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Medicine & Science in Sports & Exercise:
doi: 10.1249/MSS.0b013e3182178bb4
Basic Sciences

Expression and Function of Myostatin in Obesity, Diabetes, and Exercise Adaptation


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1Department of Integrative Physiology, University of Colorado, Boulder, CO; 2Faculty of Kinesiology, University of Calgary, Alberta, CANADA; and 3National Institute of Diabetes and Diseases of the Kidney, National Institutes of Health, Bethesda, MD

Address for correspondence: David L. Allen, Ph.D., Department of Integrative Physiology, University of Colorado, Boulder, CO 80309-0354; E-mail:

Submitted for publication November 2010.

Accepted for publication February 2011.

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Myostatin is a member of the transforming growth factor-β/bone morphogenetic protein (TGF-β/BMP) superfamily of secreted factors that functions as a potent inhibitor of skeletal muscle growth. Moreover, considerable evidence has accumulated that myostatin also regulates metabolism and that its inhibition can significantly attenuate the progression of obesity and diabetes. Although at least part of these effects on metabolism can be attributable to myostatin's influence over skeletal muscle growth and therefore on the total volume of metabolically active lean body mass, there is mounting evidence that myostatin affects the growth and metabolic state of other tissues, including the adipose and the liver. In addition, recent work has explored the role of myostatin in substrate mobilization, uptake, and/or utilization of muscle independent of its effects on body composition. Finally, the effects of both endurance and resistance exercise on myostatin expression, as well as the potential role of myostatin in the beneficial metabolic adaptations occurring in response to exercise, have also begun to be delineated in greater detail. The purpose of this review was to summarize the work to date on the expression and function of myostatin in obesity, diabetes, and exercise adaptation.

In 1997, hypermuscularity was described in mice carrying a targeted inactivation of a novel transforming growth factor-β/bone morphogenetic protein (TGF-β/BMP) family member, growth/differentiation factor 8 (GDF-8) (39). This gene was named myostatin for its ability to inhibit muscle differentiation and growth (39). Myostatin was subsequently identified as the mutated allele in the highly muscular Belgian Blue breed of cattle (12,23,40), and naturally occurring mutations have also been associated with an increase in muscle mass in dogs (45) and humans (59). Furthermore, mice in which myostatin protein processing or signaling is disrupted also exhibit increased muscle mass (36,70,73), whereas myostatin overexpression is associated with dramatic muscle atrophy in mice (53,74). Together, these studies have confirmed a central, critical role for myostatin in suppressing muscle growth.

The mechanisms by which myostatin achieves this suppression of muscle growth have been well defined. Like most TGF-β/BMP family members, myostatin is proteolytically cleaved in the endoplasmic reticulum into an amino terminal inhibitory prodomain and a carboxy terminal active domain (18). Secreted myostatin then circulates as an inactive multiprotein complex consisting of the carboxy dimer non-covalently bound to the prodomain and/or other inhibitory proteins such as follistatin and follistatin-like-3 (FSTL3) (7). The active myostatin dimer is freed from this inhibitory protein complex most likely by the tolloid and tolloid-like extracellular proteases located in the extracellular matrix of muscle and other tissues (68). Free myostatin then binds to the cell surface activin receptor type II or IIb (ActRII, ActRIIb), which in turn induces the phosphorylation of the SMAD family of transcription factors via the canonical TGF-β signaling pathway (52), although there is also evidence that myostatin can regulate muscle mass independent of SMAD signaling (50). Regardless of the pathway, myostatin inhibits muscle stem cell proliferation (61,62) and differentiation (29) and attenuates adult muscle fiber protein accretion (38,63,65) resulting in decreased skeletal muscle mass.

Because myostatin greatly influences skeletal muscle growth and therefore the total amount of metabolically active lean tissue, it can have profound effects on whole body metabolism. This in turn can have consequences for the development of obesity and diabetes. However, some recent work has suggested that myostatin may also affect substrate uptake and utilization independent of its effects on muscle mass. In addition, myostatin seems to have direct metabolic effects on tissues other than skeletal muscle, such as adipose and liver. This raises the possibility that the well-documented changes in myostatin expression in response to exercise training may modulate or in some way contribute to the beneficial effects of exercise through direct effects on skeletal muscle metabolic function as well as through effects on these other tissues.

The purpose of this review was to summarize the work to date on the expression and function of myostatin in obesity, diabetes, and exercise adaptation. Specifically, we will address two related questions regarding the influence of myostatin on metabolism: 1) Are the effects of myostatin signaling on the metabolism of nonmuscle tissues/cells (such as adipose or liver) direct because of myostatin signaling in these tissues or indirect because of myostatin signaling in muscle? 2) Are the effects of myostatin on metabolism due solely to its effects on cellular growth or can myostatin also influence cellular metabolism directly via changes in substrate mobilization, uptake, and/or utilization?

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Several lines of evidence demonstrate that obesity is associated with increased myostatin expression. Myostatin mRNA levels are increased in both adipose and skeletal muscle from genetically obese, leptin-deficient ob/ob mice and from wild-type mice fed a high-fat diet for 1 month (2). Muscle and circulating myostatin protein levels are also increased in obese human subjects, as is myostatin secretion from myotubes derived from myoblasts isolated from muscle biopsies of obese compared with nonobese women (19). Conversely, myostatin mRNA levels decrease during weight loss: myostatin mRNA levels were decreased in muscle and adipose from ob/ob mice on 2 wk of daily injection of recombinant leptin (2) and also decreased in muscle biopsies from obese human patients after weight loss due to either biliopancreatic diversion (42) or gastric bypass surgery (48).

Moreover, the experimental manipulation of myostatin expression or signaling can dramatically affect the development of obesity in mice. For example, muscle-specific overexpression of myostatin caused a decrease in muscle mass and an increase in epididymal fat pad mass (53). Conversely, several studies have shown that inactivation of myostatin can attenuate the development of obesity in mice. Crossing myostatin null mice with genetically obese ob/ob or agouti lethal yellow mice attenuated the increased adipose mass, hyperglycemia, hyperlipidemia, and hyperinsulinemia typically observed in these genetically obese animals (41). Postnatal transgenic overexpression of the inhibitory myostatin prodomain in mice also increased muscle growth and attenuated the effects of 2 months of a high-fat diet on increasing adipose mass and circulating insulin and glucose levels (71,72). Injection of mice with a soluble ActRIIb receptor, which disrupts signaling for myostatin and related TFG-β family members by binding them and preventing them from binding to the endogenous cell surface ActRIIb receptor, increased muscle mass and decreased fat mass in mice fed either standard chow or a high-fat diet (1). Taken together, these studies clearly demonstrate that the inhibition of myostatin signaling can greatly attenuate the development of obesity and its adverse health consequences in mice.

The antiobesogenic effects of myostatin inactivation raise the important question of whether this may be due to its direct effects on adipocyte hypertrophy or hyperplasia. In fact, several lines of evidence suggest that adipocytes may respond directly to myostatin signaling. First of all, adipocytes express the ActRIIb receptor both in vitro (52) and in vivo (2). Furthermore, ActRIIb mRNA expression is increased dramatically in adipocytes of ob/ob mice (2), suggesting that myostatin signaling may be increased in adipocytes in the obese state. However, levels of both myostatin and ActRIIb mRNA in adipose of obese mice remained several orders of magnitude lower than their levels in skeletal muscles of lean or obese mice (2), which suggests that this expression may be too low to evoke biologically meaningful responses in adipose.

Nevertheless, functional studies have shown that myostatin treatment influences adipocyte differentiation in vitro. Myostatin treatment inhibits adipogenic differentiation of the 3T3-L1 cell line and of human bone marrow-derived mesenchymal cells in vitro (14,24,52). In addition, although myostatin treatment promoted the commitment of C3H 10T1/2 mesenchymal cells to an adipogenic lineage in vitro (4,10), it produced smaller, more immature adipocytes (10). Similarly, adipose-specific transgenic overexpression of myostatin in vivo also resulted in decreased adipocyte size in vivo, although body composition was unchanged (10). However, these mice were resistant to dietary obesity due to increased energy expenditure (10). Together, these studies have suggested that myostatin may directly inhibit differentiation and/or growth of adipocytes, although this is counter to the beneficial effects of myostatin inactivation on obesity. Moreover, although these studies have demonstrated that treating adipocyte precursors in culture with myostatin, or exogenously elevating myostatin expression within adipose via transgenic means, is sufficient to decrease adipocyte size in vitro and in vivo, they do not address whether changes in endogenous myostatin expression or activity are necessary for and/or contribute to the progression of obesity.

A recent study has more directly addressed this issue. Specifically, adipose versus muscle-specific promoters were used to drive expression of a dominant negative ActRIIb gene construct to inhibit myostatin signaling to assess the relative contributions of myostatin inhibition in these two tissues to the progression of dietary obesity. Mice with muscle-specific inhibition of myostatin signaling fed a standard diet had greater muscle mass and decreased adipose depot weights and adipocyte size compared with wild-type mice. Furthermore, they gained significantly less weight and had lower fasting blood glucose, insulin, resistin, leptin, and triglycerides in response to 10 wk on a high-fat diet compared with wild-type mice (13). In contrast, mice with adipose-specific inhibition of myostatin signaling showed no alterations in lean or fat mass and no changes in circulating glucose, insulin, or adipokine levels on either a standard or a high-fat diet compared with wild-type mice (13). These data strongly suggest that the beneficial effects of myostatin inhibition on attenuating the adverse consequences of dietary obesity stem predominantly from its effects on skeletal muscle.

A study by Bernardo et al. (6) supports the hypothesis that myostatin inhibition attenuates the adverse metabolic consequences of obesity primarily through its effects on muscle and not through changes in adipose growth. Injection of ob/ob mice with a neutralizing antibody to myostatin decreased serum glucose and fatty acid levels; these changes were accompanied by increases in muscle mass, energy expenditure, and habitual activity levels but were not associated with a change in adipose mass (6). Also consistent with the interpretation that myostatin does not affect adipocyte size via direct changes in fat storage is work showing that administration of recombinant myostatin had no effect on lipid release in adipocytes in vitro or on fat mass in mice in vivo (60).

Thus, the emerging consensus is that the majority of the beneficial effects of myostatin inhibition on limiting the negative metabolic consequences of obesity seem to be an indirect consequence of the loss of myostatin signaling in skeletal muscle. Whether this is a result of increased muscle mass alone or is a result of other changes downstream of myostatin signaling in muscle that affect metabolism is not clear. Muscular transgenic mice overexpressing genes in the insulin-like growth factor signaling pathway under control of muscle-specific promoters also have decreased adiposity and improved metabolic parameters (22), suggesting that the increase in muscle mass caused by myostatin inhibition alone may account for the resistance to adipose tissue accumulation found in animals with myostatin inhibition in muscle. Specifically, the improvements in blood glucose, insulin, and/or fatty acid levels with myostatin inactivation may simply reflect an increase in substrate partitioning toward this greater lean muscle mass. In summary, the direct effects of myostatin on adipose growth and metabolism seem to be minimal, at least in the presence of adequate nutrition, and likely produce only a minor contribution to the changes occurring during the obese state.

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Recent evidence suggests that myostatin may play a role in the development of diabetes in addition to, and perhaps independent of, its effect on obesity. For instance, gene chip analysis revealed that myostatin mRNA levels were elevated in skeletal muscle biopsies from type 2 diabetics as well as from nonobese but hyperinsulinemic relatives of type 2 diabetics (47). In addition, both muscle and plasma myostatin protein levels in insulin-resistant middle-aged men were decreased by aerobic exercise training and were strongly correlated with insulin sensitivity (20). These subjects experienced decreases in circulating myostatin, insulin, and glucose levels that were not accompanied by any change in fat mass or body mass index after exercise training, strongly suggesting that these changes were not secondary to a change in adipose mass (20). Furthermore, Bernardo et al. (6) showed improvements in fed and fasted blood glucose levels without any change in adipose mass in ob/ob mice injected for 6 wk with a neutralizing antibody to myostatin. Lastly, injection of recombinant myostatin decreased insulin sensitivity in healthy male mice (20) and in mice harboring a loss-of-function mutation to myostatin on a high-fat diet (67) without a corresponding change in body mass in either study. Together, these studies have suggested that increased myostatin expression is inversely related to insulin sensitivity independent of obesity status.

These mice receiving short-term injections of recombinant myostatin in these latter two studies had decreased insulin sensitivity not only in the absence of a change in adipose mass but also in the absence of a change in muscle mass (20,67). This suggests that myostatin might directly regulate skeletal muscle glucose uptake or utilization independent of its effects on muscle mass. In this regard, myostatin has been found to directly influence glucose uptake and utilization in a cell-specific manner. For instance, myostatin treatment inhibited glucose uptake of BeWo cells, a choriocarcinoma cell line (3) yet increased glucose uptake by human placental tissue (43). Furthermore, myostatin treatment increased glucose uptake and glycolysis and inhibited glycogen synthesis in cultured skeletal muscle cells in vitro via an AMP kinase-dependent mechanism (8). The findings that myostatin increases muscle glucose uptake and glycolysis are at odds with the previously described inverse relationship between myostatin levels and insulin sensitivity, and it is not clear to what extent these in vitro results reflect the state of muscle glucose uptake in vivo. Regardless, these data suggest that myostatin may influence circulating glucose levels via direct effects on glucose uptake independent of its effects on muscle growth.

Myostatin might also affect glucose uptake indirectly through its effects on TNF-α expression, which can antagonize the effects of insulin on glucose uptake (44). A loss-of-function myostatin mutation in mice increased glucose tolerance and protected against insulin resistance in response to a high-fat diet and decreased circulating TNF-α levels as well as TNF-α mRNA levels in both muscle and adipose (67). Conversely, treatment with recombinant myostatin increased systemic TNF-α levels in myostatin mutant mice on a high-fat diet and resulted in greater insulin resistance (67).

A final question related to myostatin's role in regulating systemic glucose metabolism centers on the effects of myostatin on the liver. Increased hepatic gluconeogenesis is a consequence of hepatic insulin resistance and contributes to elevated blood glucose levels in type 2 diabetics (55), and several studies have shown that myostatin seems to modulate hepatic insulin resistance and/or glucose production. For instance, injection of mice with a recombinant soluble ActRIIb receptor increased hepatic insulin sensitivity (1). Similarly, mice homozygous for a myostatin loss-of-function mutation fed a high-fat diet had reduced hepatic steatosis and increased insulin-dependent suppression of hepatic glucose production compared with wild-type mice (67).

It is possible that these effects of myostatin on liver glucose metabolism are indirect because of the favorable effects of muscularity on energy partitioning. However, the inactivation of the gene for the myostatin binding and inhibitory protein FSTL3, which would be expected to increase myostatin activity, resulted in greater hepatic steatosis and hypertension in mice in the absence of any change in muscle mass (46). Furthermore, injection of recombinant myostatin in wild-type mice on a standard diet decreased insulin-stimulated hepatic Akt phosphorylation without affecting muscle or adipose mass (20), suggesting that insulin signaling might be directly inhibited by myostatin in the liver. In addition, there is evidence that the liver may be directly responsive to myostatin signaling. The mouse liver as well as cultured mouse and human liver cell lines are responsive to activin, which binds to the same receptors as myostatin (7,69). Consistent with this, myostatin administration can induce reporter gene activity in the HepG2 hepatocyte cell line in vitro (54).

Thus, several lines of evidence suggest that myostatin may influence liver function. A key question is whether the liver is capable of activating the latent myostatin complex. Future studies in which myostatin signaling has been selectively inactivated or overexpressed in the liver will directly address these issues.

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Studies that have examined the relationship between myostatin expression and endurance exercise adaptation have generally demonstrated changes in myostatin expression complementary to those observed with obesity and/or diabetes, i.e., endurance exercise training is usually characterized by a decrease in myostatin expression. For example, myostatin mRNA levels were decreased by more than half in gastrocnemius and vastus lateralis muscles 24 h after the last bout of a 5-d swim training regimen in rats (34). Similarly, 9 wk of cycling endurance exercise training decreased by over half myostatin mRNA levels from vastus muscle biopsies taken immediately after exercise from human hemodialysis patients (28). Myostatin mRNA levels decreased by approximately half in vastus lateralis muscle biopsies taken from older women 48 h after the final bout of a 12-wk training regimen of cycle ergometry (27). Moreover, as mentioned above, muscle and plasma myostatin protein levels decreased after 6 months of low-intensity aerobic training in prediabetic male subjects (20).

Myostatin mRNA levels seem to be decreased in response to a single bout of endurance exercise training as well. Myostatin mRNA levels were decreased approximately three- to fourfold in gastrocnemius biopsies 8 and 12 h after a single bout of running for 30 min at 75% V˙O2max in physically active men and women (16) and were similarly decreased approximately threefold in soleus and vastus lateralis biopsies taken 4 h after, but were not altered 24 h after, a running bout of 45 min at 75% V˙O2max in trained men (33). Together with the results above, these data suggest that a decrease in myostatin expression is a hallmark of both the response to chronic exercise training as well as to a single bout of endurance exercise.

Some recent studies suggest that transgenic myostatin inactivation decreases endurance exercise performance in untrained mice. Untrained myostatin null mice show a 38% lower work output in an involuntary treadmill run to exhaustion compared with untrained wild-type mice (58) and a reduced swim time to exhaustion (37) compared with wild-type mice. In addition, inducible postnatal myostatin deletion in muscle decreased voluntary wheel running primarily through a decrease in nightly running bout number (49).

The reasons for the decreased endurance performance in myostatin null mice have not been definitively established, but two explanations have been postulated. First, myostatin null mice have a greater percentage of fast/glycolytic fibers compared with wild-type mice (11,17), and thus the decrease in endurance exercise performance with myostatin inactivation may reflect the greater percentage of fatigable fast-twitch glycolytic fibers in the untrained state. Consistent with this interpretation, Matsakas et al. (37) demonstrated that blood lactate levels were significantly elevated 1 and 8 min after a swimming bout in myostatin null mice compared with wild-type mice. Second, the greater skeletal muscle fiber cross-sectional area of untrained myostatin null mice compared with wild-type mice (39) may adversely affect diffusion of oxygen or energy substrates into the contracting muscles in the untrained state.

Despite their poorer endurance performance before exercise, myostatin null mice nevertheless are able to increase comparably to wild-type mice activity of the mitochondrial enzymes citrate synthase in response to run training (58) and succinate dehydrogenase in response to swim training (37), respectively. Myostatin null mice also underwent a similar IIb-to-IIa shift in myosin heavy chain expression as wild-type mice in response to wheel running training (37). Thus, myostatin inactivation does not adversely affect the contractile and metabolic fiber-type adaptations accompanying endurance exercise training. Moreover, any differences in posttraining performance do not seem to be driven by an inability of myostatin inactivated animals to carry out normal fiber-type shifts and/or increases in muscle oxidative potential with endurance training. On the other hand, plantaris muscle fiber cross-sectional areas were significantly increased in wild-type mice but actually decreased in myostatin null mice in response to 5 wk of voluntary wheel running training (37). These authors suggested that the decrease in fiber cross-sectional area in myostatin null mice may have contributed to their decreased endurance exercise performance relative to wild-type mice by decreasing power output per unit time (37).

Interestingly, myostatin inhibition through injection of a myostatin-neutralizing antibody potentiated exercise performance when combined with endurance exercise training in older mice. Whereas 4 wk of injection of a myostatin-neutralizing antibody without daily treadmill training had no effect on treadmill performance parameters in 24-month-old mice, myostatin inhibition combined with treadmill training actually increased treadmill run time and distance to exhaustion compared with untrained control mice and trained mice not injected with the antimyostatin antibody (30). This improvement in exercise function may reflect the effects of myostatin inhibition on attenuating sarcopenia, the age-associated loss in muscle mass, resulting in decreased muscle mass loss with age that allowed these older animals to maintain greater power output during exercise. Consistent with this, although the antimyostatin treatment in these aged mice increased muscle mass by <15%, it attenuated the loss in muscle mass due to aging alone (30). In addition, unlike myostatin null mice (11), adult mice treated with antimyostatin approaches do not undergo an increase in glycolytic fiber types compared with untreated mice (15,35), and this too may have allowed these mice to improve their endurance exercise performance in contrast to the decrement in performance demonstrated for myostatin null mice. Future experiments will need to explore separately the effects of age and adult-onset myostatin inhibition on exercise performance to better delineate the effects of myostatin inhibition on endurance exercise performance.

A final point of relevance to the effects of myostatin on endurance exercise performance concerns the expression and function of myostatin in the heart, but here the results have not been consistent. Myostatin is expressed in the heart (5), and myostatin mRNA levels were increased approximately twofold in the heart by 4 wk of swim training five times per week at 90 min per bout in rats (35). However, 4 wk of twice-daily 30-min treadmill running had no effect on cardiac myostatin protein levels in rats (32). At present, it is not clear whether the conflicting results of these two studies reflect the differences in exercise modality or in mRNA versus protein evaluation used between the two studies. In addition, the function of myostatin in cardiac adaptations to endurance exercise is not clear. Cardiac-specific overexpression of myostatin decreased whereas myostatin inactivation increased heart mass and left ventricular mass in mice, but neither affected resting cardiac ejection fraction in otherwise healthy mice (5). At present, the interaction between myostatin inactivation and endurance exercise adaptation on cardiac size or function has not been addressed, specifically whether myostatin inactivation affects the physiological hypertrophy of the heart associated with endurance exercise training.

In summary, a decrease in myostatin expression in muscle seems to be a hallmark of endurance exercise training in mice and in humans. Interestingly, lifelong myostatin inactivation limits aerobic exercise performance in mice, possibly because of a larger proportion of glycolytic fibers and larger fiber size in untrained myostatin null mice, whereas myostatin inactivation combined with exercise training in older adult mice seems to increase endurance exercise performance. Moreover, myostatin inactivation does not prevent mice from undergoing the slow-to-fast fiber-type transitions accompanying endurance exercise training but reverses the increase in fiber size with endurance training, which may in turn decrease fiber power output.

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Myostatin inhibition could be considered a resistance exercise mimetic in that myostatin inactivation results in dramatic muscle hypertrophy. Because of this well-characterized effect of myostatin inhibition on muscle mass, it is plausible that a reduction in myostatin expression or function might be required for muscle to hypertrophy in response to resistance exercise. Indeed, several studies have shown that resistance exercise produces a significant decrease in skeletal muscle myostatin mRNA expression. Moreover, like endurance exercise training, this decrease seems to be a hallmark of both chronic (after a training regimen) versus acute (after a single bout) resistance exercise. For example, a 37% decrease in myostatin mRNA in the vastus lateralis of the dominant leg was observed in biopsies taken from young and old men and women 48-72 h after the final bout of a 9-wk heavy-resistance unilateral knee extension training program using a pneumatic resistance machine on which subjects trained 3 d·wk−1 completing 50 repetitions performed at near-maximal resistance (56). With respect to an acute bout of resistance exercise training, Raue et al. (51) observed a 2.2-fold decrease in myostatin mRNA in biopsies of young and old women taken 4 h after a single bout of three sets of 10 repetitions of 70% maximum knee extension, whereas Kim et al. (25) reported a 44% decrease in myostatin mRNA levels in biopsies taken 24 h after a single bout of knee extensor resistance exercise in young and old male and female subjects.

A decrease in myostatin levels in muscle, however, has not been found in all studies on resistance exercise. Willoughby (66) demonstrated a significant increase in muscle myostatin mRNA and protein in the vastus as well as an increase in serum myostatin protein levels in muscle biopsies and blood samples taken 15 min after the final bout of a 6- or 12-wk lower limb resistance training program involving three weekly bouts of three sets of six to eight repetitions of 85%-90% of one-repetition maximum of leg press and knee extension. Also, myostatin mRNA levels were not changed in vastus biopsies taken 4 h after a single bout of leg extension exercise in either endurance- or resistance-trained subjects (9). The reason for the discrepancy between these studies and the ones described above is not clear but may reflect variations in the training regimens used in terms of rest, repetition number, contraction intensity, training status, and others, as well as differences in biopsy sampling time (48-72 h vs 15 min to 4 h after exercise) between the two studies. Consistent with the fact that choice of sampling time may greatly influence interpretation of postexercise myostatin expression data, Hulmi et al. (21) demonstrated that myostatin mRNA levels were not significantly affected 1 h after the final bout of a 21-wk knee flexion and extension resistance training regimen but were significantly decreased 48 h after exercise.

Other authors have attempted to determine whether systemic myostatin protein levels are changed by resistance training. Walker et al. (64) showed that plasma myostatin protein levels were decreased by approximately 20% by Western blot in subjects after 10 wk of two daily bouts of either elbow flexor exercise or whole-body exercise, although they did not differ between the two exercise paradigms. Saremi et al. (57) also reported a modest but significant 10% decrease in serum myostatin levels by enzyme-linked immunosorbent assay after 12 wk of arm and leg press resistance training that was potentiated by creatine supplementation. However, Kim et al. (26) recently reported no change in serum myostatin levels by Western blot after 16 wk of knee extensor resistance training and reported high variability in serum myostatin levels even between untrained subjects. The differences between these studies may reflect differences in sampling time after training and/or after bout as well as the confounding effects of differences in myostatin efflux and/or clearance from the systemic circulation between-subjects or between-exercise paradigms. Thus, neither does it seem that circulating myostatin levels alone can be used as a reliable quantitative marker for training status nor do they seem to accurately reflect the mass of exercised muscle.

In summary, the effects of resistance exercise on myostatin expression seem to depend on aspects of the training regimen as well as the sampling time examined and may differ in either timing or magnitude for muscle mRNA versus muscle protein versus serum protein. Moreover, the exact role of changes in myostatin expression in response to resistance exercise is not clear. For example, an experiment in which myostatin-overexpressing transgenic mice are resistance exercise trained to determine whether myostatin inhibits resistance-induced hypertrophy has not been carried out. But in a recent cluster analysis on resistance-trained humans, whereas myostatin mRNA levels significantly decreased in muscle biopsies 24 h after a single knee extensor resistance exercise bout and 24 h after completing the final bout of a 16-wk training regimen, the decrease was the same for nonresponders, modest responders, and extreme responders with respect to changes in muscle fiber size, suggesting that the magnitude of decrease in myostatin expression was not associated with greater hypertrophic growth in response to resistance training (26). Thus, it is not clear to what extent decreases in myostatin expression may be a prerequisite for the muscle fiber hypertrophy accompanying resistance training in humans.

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Since its discovery in 1997, a vast wealth of studies have supported a strong central role for myostatin in the regulation of muscle growth. In addition, much research has established that myostatin has profound effects on metabolism and may promote the progression of obesity and diabetes. In contrast, aerobic exercise attenuates myostatin expression, and myostatin inactivation seems to potentiate the beneficial effects of endurance exercise on metabolism. Many of these effects seem to be indirect consequences of the effects of myostatin inhibition on skeletal muscle growth, increasing the lean tissue metabolic platform available for glucose and fatty acid uptake and utilization. However, myostatin seems to also have effects on skeletal muscle as well as other nonmuscle tissues (adipose, liver) that may modulate metabolism independent of or in addition to its effects muscle growth. Future studies will need to explore in more depth the contribution of direct versus indirect effects of myostatin on these nonmuscle tissues.

Furthermore, some strategies for myostatin inhibition, such as FSTL3 and soluble ActRIIb treatment, likely inhibit other TGF-β ligands in addition to myostatin. Several lines of evidence demonstrate that myostatin is not the only TGF-β family member that can inhibit muscle mass. Compared with wild-type mice, myostatin null mice expressing a follistatin transgene in muscle have an even greater increase in muscle mass than myostatin null mice, up to 4-fold compared with 2- to 2.5-fold, respectively (31). Different methods of inhibition may therefore have differing effects on metabolism because of their differing effects on substrates other than myostatin. This is not simply an academic question; pharmaceutical therapies targeting myostatin inactivation to prevent muscle atrophy will need to consider possible metabolic consequences of myostatin inactivation on other tissues and the nonspecific effects of different modes of myostatin inactivation so as to minimize potentially unwanted adverse effects. Given the effects observed in mice, the pharmaceutical potential of myostatin inhibitors is huge. Most current efforts have focused on the development of myostatin inhibitors to alleviate muscle atrophy in response to clinical wasting or prolonged muscle unloading, but clearly the beneficial effects of myostatin inhibition on metabolism and attenuation of obesity and diabetes represent another highly lucrative avenue of exploration, particularly given the poor track record of many diabetes drugs in decreasing myocardial infarction risk.

Future studies will undoubtedly refine and extend our current understanding of myostatin's roles, both direct and indirect, in metabolism. Although the initial observations of the effects of global myostatin inactivation on the development of obesity and diabetes were obviously critical to our understanding of myostatin's role in these processes, more recent studies using tissue-specific myostatin inactivation have greatly advanced our understanding of the relative contribution of myostatin's effects on skeletal muscle and its effects on adipose. Future/additional studies using neutralizing antibodies, or inducible, tissue-specific transgenics, will allow researchers to explore the role of myostatin in obesity, diabetes, and exercise adaptation without the confound of its effect on prenatal and/or early postnatal development. These and other elegant studies will greatly expand our knowledge of myostatin's role in regulating metabolism.

Part of this work was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases. D.L.A. was supported by an National Institutes of Health K01 grant from the National Institute of Arthritis, Musculoskeletal Diseases, and Stroke. D.S.H. was supported by a Discovery Grant from the Natural Sciences and Engineering Research Council of Canada. Under a licensing agreement between MetaMorphix, Inc. (MMI) and the Johns Hopkins University, A.C.M. is entitled to a share of royalty received by the university on sales of myostatin. A.C.M. and the university own MMI stock, which is subject to certain restrictions under university policy. The terms of these arrangements are being managed by Johns Hopkins University in accordance with its conflict of interest policies.

The results of the present study do not constitute endorsement by the American College of Sports Medicine.

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1. Akpan I, Goncalves MD, Dhir R, et al. The effects of a soluble activin type IIB receptor on obesity and insulin sensitivity. Int J Obes (Lond). 2009;33(11):1265-73.

2. Allen DL, Cleary AS, Speaker KJ, et al. Myostatin, activin receptor IIb, and follistatin-like-3 gene expression are altered in adipose tissue and skeletal muscle of obese mice. Am J Physiol Endocrinol Metab. 2008;294(5):E918-27.

3. Antony N, Bass JJ, McMahon CD, Mitchell MD. Myostatin regulates glucose uptake in BeWo cells. Am J Physiol Endocrinol Metab. 2007;293(5):E1296-302.

4. Artaza JN, Bhasin S, Magee TR, et al. Myostatin inhibits myogenesis and promotes adipogenesis in C3H 10T(1/2) mesenchymal multipotent cells. Endocrinology. 2005;146(8):3547-57.

5. Artaza JN, Reisz-Porszasz S, Dow JS, et al. Alterations in myostatin expression are associated with changes in cardiac left ventricular mass but not ejection fraction in the mouse. J Endocrinol. 2007;194(1):63-76.

6. Bernardo BL, Wachtmann TS, Cosgrove PG, et al. Postnatal PPARdelta activation and myostatin inhibition exert distinct yet complimentary effects on the metabolic profile of obese insulin-resistant mice. PLoS One. 2010;5(6):e11307.

7. Chen W, Woodruff TK, Mayo KE. Activin A-induced HepG2 liver cell apoptosis: involvement of activin receptors and smad proteins. Endocrinology. 2000;141(3):1263-72.

8. Chen Y, Ye J, Cao L, Zhang Y, Xia W, Zhu D. Myostatin regulates glucose metabolism via the AMP-activated protein kinase pathway in skeletal muscle cells. Int J Biochem Cell Biol. 2010;42(12):2072-8.

9. Coffey VG, Shield A, Canny BJ, Carey KA, Cameron-Smith D, Hawley JA. Interaction of contractile activity and training history on mRNA abundance in skeletal muscle from trained athletes. Am J Physiol Endocrinol Metab. 2006;290(5):E849-55.

10. Feldman BJ, Streeper RS, Farese RV Jr, Yamamoto KR. Myostatin modulates adipogenesis to generate adipocytes with favorable metabolic effects. Proc Natl Acad Sci U S A. 2006;103(42):15675-80.

11. Girgenrath S, Song K, Whittemore LA. Loss of myostatin expression alters fiber-type distribution and expression of myosin heavy chain isoforms in slow- and fast-type skeletal muscle. Muscle Nerve. 2005;31(1):34-40.

12. Grobet L, Martin LJ, Poncelet D, et al. A deletion in the bovine myostatin gene causes the double-muscled phenotype in cattle. Nat Genet. 1997;17(1):71-4.

13. Guo T, Jou W, Chanturiya T, Portas J, Gavrilova O, McPherron AC. Myostatin inhibition in muscle, but not adipose tissue, decreases fat mass and improves insulin sensitivity. PLoS One. 2009;4(3):e4937.

14. Guo W, Flanagan J, Jasuja R, Kirkland J, Jiang L, Bhasin S. The effects of myostatin on adipogenic differentiation of human bone marrow-derived mesenchymal stem cells are mediated through cross-communication between Smad3 and Wnt/β-catenin signaling pathways. J Biol Chem. 2008;283(14):9136-45.

15. Haidet AM, Rizo L, Handy C, et al. Long-term enhancement of skeletal muscle mass and strength by single gene administration of myostatin inhibitors. Proc Natl Acad Sci U S A. 2008;105(11):4318-22.

16. Harber MP, Crane JD, Dickinson JM, et al. Protein synthesis and the expression of growth-related genes are altered by running in human vastus lateralis and soleus muscles. Am J Physiol Regul Integr Comp Physiol. 2009;296(3):R708-14.

17. Hennebry A, Berry C, Siriett V, et al. Myostatin regulates fiber-type composition of skeletal muscle by regulating MEF2 and MyoD gene expression. Am J Physiol Cell Physiol. 2009;296(3):C525-34.

18. Hill JJ, Davies MV, Pearson AA, et al. The myostatin propeptide and the follistatin-related gene are inhibitory binding proteins of myostatin in normal serum. J Biol Chem. 2002;277(43):40735-41.

19. Hittel DS, Berggren JR, Shearer J, Boyle K, Houmard JA. Increased secretion and expression of myostatin in skeletal muscle from extremely obese women. Diabetes. 2009;58(1):30-8.

20. Hittel DS, Axelson M, Sarna N, Shearer J, Huffman KM, Kraus WE. Myostatin decreases with aerobic exercise and associates with insulin resistance. Med Sci Sports Exerc. 2010;42(11):2023-9.

21. Hulmi JJ, Ahtiainen JP, Kaasalainen T, et al. Postexercise myostatin and activin IIb mRNA levels: effects of strength training. Med Sci Sports Exerc. 2007;39(2):289-97.

22. Izumiya Y, Hopkins T, Morris C, et al. Fast/Glycolytic muscle fiber growth reduces fat mass and improves metabolic parameters in obese mice. Cell Metab. 2008;7(2):159-72.

23. Kambadur R, Sharma M, Smith TP, Bass JJ. Mutations in myostatin (GDF8) in double-muscled Belgian Blue and Piedmontese cattle. Genome Res. 1997;7(9):910-6.

24. Kim HS, Liang L, Dean RG, Hausman DB, Hartzell DL, Baile CA. Inhibition of preadipocyte differentiation by myostatin treatment in 3T3-L1 cultures. Biochem Biophys Res Commun. 2001;281(4):902-6.

25. Kim JS, Cross JM, Bamman MM. Impact of resistance loading on myostatin expression and cell cycle regulation in young and older men and women. Am J Physiol Endocrinol Metab. 2005;288(6):E1110-9.

26. Kim JS, Petrella JK, Cross JM, Bamman MM. Load-mediated downregulation of myostatin mRNA is not sufficient to promote myofiber hypertrophy in humans: a cluster analysis. J Appl Physiol. 2007;103(5):1488-95.

27. Konopka AR, Douglass MD, Kaminsky LA, et al. Molecular adaptations to aerobic exercise training in skeletal muscle of older women. J Gerontol A Biol Sci Med Sci. 2010;65(11):1201-7.

28. Kopple JD, Cohen AH, Wang H, et al. Effect of exercise on mRNA levels for growth factors in skeletal muscle of hemodialysis patients. J Ren Nutr. 2006;16(4):312-24.

29. Langley B, Thomas M, Bishop A, Sharma M, Gilmour S, Kambadur R. Myostatin inhibits myoblast differentiation by down-regulating MyoD expression. J Biol Chem. 2002;277(51):49831-40.

30. LeBrasseur NK, Schelhorn TM, Bernardo BL, Cosgrove PG, Loria PM, Brown TA. Myostatin inhibition enhances the effects of exercise on performance and metabolic outcomes in aged mice. J Gerontol A Biol Sci Med Sci. 2009;64(9):940-8.

31. Lee SJ. Quadrupling muscle mass in mice by targeting TGF-β signaling pathways. PLoS One. 2007;2(8):e789.

32. Lenk K, Schur R, Linke A, et al. Impact of exercise training on myostatin expression in the myocardium and skeletal muscle in a chronic heart failure model. Eur J Heart Fail. 2009;11(4):342-8.

33. Louis E, Raue U, Yang Y, Jemiolo B, Trappe S. Time course of proteolytic, cytokine, and myostatin gene expression after acute exercise in human skeletal muscle. J Appl Physiol. 2007;103(5):1744-51.

34. Matsakas A, Friedel A, Hertrampf T, Diel P. Short-term endurance training results in a muscle-specific decrease of myostatin mRNA content in the rat. Acta Physiol Scand. 2005;183(3):299-307.

35. Matsakas A, Bozzo C, Cacciani N, et al. Effect of swimming on myostatin expression in white and red gastrocnemius muscle and in cardiac muscle of rats. Exp Physiol. 2006;91(6):983-94.

36. Matsakas A, Foster K, Otto A, et al. Molecular, cellular and physiological investigation of myostatin propeptide-mediated muscle growth in adult mice. Neuromuscul Disord. 2009;19(7):489-99.

37. Matsakas A, Mouisel E, Amthor H, Patel K. Myostatin knockout mice increase oxidative muscle phenotype as an adaptive response to exercise. J Muscle Res Cell Motil. 2010;31(2):111-25.

38. McFarlane C, Plummer E, Thomas M, et al. Myostatin induces cachexia by activating the ubiquitin proteolytic system through an NF-κB-independent, FoxO1-dependent mechanism. J Cell Physiol. 2006;209(2):501-14.

39. McPherron AC, Lawler AM, Lee SJ. Regulation of skeletal muscle mass in mice by a new TGF-β superfamily member. Nature. 1997;387(6628):83-90.

40. McPherron AC, Lee SJ. Double muscling in cattle due to mutations in the myostatin gene. Proc Natl Acad Sci U S A. 1997;94(23):12457-61.

41. McPherron AC, Lee SJ. Suppression of body fat accumulation in myostatin-deficient mice. J Clin Invest. 2002;109(5):595-601.

42. Milan G, Dalla Nora E, Pilon C, et al. Changes in muscle myostatin expression in obese subjects after weight loss. J Clin Endocrinol Metab. 2004;89(6):2724-7.

43. Mitchell MD, Osepchook CC, Leung KC, McMahon CD, Bass JJ. Myostatin is a human placental product that regulates glucose uptake. J Clin Endocrinol Metab. 2006;91(4):1434-7.

44. Moller DE. Potential role of TNF-α in the pathogenesis of insulin resistance and type 2 diabetes. Trends Endocrinol Metab. 2000;11(6):212-7.

45. Mosher DS, Quignon P, Bustamante CD, et al. A mutation in the myostatin gene increases muscle mass and enhances racing performance in heterozygote dogs. PLoS Genet. 2007;3(5):e79.

46. Mukherjee A, Sidis Y, Mahan A, et al. FSTL3 deletion reveals roles for TGF-β family ligands in glucose and fat homeostasis in adults. Proc Natl Acad Sci U S A. 2007;104(4):1348-53.

47. Palsgaard J, Brøns C, Friedrichsen M, et al. Gene expression in skeletal muscle biopsies from people with type 2 diabetes and relatives: differential regulation of insulin signaling pathways. PLoS One. 2009;4(8):e6575.

48. Park JJ, Berggren JR, Hulver MW, Houmard JA, Hoffman EP. GRB14, GPD1, and GDF8 as potential network collaborators in weight loss-induced improvements in insulin action in human skeletal muscle. Physiol Genomics. 2006;27(2):114-21.

49. Personius KE, Jayaram A, Krull D, et al. Grip force, EDL contractile properties, and voluntary wheel running after postdevelopmental myostatin depletion in mice. J Appl Physiol. 2010;109(3):886-94.

50. Philip B, Lu Z, Gao Y. Regulation of GDF-8 signaling by the p38 MAPK. Cell Signal. 2005;(3):365-75.

51. Raue U, Slivka D, Jemiolo B, Hollon C, Trappe S. Myogenic gene expression at rest and after a bout of resistance exercise in young (18-30 yr) and old (80-89 yr) women. J Appl Physiol. 2006;101(1):53-9.

52. Rebbapragada A, Benchabane H, Wrana JL, Celeste AJ, Attisano L. Myostatin signals through a transforming growth factor β-like signaling pathway to block adipogenesis. Mol Cell Biol. 2003;23(20):7230-42.

53. Reisz-Porszasz S, Bhasin S, Artaza JN, et al. Lower skeletal muscle mass in male transgenic mice with muscle-specific overexpression of myostatin. Am J Physiol Endocrinol Metab. 2003;285(4):E876-88.

54. Ríos R, Fernández-Nocelos S, Carneiro I, Arce VM, Devesa J. Differential response to exogenous and endogenous myostatin in myoblasts suggests that myostatin acts as an autocrine factor in vivo. Endocrinology. 2004;145(6):2795-803.

55. Roden M, Bernroider E. Hepatic glucose metabolism in humans-its role in health and disease. Best Pract Res Clin Endocrinol Metab. 2003;17(3):365-83.

56. Roth SM, Martel GF, Ferrell RE, Metter EJ, Hurley BF, Rogers MA. Myostatin gene expression is reduced in humans with heavy-resistance strength training: a brief communication. Exp Biol Med (Maywood). 2003;228(6):706-9.

57. Saremi A, Gharakhanloo R, Sharghi S, Gharaati MR, Larijani B, Omidfar K. Effects of oral creatine and resistance training on serum myostatin and GASP-1. Mol Cell Endocrinol. 2010;317(1-2):25-30.

58. Savage KJ, McPherron AC. Endurance exercise training in myostatin null mice. Muscle Nerve. 2010;42(3):355-62.

59. Schuelke M, Wagner KR, Stolz LE, et al. Myostatin mutation associated with gross muscle hypertrophy in a child. N Engl J Med. 2004;350(26):2682-8.

60. Stolz LE, Li D, Qadri A, Jalenak M, Klaman LD, Tobin JF. Administration of myostatin does not alter fat mass in adult mice. Diabetes Obes Metab. 2008;10(2):135-42.

61. Taylor WE, Bhasin S, Artaza J, et al. Myostatin inhibits cell proliferation and protein synthesis in C2C12 muscle cells. Am J Physiol Endocrinol Metab. 2001;280(2):E221-8.

62. Thomas M, Langley B, Berry C, et al. Myostatin, a negative regulator of muscle growth, functions by inhibiting myoblast proliferation. J Biol Chem. 2000;275(51):40235-43.

63. Trendelenburg AU, Meyer A, Rohner D, Boyle J, Hatakeyama S, Glass DJ. Myostatin reduces Akt/TORC1/p70S6K signaling, inhibiting myoblast differentiation and myotube size. Am J Physiol Cell Physiol. 2009;296(6):C1258-70.

64. Walker KS, Kambadur R, Sharma M, Smith HK. Resistance training alters plasma myostatin but not IGF-1 in healthy men. Med Sci Sports Exerc. 2004;36(5):787-93.

65. Welle S, Bhatt K, Pinkert CA. Myofibrillar protein synthesis in myostatin-deficient mice. Am J Physiol Endocrinol Metab. 2006;290(3):E409-15.

66. Willoughby DS. Effects of heavy resistance training on myostatin mRNA and protein expression. Med Sci Sports Exerc. 2004;36(4):574-82.

67. Wilkes JJ, Lloyd DJ, Gekakis N. Loss-of-function mutation in myostatin reduces tumor necrosis factor alpha production and protects liver against obesity-induced insulin resistance. Diabetes. 2009;58(5):1133-43.

68. Wolfman NM, McPherron AC, Pappano WN, et al. Activation of latent myostatin by the BMP-1/tolloid family of metalloproteinases. Proc Natl Acad Sci U S A. 2003;100(26):15842-6.

69. Woodruff TK, Krummen L, Chen SA, et al. Pharmacokinetic profile of recombinant human (rh) inhibin A and activin A in the immature rat. II. Tissue distribution of [125I]rh-inhibin A and [125I]rh-activin A in immature female and male rats. Endocrinology. 1993;132:725-34.

70. Yang J, Ratovitski T, Brady JP, Solomon MB, Wells KD, Wall RJ. Expression of myostatin pro domain results in muscular transgenic mice. Mol Reprod Dev. 2001;60(3):351-61.

71. Yang J, Zhao B. Postnatal expression of myostatin propeptide cDNA maintained high muscle growth and normal adipose tissue mass in transgenic mice fed a high-fat diet. Mol Reprod Dev. 2006;73(4):462-9.

72. Zhao B, Wall RJ, Yang J. Transgenic expression of myostatin propeptide prevents diet-induced obesity and insulin resistance. Biochem Biophys Res Commun. 2005;337(1):248-55.

73. Zhu X, Hadhazy M, Wehling M, Tidball JG, McNally EM. Dominant negative myostatin produces hypertrophy without hyperplasia in muscle. FEBS Lett. 2000;474(1):71-5.

74. Zimmers TA, Davies MV, Koniaris LG, et al. Induction of cachexia in mice by systemically administered myostatin. Science. 2002;296(5572):1486-8.

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