hargreaves M. fication. Proc Natl Acad Sci USA 101: 413–424.
2009. Brief intense interval exercise 2975–2980. Kuwahara H, Horie T, Ishikawa S, Tsuda
activates AMPK and p38 MAPK signal- Hu Z, Wang H, Lee IH, Du J, Mitch WE. C, Kawakami S, Noda Y, Kaneko T,
ing and increases the expression of 2009. Endogenous glucocorticoids and Tahara S, Tachibana T, Okabe M, Melki
PGC-1alpha in human skeletal muscle. impaired insulin signaling are both J, Takano R, Toda T, Morikawa D,
J Appl Physiol 106:929–934. required to stimulate muscle wasting Nojiri H, Kurosawa H, Shirasawa T,
214 PICCIRILLO ET AL.

Shimizu T. 2010. Oxidative stress in in skeletal muscle and controls activity- Park YE, Hayashi YK, Bonne G, Arimura
skeletal muscle causes severe disturb- dependent myosin switching. Proc Natl T, Noguchi S, Nonaka I, Nishino I.
ance of exercise activity without muscle Acad Sci USA 101:10590–10595. 2009. Autophagic degradation of
atrophy. Free Radic Biol Med 48:1252– McPherron AC. 2010. Metabolic functions nuclear components in mammalian
1262 of Myostatin and GDF11. Immunol cells. Autophagy 5:795–804.
LaBeau-DiMenna, EM, Clark KA, Endocr Metab Agents Med Chem 10: Pate RR, Pratt M, Blair SN, Haskell WL,
Bauman KD, Parker DS, Cripps RM, 217–231. Macera CA, Bouchard C, Buchner D,
Geisbrecht ER. 2012. Thin, a Trim32 Menconi M, Fareed M, O’Neal P, Poylin V, Ettinger W, Heath GW, King AC, et al.
ortholog, is essential for myofibril sta- Wei W, Hasselgren PO. 2007. Role of 1995. Physical activity and public
bility and is required for the integrity glucocorticoids in the molecular regula- health. A recommendation from the
of the costamere in Drosophila. Proc tion of muscle wasting. Crit Care Med Centers for Disease Control and Pre-
Natl Acad Sci USA 109:17983–17988. 35:S602–608. vention and the American College of
Lagirand-Cantaloube J, Offner N, Csibi Moreno E, Yan M, Basler K. 2002. Evolu- Sports Medicine. Jama 273:402–407.
A, Leibovitch MP, Batonnet-Pichon S, tion of TNF signaling mechanisms: JNK- Paul PK, Gupta SK, Bhatnagar S,
Tintignac LA, Segura, CT, Leibovitch dependent apoptosis triggered by Eiger, Panguluri SK, Darnay BG, Choi Y,
SA. 2008. The initiation factor eIF3-f is the Drosophila homolog of the TNF Kumar A. 2010. Targeted ablation of
a major target for atrogin1/MAFbx superfamily. Curr Biol 12:1263–1268. TRAF6 inhibits skeletal muscle wasting
function in skeletal muscle atrophy. Moresi V, Williams AH, Meadows E, in mice. J Cell Biol 191:1395–1411.
Embo J 27:1266–1276. Flynn JM, Potthoff MJ, McAnally J, Piazza N, Gosangi B, Devilla S, Arking R,
Lecker SH, Jagoe RT, Gilbert A, Gomes Shelton JM, Backs J, Klein WH, Wessells R. 2009. Exercise-training in
M, Baracos V, Bailey J, Price SR, Mitch Richardson JA, Bassel-Duby R, Olson young Drosophila melanogaster reduces
WE, Goldberg AL. 2004. Multiple types EN. 2010. Myogenin and class II age-related decline in mobility and car-
of skeletal muscle atrophy involve a HDACs control neurogenic muscle atro- diac performance. PLoS One 4:e5886.
common program of changes in gene phy by inducing E3 ubiquitin ligases. Piccirillo R, Goldberg AL. 2012. The p97/
expression. Faseb J 18:39–51. Cell 143:35–45. VCP ATPase is critical in muscle atro-
Lee SJ. 2004. Regulation of muscle mass Mourkioti F, Kratsios P, Luedde T, Song phy and the accelerated degradation of
by myostatin. Annu Rev Cell Dev Biol YH, Delafontaine P, Adami R, Parente muscle proteins. Embo J 31:3334–3350.
20:61–86. V, Bottinelli R, Pasparakis M, Rosenthal Pi
etri-Rouxel F, Gentil C, Vassilopoulos S,
Developmental Dynamics

Li JB, Goldberg AL. 1976. Effects of food N. 2006. Targeted ablation of IKK2 Baas D, Mouisel E, Ferry A, Vignaud
deprivation on protein synthesis and improves skeletal muscle strength, A, Hourd e C, Marty I, Schaeffer L, Voit
degradation in rat skeletal muscles. Am maintains mass, and promotes regenera- T, Garcia L. 2010. DHPR alpha1S subu-
J Physiol 231:441–448. tion. J Clin Invest 116:2945–2954. nit controls skeletal muscle mass and
Lokireddy S, Wijesoma IW, Teng S, Moylan JS, Smith JD, Chambers MA, morphogenesis. Embo J 29:643–654.
Bonala S, Gluckman PD, McFarlane C, McLoughlin TJ, Reid MB. 2008. TNF Porter JD, Burns LA, McMahon EJ. 1989.
Sharma M, Kambadur R. 2012. The induction of atrogin-1/MAFbx mRNA Denervation of primate extraocular
ubiquitin ligase Mul1 induces mitoph- depends on Foxo4 expression but not muscle. A unique pattern of structural
agy in skeletal muscle in response to AKT-Foxo1/3 signaling. Am J Physiol alterations. Invest Ophthalmol Vis Sci
muscle-wasting stimuli. Cell Metab 16: Cell Physiol 295:C986–993. 30:1894–908.
613–624. Muller FL, Song W, Liu Y, Chaudhuri A, Primeau AJ, Adhihetty PJ, Hood DA.
Low P, Bussell K, Dawson SP, Billett MA, Pieke-Dahl S, Strong R, Huang TT, 2002. Apoptosis in heart and skeletal
Mayer RJ, Reynolds SE. 1997. Expres- Epstein CJ, Roberts LJ 2nd, Csete M, muscle. Can J Appl Physiol 27:349–395.
sion of a 26S proteasome ATPase subu- Faulkner JA, Van Remmen H. 2006. Raffaello A, Milan G, Masiero E, Carnio
nit, MS73, in muscles that undergo Absence of CuZn superoxide dismutase S, Lee D, Lanfranchi G, Goldberg AL,
developmentally programmed cell leads to elevated oxidative stress and Sandri M. 2010. JunB transcription fac-
death, and its control by ecdysteroid acceleration of age-dependent skeletal tor maintains skeletal muscle mass and
hormones in the insect Manduca sexta. muscle atrophy. Free Radic Biol Med promotes hypertrophy. J Cell Biol 191:
FEBS Lett 400:345–349. 40:1993–2004. 101–113
Lustgarten MS, Jang YC, Liu Y, Muller FL, Nair KS. 2005. Aging muscle. Am J Clin Ritson GP, Custer SK, Freibaum BD,
Qi W, Steinhelper M, Brooks SV, Larkin Nutr 81:953–963. Guinto JB, Geffel D, Moore J, Tang W,
L, Shimizu T, Shirasawa T, McManus Nakao R, Hirasaka K, Goto J, Ishidoh K, Winton MJ, Neumann M, Trojanowski
LM, Bhattacharya A, Richardson A, Van Yamada C, Ohno A, Okumura Y, JQ, Lee VM, Forman MS, Taylor JP.
Remmen H. 2009. Conditional knockout Nonaka I, Yasutomo K, Baldwin KM, 2010. TDP-43 mediates degeneration in
of Mn-SOD targeted to type IIB skeletal Kominami E, Higashibata A, Nagano a novel Drosophila model of disease
muscle fibers increases oxidative stress K, Tanaka K, Yasui N, Mills EM, caused by mutations in VCP/p97. J
and is sufficient to alter aerobic exercise Takeda S, Nikawa T. 2009. Ubiquitin Neurosci 30:7729–7739.
capacity. Am J Physiol Cell Physiol 297: ligase Cbl-b is a negative regulator for Romanello V, Guadagnin E, Gomes L,
C1520–1532. insulin-like growth factor 1 signaling Roder I, Sandri C, Petersen Y, Milan G,
Mammucari C, Milan G, Romanello V, during muscle atrophy caused by Masiero E, Del Piccolo P, Foretz M,
Masiero E, Rudolf R, Del Piccolo P, unloading. Mol Cell Biol 29:4798–4811. Scorrano L, Rudolf R, Sandri M. 2010.
Burden SJ, Di Lisi R, Sandri C, Zhao J, Navegantes LC, Resano NM, Migliorini Mitochondrial fission and remodelling
Goldberg AL, Schiaffino S, Sandri M. RH, Kettelhut IC. 2001. Catechol- contributes to muscle atrophy. Embo J
2007. FoxO3 controls autophagy in amines inhibit Ca(2þ)-dependent prote- 29:1774–1785.
skeletal muscle in vivo. Cell Metab 6: olysis in rat skeletal muscle through Roy S, VijayRaghavan K. 1998. Pattern-
458–471. beta(2)-adrenoceptors and cAMP. Am J ing muscles using organizers: larval
Marzetti E, Calvani R, Bernabei R, Physiol Endocrinol Metab 281:E449– muscle templates and adult myoblasts
Leeuwenburgh C. 2012. Apoptosis in 454. actively interact to pattern the dorsal
skeletal myocytes: a potential target for Paik JH, Kollipara R, Chu G, Ji H, Xiao longitudinal flight muscles of Drosoph-
interventions against sarcopenia and Y, Ding Z, Miao L, Tothova Z, Horner ila. J Cell Biol 141:1135–1145.
physical frailty: a mini-review. Geron- JW, Carrasco DR, Jiang S, Gilliland Ruas JL, White JP, Rao RR, Kleiner S,
tology 58:99–106. DG, Chin L, Wong WH, Castrillon DH, Brannan KT, Harrison BC, Greene NP,
McCullagh KJ, Calabria E, Pallafacchina DePinho RA. 2007. FoxOs are lineage- Wu J, Estall JL, Irving BA, Lanza IR,
G, Ciciliot S, Serrano AL, Argentini C, restricted redundant tumor suppressors Rasbach KA, Okutsu M, Nair KS, Yan Z,
Kalhovde JM, Lomo T, Schiaffino S. and regulate endothelial cell homeosta- Leinwand LA, Spiegelman BM. 2012. A
2004. NFAT is a nerve activity sensor sis. Cell 128:309–323. PGC-1alpha isoform induced by
MECHANISMS OF MUSCLE GROWTH AND ATROPHY 215

resistance training regulates skeletal quitin gene expression during develop- organization, and autophagy of skeletal
muscle hypertrophy. Cell 151:1319– mentally programmed cell death. muscle. Genes Dev 19:1715–1722.
1331. Neuron 5:411–419. Wasser M, Bte Osman Z, Chia W. 2007.
Sacheck JM, Hyatt JP, Raffaello A, Jagoe Solomon V, Goldberg AL. 1996. Impor- EAST and Chromator control the
RT, Roy RR, Edgerton VR, Lecker SH, tance of the ATP-ubiquitin-proteasome destruction and remodeling of muscles
Goldberg AL. 2007. Rapid disuse and pathway in the degradation of soluble during Drosophila metamorphosis. Dev
denervation atrophy involve transcrip- and myofibrillar proteins in rabbit mus- Biol 307:380–393.
tional changes similar to those of mus- cle extracts. J Biol Chem 271:26690– Xia Y, Schneyer AL. 2009. The biology of
cle wasting during systemic diseases. 26697. activin: recent advances in structure,
Faseb J 21:140–155. Taylor MV. 2006. Comparison of muscle regulation and function. J Endocrinol
Sandri M, Carraro U. 1999. Apoptosis of development in Drosophila and verte- 202:1–12.
skeletal muscles during development brates. In: Sink H, editor. Muscle devel- Yang JY, Yang WY. 2011. Spatiotempor-
and disease. Int J Biochem Cell Biol 31: opment in Drosophila. Georgetown, TX ally controlled initiation of Parkin-
1373–1390. /New York, NY: Landes Bioscience/ mediated mitophagy within single cells.
Sandri M, Sandri C, Gilbert A, Skurk C, Springer. p 169–203. Autophagy 7:1230–1238.
Calabria E, Picard A, Walsh K, Teleman AA, Hietakangas V, Sayadian Zammit PS, Heslop L, Hudon V, Rosenblatt
Schiaffino S, Lecker SH, Goldberg AL. AC, Cohen SM. 2008. Nutritional Con- JD, Tajbakhsh S, Buckingham ME,
2004. Foxo transcription factors induce trol of Protein Biosynthetic Capacity by Beauchamp JR, Partridge TA. 2002.
the atrophy-related ubiquitin ligase Insulin via Myc in Drosophila. Cell Kinetics of myoblast proliferation show
atrogin-1 and cause skeletal muscle Metab 7:21–32. that resident satellite cells are compe-
atrophy. Cell 117:399–412. Terada S, Goto M, Kato M, Kawanaka K, tent to fully regenerate skeletal muscle
Sandri M, Lin J, Handschin C, Yang W, Shimokawa T, Tabata I. 2002. Effects of fibers. Exp Cell Res 281:39–49.
Arany ZP, Lecker SH, Goldberg AL, low-intensity prolonged exercise on Zeman RJ, Zhao J, Zhang Y, Zhao W, Wen
Spiegelman BM. 2006. PGC-1alpha pro- PGC-1 mRNA expression in rat epitro- X, Wu Y, Pan J, Bauman WA, Cardozo
tects skeletal muscle from atrophy by chlearis muscle. Biochem Biophys Res C. 2009. Differential skeletal muscle
suppressing FoxO3 action and atrophy- Commun 296:350–354. gene expression after upper or lower
specific gene transcription. Proc Natl Thornell LE. 2011. Sarcopenic obesity: motor neuron transection. Pflugers
Acad Sci USA 103:16260–16265. satellite cells in the aging muscle. Curr Arch 458:525–535.
Developmental Dynamics

Sartori R, Milan G, Patron M, Opin Clin Nutr Metab Care 14:22–27. Zhao J, Brault JJ, Schild A, Cao P, Sandri
Mammucari C, Blaauw B, Abraham R, Tiao G, Lieberman M, Fischer JE, M, Schiaffino S, Lecker SH, Goldberg AL.
Sandri M. 2009. Smad2 and 3 tran- Hasselgren PO. 1997. Intracellular regu- 2007. FoxO3 coordinately activates protein
scription factors control muscle mass in lation of protein degradation during sep- degradation by the autophagic/lysosomal
adulthood. Am J Physiol Cell Physiol sis is different in fast- and slow-twitch and proteasomal pathways in atrophying
296:C1248–1257. muscle. Am J Physiol 272:R849–856. muscle cells. Cell Metab 6:472–483.
Schakman O, Gilson H, Thissen JP. 2008. Tiefenbock SK, Baltzer C, Egli NA, Frei Zheng J, Edelman SW, Tharmarajah G,
Mechanisms of glucocorticoid-induced C. 2010. The Drosophila PGC-1 homo- Walker DW, Pletcher SD, Seroude L.
myopathy. J Endocrinol 197:1–10. logue Spargel coordinates mitochondrial 2005. Differential patterns of apoptosis
Schnorrer F, Sch€onbauer C, Langer CC, activity to insulin signalling. Embo J in response to aging in Drosophila. Proc
Dietzl G, Novatchkova M, Schernhuber 29:171–183. Natl Acad Sci USA 102:12083–12088.
K, Fellner M, Azaryan A, Radolf M, Tinkerhess MJ, Healy L, Morgan M, Zhou X, Wang JL, Lu J, Song Y, Kwak
Stark A, Keleman K, Dickson BJ. 2010. Sujkowski A, Matthys E, Zheng L, KS, Jiao Q, Rosenfeld R, Chen Q,
Systematic genetic analysis of muscle Wessells RJ. 2012. The Drosophila Boone T, Simonet WS, Lacey DL,
morphogenesis and function in Dro- PGC-1a homolog spargel modulates the Goldberg AL, Han HQ. 2010. Reversal
sophila. Nature 464:287–291. physiological effects of endurance exer- of cancer cachexia and muscle wasting
Schubiger M, Wade AA, Carney GE, cise. PLoS One 7:e31633. by ActRIIB antagonism leads to pro-
Truman JW, Bender M. 1998. Drosoph- van Rooij E, Doevendans PA, de Theije longed survival. Cell 142:531–543.
ila EcR-B ecdysone receptor isoforms CC, Babiker FA, Molkentin JD, de Zimmers TA, Davies MV, Koniaris LG,
are required for larval molting and for Windt LJ. 2002. Requirement of nuclear Haynes P, Esquela AF, Tomkinson KN,
neuron remodeling during metamorpho- factor of activated T-cells in calcineurin- McPherron AC, Wolfman NM, Lee SJ.
sis. Development 125:2053–2062. mediated cardiomyocyte hypertrophy. J 2002. Induction of cachexia in mice by
Schulze PC, Spate U. 2005. Insulin-like Biol Chem 277:48617–48626. systemically administered myostatin.
growth factor-1 and muscle wasting in Wallace GQ, McNally EM. 2009. Mech- Science 296:1486–1488.
chronic heart failure. Int J Biochem anisms of muscle degeneration, Zirin J, Cheng D, Dhanyasi N, Cho J,
Cell Biol 37:2023–2035. regeneration, and repair in the mus- Dura JM, Vijayraghavan K, Perrimon
Schwartz LM. 1992. Insect muscle as a cular dystrophies. Annu Rev Physiol N. 2013. Ecdysone signaling at meta-
model for programmed cell death. J 71:37–57. morphosis triggers apoptosis of Dro-
Neurobiol 23:1312–1326. Wang X, Blagden C, Fan J, Nowak SJ, sophila abdominal muscles. Dev Biol
Schwartz LM, Myer A, Kosz L, Engelstein Taniuchi I, Littman DR, Burden SJ. 2005. doi:pii: S0012-1606(13)00483-1. 10.1016/
M, Maier C. 1990. Activation of polyubi- Runx1 prevents wasting, myofibrillar dis- j.ydbio.2013.08.029.