Critical Review
Myostatin: Expanding Horizons
1
Department of Biochemistry, Yong Loo Lin School of Medicine, National
University of Singapore (NUS), Singapore
2
Department of Cell & Molecular Biology, Brenner Centre for Molecular
Medicine, Singapore Institute of Clinical Sciences (SICS), Singapore
3
School of Biological Sciences, Nanyang Technological University,
Singapore
Abstract
Myostatin is a secreted growth and differentiation factor that
belongs to the TGF-b superfamily. Myostatin is predominantly
synthesized and expressed in skeletal muscle and thus exerts
a huge impact on muscle growth and function. In keeping with
its negative role in myogenesis, myostatin expression is
tightly regulated at several levels including epigenetic, tran-
scriptional, post-transcriptional, and post-translational. New
Keywords: myostatin; skeletal muscle; muscle wasting;
cachexia; sarcopenia; insulin resistance
Introduction
Myostatin, earlier known as growth and differentiation factor
8 (GDF-8), is a member of the TGF-b superfamily. Myostatin
has a tremendous impact on the growth and development of
skeletal muscle, such that genetic deletions or mutations in the
myostatin gene cause a dramatic increase in skeletal muscle
mass. The muscle hypertrophy phenotype in the absence of
myostatin is present in various mammalian species including
rodents, farm and domestic animals and humans, thus under-
scoring the important function of myostatin in muscle (1–5).
Further evidence for the negative role that myostatin plays
during myogenesis has been observed in several studies that
have assessed myostatin function during muscle growth and
C 2015 International Union of Biochemistry and Molecular Biology
V
Volume 67, Number 8, August 2015, Pages 589–600
Address correspondence to: Mridula Sharma, National University of Singa-
pore, Department of Biochemistry, 8 Medical Drive, MD7, Singapore
117597.
E-mail: bchmridu@nus.edu.sg
Received 20 May 2015; Accepted 29 May 2015
DOI 10.1002/iub.1392
Published online 25 August 2015 in Wiley Online Library
(wileyonlinelibrary.com)
IUBMB Life
Mridula Sharma1,2*
Craig McFarlane2
Ravi Kambadur2,3
Himani Kukreti1
Sabeera Bonala2
Shruti Srinivasan1
revelations regarding myostatin regulation also offer mecha-
nisms that could be exploited for developing myostatin antag-
onists. Increasingly, it is becoming clearer that besides its
conventional role in muscle, myostatin plays a critical role in
metabolism. Hence, molecular mechanisms by which myosta-
tin regulates several key metabolic processes need to be fur-
ther explored. V
C 2015 IUBMB Life, 67(8):589–600, 2015
cancer
repair (6–9). Furthermore, high levels of myostatin are linked
with muscle wasting seen during cancer (10), HIV infection
(11), liver disease (12), COPD (13), and during aging (14,15).
Moreover, systemic expression of myostatin in mice has been
shown to induce cachectic-like muscle wasting (16). In addi-
tion to regulating muscle growth, more recently myostatin has
been shown to affect glucose and fat metabolism (1), and as
such is associated with the development of obesity, insulin
resistance, and type 2 diabetes (T2D; (17–20)).
In this review article, we discuss the recent developments
in our understanding of myostatin regulation and function.
Myostatin Structure and Processing
Similar to other TGF-b superfamily members myostatin is syn-
thesised as a precursor protein (375 amino acids) bearing an
N-terminal (NH2) core of hydrophobic amino acids, which acts
as a signal sequence for secretion ((3); Fig. 1). The C-terminal
(COOH) region of myostatin has nine conserved cysteine amino
acids that are used for homodimerisation and formation of the
“cysteine knot” structure, a hallmark feature of TGF-b super-
family members ((3,21); Fig. 1). The proteolytic processing of
52 kDa myostatin precursor protein occurs in the Golgi at the
RSRR site by the action of the serine protease furin or other
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Myostatin structure and proteolytic processing. Sche-
FIG 1 matic representation of the structure of myostatin
protein. Precursor myostatin protein contains an N-
terminal (NH2) signal peptide (SP) for secretion and
a C-terminal (COOH) region that contains nine con-
served cysteine residues (c), which are critical for
eventual homodimerisation and “cysteine knot” for-
mation. Precursor myostatin protein is proteolytically
processed by the serine protease Furin at the Golgi
to give rise to LAP and mature myostatin.
members of the proprotein convertase family ((3,22,23); Fig.
1). As a result of the enzymatic reaction, a 36/40 kDa Latency-
Associated Peptide (LAP) and a 12.5/26 kDa mature peptide,
corresponding to a C-terminal monomer or dimer respectively,
have been observed ((9,22), (24); Fig. 1). Both mature and LAP
forms of myostatin are secreted into the circulation (22,25),
allowing myostatin to function in an autocrine, paracrine, or
endocrine manner. The mature myostatin peptide has been
shown to interact with the Activin Type IIB receptor (ActRIIB)
and the TGF-b type I receptor, ALK5, and signal through
canonical smad2/smad3 proteins (22,26,27).
The importance of myostatin proteolytic processing is quite
clear, as mutation of the myostatin RSRR processing site to the
amino acids GLDG leads to prominent skeletal muscle hyper-
trophy in mice (28). Members of the bone morphogenetic pro-
tein-1/tolloid (BMP-1/TLD) family of metalloproteinases have a
critical function in removal of the myostatin LAP region from
the latent myostatin complex in the circulation, leading to acti-
vation of mature myostatin (29). In support, generation of a
mutated LAP peptide, which cannot be cleaved by BMP-1/TLD,
resulted in increased muscle mass in vivo. During myoblast
differentiation, the extent of proteolytic processing is downre-
gulated via a feedback loop wherein the expression of the ser-
ine protease furin is negatively regulated by myostatin. This
mechanism has been proposed to regulate myostatin levels
during fetal muscle development to allow for timely myogenic
differentiation (24). Thus, proteolytic processing of myostatin
plays an important role in regulation of myostatin function.
Regulation of Myostatin
Transcriptional Regulation of Myostatin
As is typical of many muscle-specific genes, the 50 promoter/
enhancer region of the myostatin gene contains several evolu-
tionarily conserved E-Box sequence motifs. (30,31). The E-Box
motif, CANNTG, is the canonical binding site for basic Helix-
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Loop-Helix (bHLH) transcription factors, such as MyoD, Myf5
and myogenin. The myostatin promoter is preferentially acti-
vated by MyoD, with peak activity observed during the G1
phase of the cell cycle when MyoD is expressed maximally.
Thus, MyoD activates the myostatin promoter in a temporal
fashion, presumably to allow for timely myostatin-mediated
control of cell cycle arrest (31).
Mef2 transcription factors play an integral role in the tran-
scription of several muscle specific genes during myoblast dif-
ferentiation. Putative mef2 binding motifs have been observed
in the myostatin promoter; however, the number of mef2
motifs is variable across different species (31–34). A report by
Wang et al., (2008) indicated that in rat cardiomyocytes,
angiotensin II-induced myostatin expression is via mef2 and
that this increase in myostatin is believed to inhibit cardiac
myocyte hypertrophy (35). Mef2 has also been shown to
increase myostatin promoter activity in myoblasts, which was
proposed to be a potential mechanism through which Mef2
may restrain muscle growth and differentiation (33).
Several FoxO binding motifs have also been observed in
the myostatin promoter suggesting that the FoxO family of
transcription factors may control myostatin transcription.
Indeed, type IIB, glycolytic muscle fibers express higher levels
of myostatin and FoxO1 mRNAs than type I oxidative fibers
(36). Furthermore, an additive effect on the regulation of myo-
statin transcription was observed when both FoxO and Smad2
transcription factors were transfected into myoblasts resulting
in inhibition of myoblast differentiation (36). The authors fur-
ther proposed that during atrophy when FoxO activity is
enhanced these factors could in turn increase the expression
of myostatin (36).
Considering the potent negative function of myostatin dur-
ing myogenesis, it is not surprising that myostatin is able to
negatively auto regulate its own transcription. In fact, previous
studies have revealed that myostatin expression at the mRNA
level and myostatin promoter activity was reduced in muscle
cells upon exposure to exogenous myostatin (37). This inhibi-
tion of myostatin transcription was mediated through smad7
(27,37). Consistent with this, an increased expression of myo-
statin mRNA and reduced smad7 expression is observed in
Belgian Blue cattle, in which functional myostatin protein is
absent (37).
The contextual control of myostatin transcription has been
highlighted in some contemporary studies. Recent findings
show that inflammatory factors, such as TNF-a, and increased
oxidative stress can stimulate myostatin production. The
increased myostatin transcription due to TNF-a and hydrogen
peroxide treatment was attributed to activation of NF-jB and
its subsequent binding to myostatin promoter sequences (38).
NF-jB directed regulation of myostatin transcription in myo-
blasts was also reported under conditions of hyperammonemia
(39). In addition, high glucose loading has been shown to
increase myostatin expression in muscle cells and HepG2 liver
cells, which was shown to be due to carbohydrate-responsive
element-binding protein (ChREBP) (Fig. 2a) binding to
Myostatin

Summary of myostatin function during muscle wast-
FIG 2 ing and insulin resistance. (a) Increased myostatin
levels can promote the development of insulin resist-
ance. High glucose and palmitate result in transcrip-
tional activation of myostatin through the action of
carbohydrate-responsive element-binding protein
(ChREBP) and sterol regulatory element binding
protein-1c (SREBP1c), respectively. Elevated myosta-
tin levels lead to increased expression of Casitas B-
lineage lymphoma b (Cblb) and phosphotyrosine
interaction domain containing 1 (PID1) through
Smad3- and NFjB-dependent signaling mechanisms
respectively, which in turn target and repress insulin
signaling. Impaired insulin signaling results in
reduced glucose uptake and the eventual develop-
ment of insulin resistance. (b) Myostatin promotes
the development of skeletal muscle wasting. Epige-
netic and genetic factors lead to increased levels of
myostatin during skeletal muscle wasting. Increased
levels of myostatin result in activation of canonical
Smad3 signaling and increased expression of Fork-
head Box O (FoxO) transcription factors. Inhibition of
pAkt by myostatin promotes the activation and sub-
sequent nuclear translocation of FoxO transcription
factors to increase the expression of downstream tar-
get genes. Increased FoxO activation results in
increased expression of the ubiquitin E3 ligases
Atrogin-1 and MuRF1, enhanced ubiquitin-
proteasome pathway (UPP)-mediated protein degra-
dation and muscle wasting. Myostatin has further
been shown to increase the expression of miR-1,
which inhibits HSP70 and subsequently reduces pAkt
levels leading to increased FoxO, Atrogin-1 and
MuRF1 expression and the development of skeletal
muscle wasting.
carbohydrate response element (ChoRE) present in the myo-
statin promoter region (17). Similarly, palmitate-mediated
activation of sterol regulatory element binding protein-1c
(SREBP1c) can also activate myostatin transcription (Fig. 2a)
SHARMA ET AL.
through binding to a sterol regulatory element present in the
myostatin promoter to promote insulin resistance (17). In
addition, myostatin transcription is upregulated in skeletal
muscle of streptozotocin-induced type 1 diabetic mice through
the action of the Foxa2 transcription factor, which is activated
due to reduced insulin signaling in type 1 diabetic muscle (40).
Post-Transcriptional Regulation of Myostatin
One of the modes of post-transcriptional regulation of genes is
through the action of microRNAs. Clop et al., (2006) first
reported the involvement of microRNAs in regulation of myo-
statin in Texel sheep, which express low levels of myostatin
concomitant with a muscle hypertrophy phenotype (41). The
authors reported a G to C single nucleotide polymorphism in
the 3’UTR of the myostatin gene in Texel sheep making it a
target of the muscle-specific microRNA miR206, which
resulted in inhibition of myostatin and increased musculature
(41). After this initial finding there have been additional
reports highlighting myostatin regulation by microRNAs,
including miR-27a/b, miR-208a/b and miR-499. Several inde-
pendent groups have revealed myostatin as a target of miR-
27a/b (42–45) using both in vitro and in vivo models. Allen
et al., (2007) observed higher expression of mature myostatin
mRNA in fast twitch muscles when compared with slow-twitch
muscles, although it was noted that myostatin pre-mRNA
expression levels were similar between fast and slow muscle
types (42). This observation led them to investigate post-
transcriptional control of myostatin, and results revealed that
miR-27a/b repressed myostatin expression and was highly
expressed in slow-twitch muscles, where reduced myostatin
expression was noted (42). Taken together these data reveal
that miR-27a/b may play an important role in regulating mus-
cle fibre type-specific expression of myostatin. Huang et al.,
(2012) further demonstrated an inverse relationship between
miR-27a and myostatin expression in proliferating C2C12
myoblasts and postulated that miR-27a promotes myoblast
proliferation by targeting myostatin (46). In addition, further
work has shown that miR-27a is responsible for decreased
myostatin expression in C2C12 myoblasts treated with leucine,
thereby promoting leucine-induced proliferation of myoblasts
(43). MiR-27a has also been shown to target bovine myostatin
30 UTR in the Piedmontese cattle breed (45). Piedmontese cattle
have low levels of mature myostatin because of C313Y mis-
sense mutation in the myostatin gene and hence exhibit skele-
tal muscle hypertrophy and hyperplasia (2,47,48). Although
the majority of Piedmontese cattle have this mutation, the
degree of resulting skeletal muscle hypertrophy is variable.
Miretti et al., (2013) have suggested that this conformational
difference could be due to the differential expression of miR-
27a (45).
Recent work from our laboratory has revealed that miR-
27a/b plays a role in feedback negative autoregulation of myo-
statin (44). Our results show that myostatin up-regulates the
expression of miR-27a/b, via a smad3-dependent mechanism,
to inhibit its own expression. Further analysis revealed that
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miR-27a/b-mediated inhibition of myostatin has a role in pro-
moting satellite cell (SC) activation, increasing myoblast prolif-
eration, and preventing muscle wasting (44). Similarly, Yang
et al., (2014) have also demonstrated that miR-27a positively
regulates porcine myoblast proliferation through inhibiting
myostatin (49).
In an earlier study in which the effect of essential amino
acids (EAA) on muscle protein synthesis and muscular hyper-
trophy in humans was analyzed, expression analysis for miR-
NAs revealed that miR-499 and miR-208b were upregulated
within 3 h of ingestion of 10g of EAA in vastus lateralis human
skeletal muscle (50). Both miR-499 and miR-208b are encoded
by the introns of myosin genes, miR-208b from the Myhc7
gene and miR-499 from the Myhc7b gene, respectively (51).
While Drummond et al., (2009) reported that reduced expres-
sion of myostatin correlated with increase expression of these
microRNAs, myostatin was not validated as a direct target of
miR-499 and miR-208b in the study. However, a later study
established myostatin to be a valid target of miR-499 (52).
Another related microRNA, miR-208a that is heart specific and
encoded by an intron of the Myhc6 gene (51) was also shown
to target myostatin (53). Callis et al., 2009 revealed that over-
expression of miR-208a in mice heart induced hypertrophic
growth and led to repression of myostatin, suggesting myosta-
tin to be a potential target of miR-208a (53).
Epigenetic Regulation of Myostatin
Apart from the regulation of myostatin by microRNAs, epige-
netic mechanisms also regulate myostatin. Fan et al., (2012)
identified that sulphoraphane (SFN), a bioactive compound
that is abundant in cruciferous vegetables, like broccoli and
cauliflower, is a negative regulator of myostatin in porcine SCs
(54). The authors found that in addition to being a histone
deacetylase inhibitor, SFN is also a DNA methyltransferase
inhibitor, and when compared with trichostatin A and 5-aza-
2’-deoxycytidine, SFN significantly repressed myostatin
expression. This epigenetic repression of myostatin was attrib-
uted in part to hypoacetylation of the MyoD binding sites in the
myostatin promoter (54).
Histone methyl transferases belonging to the SMYD family
are highly expressed in myogenic tissue (55,56), thus showing
the potential to be important regulators of skeletal muscle
mass. Recently one of the SMYD family members, SMYD3, was
demonstrated to be involved in epigenetic regulation of myo-
statin. Proserpio et al., (2013) have shown that SMYD3 helps
chromatin recruitment of BRD4 (Bromodomain protein) and p-
TEFb (positive transcription elongation factor complex) to the
myostatin promoter. In doing so, these proteins facilitate early
transcriptional elongation of myostatin mRNA thus positively
regulating myostatin expression. Moreover, SMYD3 expression
was increased during Dex-induced atrophy in C2C12 myotubes
(57), a condition known to increase myostatin expression
(58,59).
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Post-Translational Regulation of Myostatin
Several reports have revealed that myostatin function is regu-
lated via protein-protein interactions. The sarcomeric protein
titin-cap has been shown to bind to mature myostatin protein
(60). Overexpression of titin-cap in myoblasts did not alter
myostatin synthesis and processing, however myoblast prolif-
eration increased. Based on these results it was concluded
that titin-cap modulates the secretion of myostatin (60).
Another protein that regulates myostatin secretion is human
small glutamine-rich tetratricopeptide repeat-containing pro-
tein (hSGT), which was found to interact with myostatin within
myoblasts (61). The C-terminal region of hSGT and the N-
terminal signal peptide region of myostatin were essential for
this association (61). Previously, follistatin had been shown to
interact with mature myostatin thereby inhibiting its binding
to ActRIIB (22). Consistent with this, follistatin inhibits myosta-
tin activity and rescues the inhibition of muscle differentiation
imposed by myostatin (62). Conversely, follistatin-null mice
have diminished muscle mass at birth, concomitant with
increased myostatin activity (63). Interestingly, transgenic
mice overexpressing follistatin show a hypermuscular pheno-
type that is greater than the observed myostatin-null pheno-
type (22), indicating that follistatin may in fact control the
activity of additional negative regulators of muscle growth.
Similar to follistatin, follistatin-related gene also interacts with
mature myostatin peptide indicated by a dose-dependent
decrease in myostatin activity in reporter gene analysis experi-
ments (25). In the circulation, Growth and differentiation
factor-associated serum protein-1 (GASP-1) was found to bind
to mature and LAP portions of myostatin. GASP-1 also inhibits
myostatin signaling as indicated by reporter gene analysis
(64). In agreement with these results, overexpression of GASP-
1 leads to muscle hypertrophy in mice (65). Furthermore, our
group has reconciled the role of GASP-1 as a positive regulator
of myogenesis by establishing it as a transcriptional target of
peroxisome proliferator-activated receptorb/d (PPARb/d). Spe-
cifically, our data revealed that PPARb/d positively regulated
myogenesis by enhancing the transcription of GASP-1, which
in turn abrogates myostatin activity during myogenesis (66).
Additionally, decorin, a leucine-rich repeat extracellular
proteoglycan, has been shown to interact with mature myosta-
tin, in a Zn21-dependent manner (67). This interaction was
demonstrated to relieve the inhibitory effect of myostatin on
myoblast proliferation in vitro. Recently, myostatin was found
to interact with another extracellular matrix protein, laminin,
and this interaction was able to inhibit myostatin signaling in
myoblasts (68). Laminins are large proteins present in basal
lamina and mutations in laminin are known to cause myopa-
thy. In a previous report, whereby laminin alpha 2-null mice
(dy) were crossed with mstn-null mice, an improvement in
muscle regeneration was observed; however, the pathology
due to loss of laminin was exacerbated (69). These results sug-
gest that while laminin can regulate myostatin activity, myo-
statin might not regulate or improve laminin function.
Myostatin
 Altogether, it is clear that myostatin levels are tightly regu-
lated through a combination of transcriptional, posttranscrip-
tional, epigenetic, and post-translational mechanisms.
Myostatin in Obesity and T2D
Recently, our understanding of function of myostatin outside
its conventional role in muscle growth is gaining momentum.
Early reports have shown that absence of myostatin affects
body metabolism leading to enhanced resistance to obesity
and improved sensitivity to insulin in both high fat fed (HFD)
mouse models and in genetically obese mice (18,70–72). More
recently, work from our laboratory has revealed that elevated
AMPK and PPAR signaling in myostatin-null muscle, as well as
enhanced COX-2-mediated prostaglandin synthesis, lead to the
improved insulin sensitivity, increased peripheral tissue fatty
acid oxidation and enhanced beige phenotype of white adipo-
cytes observed in myostatin-null mice upon HFD feeding
(19,20). However, elevated levels of myostatin have been
reported in both mice and humans suffering from obesity
(73,74). Allen et al., reported increased mRNA and protein lev-
els of myostatin in muscle and adipose tissues of leptin defi-
cient obese mice as well as in HFD fed wild type mice (73).
Furthermore, Hittel et al., reported higher levels of serum
myostatin and increased secretion of myostatin by myotubes
derived from muscle biopsies of obese women (74). In addition,
activation of myostatin signaling resulted in increased fat
accumulation in mice with subsequent muscle loss (75). Collec-
tively, these studies suggest that myostatin behaves as a cru-
cial factor in regulating whole body metabolism.
Palsgaard et al. for the first time reported higher mRNA
levels of myostatin in type 2 diabetic muscles as well as in
non-obese insulin resistant subjects (76). Later, Hittel et al.
reported that exogenous injection of myostatin elevates insulin
resistance in both muscle and liver of mice and that the levels
of myostatin decreased with aerobic exercise, thus improving
insulin sensitivity in humans (77). Moreover, inhibition of myo-
statin activity in liver protects from developing insulin resist-
ance upon HFD feeding in mice (70). Taken together, these
conclusions suggest that myostatin levels correlate with the
extent of insulin resistance with or without associated obesity.
However, these studies do not delineate the major signaling
mechanism behind myostatin-mediated insulin resistance.
Subsequent studies from our group have identified that
myostatin signals via smad3 to increase the expression of Casi-
tas B-lineage lymphoma b (Cblb) (Fig. 2a) in both muscle and
liver tissues (17). Cblb is an ubiquitin E3 ligase that has been
shown to specifically degrade insulin receptor substrate 1
(IRS1) protein in muscle. The myostatin-Cblb-IRS1 signaling
mechanism was further validated in both in vitro and in vivo
insulin resistance models (17). IRS1 is a critical mediator in
the insulin-signaling pathway (78–80); as such degradation of
IRS1 is associated with impairment in further activation of
PI3K/Akt/Glut-4 signaling. Consistent with this, activation of
SHARMA ET AL.
myostatin-Cblb signaling resulted in hypophosphorylation of
Akt, and subsequent development of insulin resistance (17).
Recent work from our lab has established myostatin as an
inducer of Phosphotyrosine Interaction Domain containing 1
(PID1) protein in human muscle cells (81). PID1 is well known
for its role in the development of insulin resistance in both
white adipocytes and murine C2C12 muscle cells (82,83).
Bonala et al. identified that myostatin signals via NF-jB to
activate PID1 gene transcription (Fig. 2a) and that myostatin
activation of PID1 affected the phosphorylation status of IRS1,
but not total IRS1 protein levels in human muscle cells (81).
The subsequent hypophosphorylation of IRS1 prevented fur-
ther PI3K/Akt/Glut-4 signaling resulting in reduced glucose
uptake by muscle cells (81). These results suggest that myosta-
tin can act as potent inducer of insulin resistance through both
Cblb- and PID1-mediated inhibition of insulin signaling.
Elevated serum levels and expression of myostatin have
also been observed in muscle from a streptozotocin-induced
type 1 diabetic mouse model. Interestingly, the levels of myo-
statin could be abrogated by administering insulin to the type
1 diabetic mice (84). However, results from this study indicate
a primary role for myostatin in promoting muscle atrophy in
type 1 diabetic mice, as opposed to regulating insulin
sensitivity.
Myostatin and Skeletal Muscle Wasting
Myostatin has been shown to play a causative role during skel-
etal muscle wasting. In fact, intramuscular injection of myosta-
tin protein producing and secreting CHO cells leads to the
induction of cachectic-like skeletal muscle wasting in mice
(16). Mechanistically myostatin-induced muscle wasting results
from both impaired protein synthesis and enhanced ubiquitin-
proteasome pathway-mediated protein degradation of critical
muscle-specific proteins (85–87). Specifically, work from our
lab has revealed that excess myostatin results in impaired
IGF-1/Akt/PI3K signaling, which resulted in enhanced activa-
tion of the transcription factor Forkhead box O1 (FoxO1; Fig.
2b). Myostatin-mediated activation of FoxO1 led to increased
expression of atrophy-related genes, including the Ubiquitin
E3 ligases Atrogin-1 and MuRF1 and enhanced protein ubiqui-
tination (Fig. 2(86)). A further study by Durieux et al., (2007)
revealed that over expression of myostatin in muscle resulted
in significant loss of skeletal muscle mass, which was associ-
ated with reduced expression of muscle structural genes,
including myosin heavy chain and desmin (88). More recently,
Lokireddy et al., (2011) have established that myostatin signals
in a smad3-dependent manner to activate FoxO1 and Atrogin-
1, to promote the ubiquitination and subsequent proteasome-
mediated degradation of sarcomeric proteins during muscle
wasting (85).
Results from our laboratory have also demonstrated that
myostatin facilitates translocation of the glucocorticoid recep-
tor to the nucleus during dexamethasone-induced muscle
wasting to induce the expression of miR-1 (58). It was further
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shown that subsequently miR-1 targets and represses HSP70,
leading to reduced p-Akt levels, enhanced FoxO3 activity and
upregulation of the Ubiquitin E3 ligases MuRF1 and Atrogin-1
(Fig. 2(58)). These results reveal a novel mechanism for
dexamethasone-mediated muscle wasting as well as a poten-
tial mechanism through which myostatin downregulates the
levels of p-Akt.
Myostatin and Chronic Obstructive
Pulmonary Disease (COPD)
COPD is characterized by obstruction of airflow, which not
only affects lung function but also has significant systemic con-
sequences. One of the secondary complications of COPD is pul-
monary cachexia, manifested as peripheral muscle dysfunc-
tion, respiratory muscle dysfunction and a loss of total body
mass. Approximately 30–40% of people with COPD undergo
muscle wasting. Consistent with this, Doucet et al., (2010)
noted increased expression of the ubiquitin proteasome E3
ligases Atrogin-1 and MuRF-1 in muscle of COPD patients
together with increased FoxO1 protein levels, when compared
with healthy controls (89). Another phenomenon that occurs in
patients suffering from COPD is the decline in oxidative muscle
phenotype, resulting in reduced energy output and increased
oxidative stress (90). In fact, cachectic COPD patients display
higher levels of oxidative stress as compared with noncachec-
tic COPD patients and healthy controls, at rest and following
physical exercise (91,92), as well as increased mitochondrial
reactive oxygen species production (93). The manifestations
associated with COPD progression, including increased protea-
somal activity and elevated oxidative stress, point to a possible
role for myostatin in COPD. Most certainly, myostatin has been
implicated in development of oxidative stress in skeletal mus-
cle through increasing TNF-a signaling, via a mechanism
involving NF-jB and NADPH oxidase (38). Interestingly, myo-
statin activation of TNF-a acts as a novel feed forward mecha-
nism to promote further production of myostatin (38). Several
additional studies support a role for myostatin during COPD-
induced muscle wasting. Myostatin expression has been shown
to negatively correlate with muscle strength during COPD (94).
Plant et al., (2010) have further shown increased expression of
myostatin as well as the Ubiquitin E3 ligases Atrogin-1 and
Nedd4 in the vastus lateralis muscle of COPD patients (95).
Furthermore, circulating myostatin levels are increased in the
serum of patients with COPD and correlate with decreased
skeletal muscle mass (13).
Myostatin and Liver Diseases
Chronic necrosis and inflammation of liver eventually results
in cirrhosis of the liver that in turn is compounded by loss of
skeletal muscle mass (96). Loss of muscle mass contributes to
weakness and frailty in cirrhotic patients, furthermore skeletal
muscle mass is not restored even after liver transplantation
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(96). Although loss of muscle mass has a detrimental effect in
liver cirrhosis patients, the mechanisms behind muscle loss
linked with liver diseases had until recently remained unex-
plored. Recent research indicates that myostatin is a key factor
involved in muscle wasting seen in patients with liver diseases.
Indeed, higher levels of circulatory myostatin were noted in
patients with end-stage liver disease (12). Increased myostatin
expression was also observed in skeletal muscle of patients
with cirrhosis (39,97). In cirrhosis urea metabolism gets dis-
turbed and as a result hyperammonemia is seen in muscle.
Qiu et al., (2013) recently demonstrated that hyperammonemia
induces NF-jB signaling leading to increased myostatin tran-
scription (39). Myostatin has also been implicated in muscle
wasting associated with post-transplantation of liver during
which, steroid therapy, mTOR inhibitors or calcineurin inhibi-
tors are used. Specifically, glucocorticoids and calcineurin
inhibitors are known to induce myostatin and hence are likely
to exacerbate muscle wasting in liver transplant patients
(98–100).
Myostatin and Chronic Kidney Disease
(CKD)
One of the comorbidities frequently noted in chronic kidney
disease is a rapid onset of muscle wasting. The loss of muscle
mass in these patients is marked by increased protein break-
down, insulin resistance, excessive glucocorticoid production,
and impaired p-Akt signaling. Work by Zhang et al., 2011 has
revealed a 2- to 3-fold increase in the expression of myostatin
in the muscles of mice with CKD (101). Subsequent pharmaco-
logical inhibition of myostatin, by subcutaneous injections of
an anti-myostatin peptibody, reversed the loss of body weight
and muscle mass and reduced the levels of circulating inflam-
matory cytokines in mice with CKD. Furthermore, antagonism
of myostatin led to reduced muscle protein degradation, con-
comitant with increased muscle protein synthesis (101). More
recently, Stat3-mediated induction of myostatin has been
implicated in promoting the muscle loss associated with CKD
(102). Specifically, Zhang et al., 2013 demonstrated that acti-
vation of Stat3 resulted in increased levels of myostatin, via a
mechanism involving the transcription factor CCAAT/
enhancer-binding protein d (C/EBPd) to stimulate skeletal mus-
cle loss during CKD (102). In another study, TNF-a induced
myostatin was alleged to activate autophagy related genes and
the ubiquitin proteosomal system in muscle of rats with CKD,
resulting in muscle wasting (103).
Myostatin and Cancer Cachexia
Cachexia is a multifactorial syndrome associated with chronic
disease that is accompanied by several symptoms including
loss of body weight, skeletal muscle loss, and wasting with
associated asthenia (loss of muscle strength), loss of body fat
and changes in lipid, carbohydrate and protein metabolism
Myostatin
(104,105). Cachexia is associated with many chronic diseases
including cancer and importantly cancer cachexia is exhibited
by 80% of all patients who possess advanced tumors of pan-
creatic, lung and gastric origin, and it is responsible for over
30% of cancer-related fatalities (106,107).
Myostatin is a secreted pro-cachectic growth factor that
promotes the development of cachectic-like skeletal muscle
wasting (16). Elevated levels of myostatin expression as well
as enhanced myostatin signaling have been shown to correlate
with the progression of cancer and cancer-associated cachexia
in several experimental models of cancer cachexia. Myostatin
mRNA and protein levels were increased in rats 7 days follow-
ing Yoshida AH-130 hepatoma tumor transplantation (108)
and in mice following inoculation with the S-180 mouse ascitic
tumor (109). In addition, transplantation of C26 adenocarci-
noma cells and LP07 lung tumor cells into mice also correlated
with elevated myostatin protein levels in skeletal muscle
(110–112). Increased serum and muscle-specific expression of
myostatin was further noted in a chemically induced model of
urothelial carcinogenesis (113). Further evidence for the role
of myostatin during cancer cachexia is provided through inhib-
itor studies. Liu et al. demonstrated that injection of antisense
RNA oligonucleotides targeted to myostatin into S-180 mouse
ascitic tumor inoculated mice resulted in decreased myostatin
expression and an associated increase in skeletal muscle mass
(109). Furthermore, antibody-mediated myostatin inhibition
prevented loss of muscle mass and muscle weakness associ-
ated with injection of Lewis lung carcinoma cells into mice
(114). Antagonism of myostatin signaling through addition of a
soluble receptor antagonist (sActRIIB) has also shown utility in
overcoming cancer associated cachexia. Addition of sActRIIB
in both mice injected with Lewis lung carcinoma and C26 cells
resulted in reversal of muscle wasting (112,115,116) and
improved muscle strength (112,116). In addition, prolonged
survival was noted in C26 tumor bearing mice administered
sActRIIB (112). In a recent report, genetic inactivation of myo-
statin in Apcmin/1 mice (a model of colorectal cancer) resulted
in a significant reduction in the number and size of intestinal
polyps and prevented loss of muscle mass (117). In the same
report, wildtype and myostatin-null (Mstn2/2) mice were
injected with Lewis lung carcinoma tumor cells (LLC); LLC
tumor growth was reduced and the expression of both MuRF1
and Atrogin-1 was inhibited in Mstn2/2 muscle, when com-
pared with wildtype controls. Another noteworthy observation
was the reduced protein levels of lipidated LC3b-II (an autoph-
agy related marker) in the muscle of LLC tumor bearing
Mstn2/2 mice when compared with LLC tumor bearing wild-
type mice, suggesting that loss of myostatin also prevents
induction of autophagy-related genes. With regards to autoph-
agy, the in vivo results seen here concur with the report by
Lee et al., (2011), wherein myostatin was shown to induce
autophagy in C2C12 myoblasts (118).
While several lines of evidence support a role for myosta-
tin in cancer-associated cachexia in rodents, the role of myo-
statin in cancer cachexia in humans remains less clear. A
SHARMA ET AL.
recent study by Aversa et al. has revealed that myostatin pro-
tein levels were increased in skeletal muscle from patients
with gastric cancer; although in the same study no change in
skeletal muscle myostatin protein levels were noted in patients
with lung cancer (10). A study by Sim et al. detected a signifi-
cant increase in myostatin expression in Central neurocytoma
tumor tissue when compared with healthy normal tissue (119).
Several subsequent articles have failed to show increased myo-
statin during cancer cachexia and in fact a study by D’orlando
et al. reports no change in myostatin mRNA expression in gas-
tric cancer patients, when compared with healthy individuals
(120), although no assessment of myostatin muscle protein lev-
els or serum levels were made. In a separate study, myostatin
mRNA was further assessed in gastric cancer patients, who
have minimal or no loss of muscle mass, and results revealed
a significant decrease in myostatin mRNA in muscle tissue
from gastric cancer patients (121). However, in this study, the
patients were at an early stage of cancer progression and it
was suggested that changes in myostatin may become appa-
rent as the cancer progresses. In a further study, Breitbart
et al. have described the use of an immunoradiometric sand-
wich assay to detect myostatin prodomain in patients with gas-
trointestinal or hepatic cancer undergoing acute weight loss.
Results revealed no increase, but a decrease, in myostatin pro-
domain levels in serum samples from cancer patients, when
compared with healthy controls (122). It is important to high-
light that this assay only detects the N-terminal myostatin pro-
domain, also referred to as the latency associated peptide
(LAP) region, and not the biologically active C-terminal mature
ligand of myostatin. As the prodomain acts as a potent antago-
nist of myostatin function (123) it remains to be determined
how lowered myostatin prodomain serum levels, as observed
in this cancer cachexia model, would in turn affect myostatin
biological activity.
Although evidence to date has clearly linked myostatin
with the progression of cancer-associated cachexia in rodent
models, additional studies should be undertaken using larger
samples sizes and well-stratified patients to fully characterize
myostatin function during cancer-cachexia in humans. Fur-
thermore, several molecular and biochemical techniques need
to be employed in these studies to carefully assess not only
myostatin gene expression changes but also myostatin protein
levels in tumor tissue, skeletal muscle and in circulation.
Nevertheless, recent clinical trials with myostatin inhibitors
(including LY2495655 and BYM-338) appear to be promising
in preserving muscle mass and thus offer hope of treatment
for cachetic patients (124).
Myostatin and Sarcopenia
Sarcopenia is the decline in skeletal muscle mass and function
associated with the normal aging process (125,126). Differen-
ces in the expression of myostatin have been described during
aging-related skeletal muscle wasting. myostatin mRNA has
been shown to decrease in aged rats (127,128), although
595

Baumann et al. noted increased myostatin protein levels dur-
ing aging (127). In a separate study, age-induced reduction of
skeletal muscle mass in rats was associated with increased
muscle-specific myostatin protein and mRNA expression (129).
However, in contrast, a study by Kawada et al. failed to show
age-related differences in skeletal muscle myostatin protein
levels in mice (130). Similar to the variations in myostatin
expression observed in rodent studies, decreased myostatin
mRNA expression (131), unaltered myostatin mRNA (132,133)
and serum levels (134) as well as increased myostatin mRNA,
protein and serum levels (14,15,135–137), have all been previ-
ously reported in humans during aging. More recently, work
by Patel et al. has revealed that myostatin mRNA expression is
reduced in aged individuals that have a higher grip strength,
suggesting that myostatin may play a role in regulating muscle
strength during aging (138).
The disparity between the findings from these different
rodent and human studies has complicated our understanding
of the role of myostatin during sarcopenia. The differences
observed in myostatin expression suggest that the effect of
myostatin during aging may be limited to specific stages of
sarcopenia, or more probably, that changes in myostatin activ-
ity cannot be directly implied from expression analysis alone.
Most certainly previous studies, as reviewed above, have
revealed that myostatin expression and activity is tightly regu-
lated at several levels, including transcriptionally, post-
transcriptionally and in circulation through the action of sev-
eral interacting proteins. Furthermore, it is established that
myostatin can in fact inhibit its own expression and activity
through negative feedback mechanisms involving smad7 (37)
and more recently microRNA-27a/b (44). Taken together these
data suggest that changes in myostatin expression observed
during aging may not be reflective of myostatin activity, or for
that matter myostatin function, during sarcopenia. This sug-
gests that a more robust approach should be undertaken,
involving a more complete assessment of both inactive and
active forms of myostatin, which can then be correlated to the
progression of sarcopenia.
That being said, further evidence underscoring the role of
myostatin during sarcopenia can be seen in studies on myosta-
tin-null (mstn-null) mice. Aged mstn-null mice maintain
increased muscle mass and myofibre area when compared
with aged wild type mice (139–141). Further work from our
lab revealed that the pool of muscle stem cells (SCs) was con-
sistently higher in mstn-null mice and although SC activation
declined during aging in both wildtype and mstn-null mice, a
higher proportion of active SCs was maintained in mstn-null
mice irrespective of age (140). Muscle from aged mstn-null
mice also regenerated more robustly when compared with
wildtype counterparts following both cardiotoxin and notexin-
induced injury (140,141). These data suggest that prolonged
absence of myostatin has beneficial effects during aging and
reduces the extent of sarcopenia.
Several additional studies have also assessed the effect of
postnatal myostatin inhibition on aging-associated muscle loss.
596
IUBMB LIFE
Work from our laboratory has shown that antagonism of myo-
statin through addition of a dominant negative mimetic protein
(Mstn-ant1) leads to enhanced muscle regeneration following
notexin injection, with accelerated nascent fiber formation,
reduced fibrosis, and increased myofibre size, when compared
with saline injected controls (142). Furthermore, treatment
with Mstn-ant1 resulted in increased SC activation and
enhanced grip strength in aged mice (142). Studies by LeBras-
seur et al. and Murphy et al. have assessed the utility of
antibody-mediated blockade of myostatin during aging in mice
(143,144). Myostatin inhibition resulted in increased muscle
mass and function in aged mice (143,144), with a noticeable
increase in muscle performance in response to exercise (144).
In addition, treatment of aged mice with a soluble form of the
myostatin receptor (ActRIIB-Fc) and recombinant myostatin
propeptide (Propeptide-Fc), both inhibitors of myostatin,
resulted in increased muscle mass (145,146) and function
(146) when compared with vehicle treated controls. Taken
together these data suggest that postnatal inactivation of myo-
statin may be an effective approach to overcome the loss of
muscle mass and function observed during sarcopenia.
Conclusions
Since the discovery of myostatin in 1997, considerable pro-
gress has been made in understanding myostatin function not
only in skeletal muscle but also in heart and adipose tissue.
Myostatin appears to be a versatile protein with a wide range
of functions (Figs. 2a and 2b); hence, exciting new develop-
ments are expected in myostatin research in the near future.
Acknowledgements
The authors thank all the researchers who have contributed to
myostatin research. They acknowledge the support of National
Research Foundation (NRF), and NMRC (BnB), Singapore.
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