Building muscle, browning fat and preventing obesity by inhibiting myostatin

Article (PDF Available)inDiabetologia 55(1):13-7 · November 2011with63 Reads
DOI: 10.1007/s00125-011-2361-8 · Source: PubMed
Abstract
The obesity epidemic is an overwhelming global health concern. Interventions to improve body weight and composition aim to restore balance between nutrient intake and energy expenditure. Myostatin, a powerful negative regulator of skeletal muscle mass, has emerged as a potential therapeutic target for obesity and type 2 diabetes mellitus because of the prominent role skeletal muscle plays in metabolic rate and insulin-mediated glucose disposal. In fact, inhibition of myostatin by genetic manipulation or pharmacological means leads to a hypermuscular and very lean build in mice. The resistance of myostatin-null mice to diet-induced obesity, fat mass accumulation and metabolic dysfunction has been presumed to be a result of their large skeletal muscle mass; however, in this issue of Diabetologia, Zhang et al. (doi: 10.1007/s00125-011-2304-4 ) provide evidence that myostatin inhibition also significantly impacts the phenotype of white adipose tissue (WAT). The authors reveal elevated expression of key metabolic genes of fatty acid transport and oxidation and, intriguingly, the presence of brown adipose tissue-like cells in WAT of myostatin-null mice. They also show that pharmacological inhibition of myostatin replicates several of the protective benefits conveyed by its genetic inactivation. Herein, these data, areas in need of further investigation and the evidence that implicates myostatin as a target for obesity and type 2 diabetes mellitus are discussed.

Figures

COMMENTARY
Building muscle, browning fat and preventing obesity
by inhibiting myostatin
N. K. LeBrasseur
Received: 8 September 2011 / Accepted: 4 October 2011 / Published online: 6 November 2011
#
Springer-Verlag 2011
Abstract The obesity epidemic is an overwhelming global
health concern. Interventions to improve body weight and
composition aim to restore balance between nutrient intake
and energy expenditure. Myostatin, a powerful negative
regulator of skeletal muscle mass, has emerged as a
potential therapeutic target for obesity and type 2 diabetes
mellitus because of the prominent role skeletal muscle plays
in metabolic rate and insulin-mediated glucose disposal. In
fact, inhibition of myostatin by genetic manipulat ion or
pharmacological means leads to a hypermuscular and very
lean build in mice. The resistance of myostatin-null mice to
diet-induced obesity, fat mass accumulation and metabolic
dysfunction has been presumed to be a result of their large
skeletal muscle mass; however, in this issue of Diabetologia,
Zhang et al. (doi:10.1007/s00125-011-2304-4) provide evi-
dence that myostatin inhibition also significantly impacts the
phenotype of white adipose tissue (WAT). The authors reveal
elevated expression of key metabolic genes of fatty acid
transport and oxidation and, intriguingly, the presence of
brown adipose tissue-like cells in WAT of myostatin-null
mice. They also show that pharmacological inhibition of
myostatin replicates severa l of the protective benefits
conveyed by its genetic inactivation. Herein, these data,
areas in need of further investigation and the evidence that
implicates myostatin as a target for obesity and type 2
diabetes mellitus are discussed.
Keywords ActRIIB
.
Adipogenesis
.
Brown fat
.
Diabetes
.
Fatty acid oxidation
.
Myostatin
.
Skeletal muscle
Abbreviations
ActRIIB Activin type IIB receptor
AMPK AMP-activated protein kinase
BAT Brown adipose tissue
sActRIIB Soluble decoy activin type IIB receptor
UCP Uncoupling protein
WAT White adipose tissue
Over two billion adults worldwide are obese or overweight
[1]; a statistic that reflects the widespread and fundamental
imbalance between energy consumed and energy expended.
Exercise is an effective and beneficial means to promote
energy utilisation in the battle against obesity [2]. However,
adoption of a more physically active lifestyle, much like
improved dietary habits, remains poor and underscores the
need for alternative interventions. In this issue of Diabetologia,
Zhang and colleagues offer additional support for myostatin
inhibition as a potential strategy to counter obesity, and reveal
an intriguing new mechanism by which it enhances energy
expenditure in mice [3].
Myostatin and the impressive double-muscled phe-
notype of myostatin-null mice were discovered by the
laboratory of Dr Se-Jin L ee in 1997 [4]. Myostatin (also
known as growth and differentiation factor 8 [GDF-8]) is a
member of the TGF-β superfamily. It is predominantly
produced in skeletal muscle where it actively suppresses
N. K. LeBrasseur (*)
Robert & Arlene Kogod Center on Aging, Mayo Clinic,
200 First Street SW,
Rochester, MN 55905, USA
e-mail: lebrasseur.nathan@mayo.edu
N. K. LeBrasseur
Department of Physical Medicine & Rehabilitation, Mayo Clinic,
Rochester, MN, USA
N. K. LeBrasseur
Department of Physiology & Biomedical Engineering,
Mayo Clinic,
Rochester, MN, USA
Diabetologia (2012) 55:1317
DOI 10.1007/s00125-011-2361-8
cell growth and differentiation by signalling through the
activin type IIB receptor (ActRIIB). Myostatin has been
highly conse rved across e volution [ 5] , and natural ly
occurring loss-of-function mutations augment skeletal
muscle growth in multiple species, including humans [6].
As a result, there has been great interest in developing
inhibitors of myostatin (e.g. antibodies, soluble decoy
ActRIIB [sActRIIB] and propeptides) to build and/or
regenerate skeletal muscle in the face of ageing (sarcopenia)
and disease (cachexia and degeneration) (for examples, see
[711]).
Skeletal muscle is the primary site of insulin-
mediated glucose disposal, the largest reservoir of
glycogen in the human body and a key determinant of
energy expenditure. Hence, several recent studies have
also investigated the effects of genetic and pharmaco-
logical inhibition of myostatin, and the resultant resis-
tance exercise-trained phenotype, on the prevention and
treatment of obesity and type 2 diabetes mellitus
(reviewedin[12, 13]). Similar to these reports, Zhang
and colleagues demonstrate that inhibition of myostatin
increases skeletal m uscle mass and prevents accumula-
tion of body weight, fat mass, and circulating concen-
trations of triacylglycerol causedbyhigh-fatfeeding[3].
However, while earlier studies have universally concluded
these benefits were secondary to the increase in skeletal
muscle, Zhang et al. show remarkable changes in the adipose
tissue of myostatin-null mice. Specifically, the authors
demonstrate that compared with wild-type mice, white
adipose tissue (WAT) of myostatin-deficient mice more
highly expresses key genes of lipid transport, synthesis,
hydrolysis and oxidation. They also measured an increase in
the expression of genes encoding transcription factors and
uncoupling proteins (UCP) that are more common to brown
adipose tissue (BAT). In fact, histological analysis of WAT
explants derived from myostatin-deficient mice revealed the
presence of BAT-like cells, defined by their relatively small
diameter, inclusion of multilocular lipid droplets and positive
staining for UCP-1. A phenotypic shift of WAT towards its
more metabolically active counterpart, BAT, is now
commonly referred to as browning or beiging.This
phenomenon is of particular interest to the fields of
obesity and type 2 diabetes mellitus because BAT is a
powerful energy-burning and heat-producing tissue that has
recently been confirmed to be present and active in adult
humans [1416]. Of note, Zhang et al. report myostatin-null
mice were C warmer than wild-type mice, and WAT
explants (as well as liver explants and cultures of primary
myotubes) from myostatin-null mice demonstrated higher
rates of fatty acid oxidation than wild-type mic e [3].
Collectively, these data suggest inactivation of myostatin
protects mice from diet-induced obesity not only because of
increased energy utilisation by a larger mass of skeletal
muscle, but also as a result of enhanced metabolic activity in
WAT and potentially in other tissues.
Importantly, from a therapeutic perspective, the
authors also show that pharmacological inhibition of
myostatin replicates several of the protective benefits
conveyed by its genetic inactivation. In the present
study, treatment of mice with sActRIIB (5 mg/kg, three
times per week) concurrent with 12 weeks of high-fat
feeding prevented the significant increases in body
weight, WAT depot weights and circulating triacylgly-
cerols observed in mice receiving vehicle. These data
corroborate those of Akpan et al. from a study in which
high-fat fed mice receiving sActRIIB for 10 weeks also
gained less fat mass and had lower glucose and
cholesterol concentrations compared with vehicle-
treated mice [17]. Zhang and colleagues a lso observed
that administration of sActRIIB prevented the significant
downregulation of key genes of uncoupling and oxidative
metabolism in WAT that was observed in vehicle-treated
mice in response to high-fat feeding. While ActRIIB binds
a broad repertoire of ligands, the similar phenotype
between myostatin-null and sActRIIB-treated mice sug-
gests inhibition of myostatin largely accounts for the
benefits observed. These data support the notion that
myostatin blockade may be a viable strat egy to prevent
obesity in h uma ns (illustrated in Figs 1 and 2). Whether or
not pharmacological inhibition of myostatin can also
attenuate the progression of or reverse obesity remains to
be determined.
It is plausible that myostatin inhibition improves the
gene expres sion pr ofil e and met abolic sta te of WAT
through direct and/or indirect mechanisms. With regard
to a direct mechanism, the prevention of myostatin and
other ActRIIB ligands from eliciting signals in adipo-
cytes, preadipocytes and/or mesenchymal stem cells
may have altered gene expression and/or cell differen-
tiation. In a very recent publication in Diabetologia,the
authors of the current study reported an increased
abundance and activity of the fuel-sensing enzyme
AMP-activated protein kinase (AMPK) in the adipose
tissue, liver and skeletal muscle of mice lacking myo-
statin [18]. While it is uncle ar how the absence of
myostatin stimulates AMPK signalling, it is a mechani sm
that would attenuate fatty acid synthesis and promote
fattyacidoxidationinWAT(reviewedin[19]). However,
the role of myostatin in adipogenesis is controversial and
the direct effects of myostatin inhibit ion on adipogenesis
have not been thoroughly studied. Moreover, a serious
challenge to the hypothesis that myostatin inhibition
directly affects WAT comes from an elegant study that
assessed whether targeted expression of a dominant
negative A ctRIIB in adipose tissue would prevent diet-
induced obesity and metabolic dysfunction [20]. The
14 Diabetologia (2012) 55:1317
results convincingly showed that there were no beneficial
effects of inhibiting myostati n signalling in adipose tissue
on weight gain, fat mass, adipocyte size, glucose homeostasis
or circulating leptin or triacylglycerol concentrations. In
contrast, muscle-specific expression of dominant negative
ActRIIB improved all of these variabless of body composition
and metabolism, suggesting that the adaptations in WAT
phenotype in response to myostatin inhibition are primarily
indirect and secondary to changes in skeletal muscle. A
growing body of evidence highlights skeletal muscle as a
prominent node in the powerful and complex cross-talk
between metabolically active tissues. For instance, mice
homozygous for a mutation in the myostatin gene are resistant
to diet-induced hepatic steatosis, elevations in in flamma tor y
cytokines and macrophage infiltration/activation in adi-
pose tissue and skeletal muscle compared with wild-type
and heter ozygous mi ce [21]. Postnatal blockade of
myostatin with a n eutralising antibody in o bese
insulin-resistant mice significantly improved glucose
homeostasis, lowered circulating triacylg lycerols and
increased circulating concentrations of the adipose
tissue-derived cytokine, adiponectin [17, 22]. The
absence of myostatin also appears to protect high-fat-
fed LDL receptor-null mice from dyslipidaemia and
atherogenesis, as LDL receptor/myostatin double knock-
out mice have decreased VLDL generation, improved
lipid profiles and reduced atherogenesis progression
[23]. In view of the coordinated responses of muscle,
liver, adipose tissue and the vasculature highlighted in
these models, it is likely that the benefits of myostatin
inhibition on WAT gene expression and metabolic activity
observed by Zhang et al. are predominantly indirect.
Nonetheless, the significant effect of myostatin inhibition
on the phenotype of WAT deserves further study. The
Fig. 1 Myostatin inhibition may be a strategy to prevent diet-induced
changes in body weight and body composition. High-fat feeding
increases body weight, fat mass and circulating concentrations of
leptin and triacylglycerols (TAGs) (illustrated in a). In mice, Zhang
and colleagues demonstrate that inhibition of myostatin signalling,
through delivery of a soluble ActRIIB decoy receptor (sActRIIB),
increases skeletal muscle mass and body temperature and minimises
the deleterious effects of nutrient excess. As illustrated in b, their
findings raise the poss ibility that in humans, pharmacol ogical
inhibition of myostatin and potentially other ActRIIB ligands may
prevent the development of obesity
Diabetologia (2012) 55:1317 15
possibility of a network of hormonal communication (e.g.
myokines) between skeletal muscle and adipose tissue, as
well as other metabolically important organs, is of
particular interest.
From a c linical perspective, there is a growing body
of clinical evidence to support myostatin blockade as a
therapeutic strategy for obesity and type 2 di abetes
mellitus. For example, increased myostatin production
and, more impressively, myostatin secretion has been
observed in skeletal muscle and adipose tissue samples
derived from obese and extremely obese women.
Increased circulating levels of myostatin in this cohort
were found to be correlated with insulin resistance [24].
In addition, the expression of the gene encoding m yostatin
(MSTN) in s keletal muscle of obese patients undergoing
gastric b ypass surgery was significantly decreased in
response to weight loss and associated with improved
insulin action [25, 26]. Increased expression of MSTN was
also recently detected in skeletal muscle biopsies of
healthy but at risk first-degree relatives of patients with
type 2 di abetes mellitus [ 27]. Collectively, these clinical
observations suggest t hat myostatin may contribute to
deleterious changes in body weight, body composition and
whole-body metabolism. Based on previous studies
referred to in this commentary and new insights from
Zhang and colleagues, myostatin inhibition may be a
strategy to enhance energy expenditure in the battle
against obesity and type 2 diabetes mellitus.
Fig. 2 Inhibition of myostatin improves the metabolic state of skeletal
muscle and adipose tissue. Diet-induced obesity leads to alterations in
the quantity and quality of skeletal muscle (top insets) and adipose
tissue (bottom insets). While several studies have shown that
myostatin inhibition leads to an increase in skeletal muscle mass and
fibre size (1) (untreated vs treated with sActRIIB), Zhang et al.
provide additional evidence in mice that suggest myostatin inhibition
may confer salutary effects on the metabolic state of skeletal muscle
and adipose tissue in humans. As illustrated, myostatin inhibition may
abrogate the accumulation of extra- and intramyocellular lipids (2) and
promote fatty acid oxida tion i n s keleta l muscle by preventing
reductions in the expression, abundance and activity of key mediators
of oxidative metabolism caused by high-fat feeding (3). Their data
also imply that diet-induced adipocyte hypertrophy (4), accumulation
of triacylglycerols (5) and infiltration of macrophages (6, illustrated in
a) in adipose tissue may be prevented by myostatin inhibition. Similar
to skeletal muscle, these salutary effects of inhibiting myostatin appear
to be mediated by the maintained expression, abundance and activity
of key mediators of fatty acid transport and oxidation in adipose tissue
in response to high-fat feeding. Intriguingly, Zhang and colleagues
also provide evidence that myostatin inhibition drives the browning
of WAT in mice, meaning, the appearance of energy consuming,
mitochondrial-rich and thermogenic brown fat-like cells (6, illustrated
in b). Collectively, these data obtained in mice provide further support
for myostatin inhibition as a potential means to prevent obesity and
type 2 diabetes mellitus in humans
16 Diabetologia (2012) 55:1317
Acknowledgements The author would like to thank Gu nther
Chanange from the Mayo Clinic Center for Innovation, for creating
the illustrations in this manuscript. This author would also like to
acknowledge the support of Mayo Clinic and a generous gift from
Robert and Arlene Kogod.
Contribution statement NK LeBrasseur was responsible for the
conception, writing and final approval of this article.
Duality of interest The author declares that there is no duality of
interest associated with this manuscript.
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    • "For this reason, myostatin blockade (e.g. antibodies, soluble decoy activin receptor type II B or propeptides) has been proposed as a therapeutic target for the treatment of muscular dystrophies , sarcopenia, cachexia and other muscle-wasting conditions (Lebrasseur 2012). The loss of functional myostatin not only increases muscle mass, but also decreases body fat accumulation. "
    [Show abstract] [Hide abstract] ABSTRACT: Skeletal muscle is the largest organ determining whole-body insulin sensitivity and metabolic homeostasis. Adaptive changes of skeletal muscle in response to physical activity include adjustments in the production and secretion of muscle-derived bioactive factors, known as myokines, such as myostatin, IL-4, 6, 7 and 15, myonectin, follistatin-like 1 or LIF. These myokines not only act locally in the muscle in an autocrine/paracrine manner, but also are released to the bloodstream as endocrine factors to regulate physiological processes in other tissues. Irisin, derived from the cleavage of FNDC5 protein, constitutes a myokine that induces myogenesis and fat browning (switch of white adipocytes to brown-fat-like cells) together with a concomitant increase in energy expenditure. Besides being a target for irisin actions, the adipose tissue also constitutes a production site of FNDC5. Interestingly, irisin secretion from subcutaneous and visceral fat depots is decreased by long-term exercise training and fasting, suggesting a discordant regulation of FNDC5/irisin in skeletal muscle and adipose tissue. Accordingly, our group has recently reported that the adipokine leptin differentially regulates FNDC5/irisin expression in skeletal muscle and fat, confirming the cross-talk between both tissues. Moreover, irisin secretion and function are regulated by other myokines, such as follistatin or myostatin, as well as by other adipokines, including fibroblast growth factor 21 (FGF-21) and leptin. Taken together, myokines have emerged as novel molecular mediators of fat browning and their activity can be modulated by adipokines, confirming the cross-talk between skeletal muscle and adipose tissue in order to regulate thermogenesis and energy expenditure. This article is protected by copyright. All rights reserved.
    Full-text · Article · Apr 2016
    • "Targeted deletion of the myostatin gene in mice (Mstn −/− ) reproduces the hypermuscular phenotype and results mainly from muscle fiber hyperplasia and also from hypertrophy [4] . Mstn −/− mice also display significant metabolic improvements including reduced adiposity, increased insulin sensitivity, and resistance to obesity111213. Myostatin is synthesized as a precursor protein, and following processing, mature myostatin is released as a 24- kDa covalent homodimer with its propeptide remaining non-covalently bound, forming an inactive latent complex [5]. "
    [Show abstract] [Hide abstract] ABSTRACT: Background: Loss of skeletal muscle mass and function in humans is associated with significant morbidity and mortality. The role of myostatin as a key negative regulator of skeletal muscle mass and function has supported the concept that inactivation of myostatin could be a useful approach for treating muscle wasting diseases. Methods: We generated a myostatin monoclonal blocking antibody (REGN1033) and characterized its effects in vitro using surface plasmon resonance biacore and cell-based Smad2/3 signaling assays. REGN1033 was tested in mice for the ability to induce skeletal muscle hypertrophy and prevent atrophy induced by immobilization, hindlimb suspension, or dexamethasone. The effect of REGN1033 on exercise training was tested in aged mice. Messenger RNA sequencing, immunohistochemistry, and ex vivo force measurements were performed on skeletal muscle samples from REGN1033-treated mice. Results: The human monoclonal antibody REGN1033 is a specific and potent myostatin antagonist. Chronic treatment of mice with REGN1033 increased muscle fiber size, muscle mass, and force production. REGN1033 prevented the loss of muscle mass induced by immobilization, glucocorticoid treatment, or hindlimb unweighting and increased the gain of muscle mass during recovery from pre-existing atrophy. In aged mice, REGN1033 increased muscle mass and strength and improved physical performance during treadmill exercise. Conclusions: We show that specific myostatin antagonism with the human antibody REGN1033 enhanced muscle mass and function in young and aged mice and had beneficial effects in models of skeletal muscle atrophy.
    Full-text · Article · Oct 2015
    • "In a cross-sectional study of younger, middle-aged and older men and women, the serum myostatin concentrations were shown to increase with age and were inversely correlated with skeletal muscle mass (Yarasheski et al. 2002 ). Obesity and insulin resistance increase expression of myostatin in skeletal muscle (Hittel et al. 2009 ; Allen et al. 2011 ) and adipose tissue samples obtained from obese and extremely obese women revealed elevated levels of circulating myostatin (LeBrasseur 2012 ). As a consequence of obesity, an increase in myostatin represents a risk for skeletal muscle health and systemic metabolism in older individuals (Sakuma et al. 2014 ). "
    [Show abstract] [Hide abstract] ABSTRACT: An age-dependent decline in skeletal muscle mass, strength, and endurance during the aging process is a physiological development, but several factors may exacerbate this process, leading to the threatening state of sarcopenia, frailty, and eventually higher mortality rates. Obesity appears to be such a promoting factor and has been linked in several studies to sarcopenia. The reason for this causal association remains poorly understood. Notwithstanding the fact that a higher body mass might simply lead to diminished physical activity and therefore contribute to a decline in skeletal muscle, several molecular mechanisms have been hypothesized. There could be an obesity derived intracellular lipotoxicity (i.e., elevated intramuscular levels of lipids and their derivatives), which induces apoptosis by means of an elevated oxidative stress. Paracrine mechanisms and inflammatory cytokines, such as CRP and IL-6 could be confounders of the actual underlying pathological mechanism. Due to a cross-talk of the hypothalamo-pituitary axis with nutritional status, obese subjects are more in a catabolic state of metabolism, with a higher susceptibility to muscle wasting under energy restriction. Obesity induces insulin resistance in the skeletal muscle, which consequently leads to perturbed metabolism, and misrouted signaling in the muscle cells. In obesity, muscle progenitor cells could differentiate to an adipocyte-like phenotype as a result of paracrine signals from (adipo)cytokines leading to a reduced muscular renewal capacity. The present review outlines current knowledge concerning possible pathways, which might be involved in the molecular pathogenesis of sarcopenic obesity.
    Full-text · Article · Nov 2014
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