Aerobic and resistance exercise reduces muscle and circulating Mstn levels in human subjects whether acute or chronic (11
). While there have been prior studies of circulating Mstn protein in relation to body mass, age, gender and exercise (6
) ours is the first to describe a significant decrease in circulating Mstn protein with aerobic exercise training. This is also the first study to show a significant correlation between circulating Mstn and insulin sensitivity. While this did not prove a cause-effect relationship per se
, we were able to induce whole-body insulin resistance in mice with the short-term administration of recombinant Mstn (36
). This finding suggests that small changes in circulating Mstn can produce significant changes in insulin sensitivity in both liver and muscle. However, since myostatin levels were assayed > 12 hours after their last injection it is possible that serum levels were much higher at an earlier time point. These findings also support previously published studies in our laboratory in which we hypothesized a relationship between circulating Mstn and insulin resistance (8
Interestingly, the post-natal suppression of circulating Mstn protein using anti-Mstn antibodies, soluble ActRIIB receptor and Mstn propeptide prevents dietary induced insulin resistance in mice (19
). In fact, recent evidence suggests that improvements in insulin sensitivity and aerobic endurance in mice after short-term Mstn inhibition were as effective as four weeks of aerobic exercise training, suggesting a potential complementary role for myostatin antagonists in the treatment of obesity and type 2 diabetes (19
). It is therefore plausible that exercise-associated decreases in muscle and plasma Mstn may contribute to improvements in whole-body insulin sensitivity.
We had previously hypothesized that increased muscle and plasma Mstn is a secondary response to acquired insulin resistance with physical inactivity (8
). While the evidence presented in this study would appear to support this hypothesis it creates a minor logical paradox, wherein increased circulating Mstn is both cause and effect of insulin resistance. The data presented in this and other exercise studies indicate that muscle activity levels primarily dictate Mstn expression levels and that the secondary effects are metabolic. In fact, in addition to muscle (7
) Mstn signaling has been shown to play a role in the metabolic adaptation of liver (36
), heart (31
) and placenta (26
) suggesting a broad role in metabolic cross-talk between organs. Although we found no evidence that Mstn altered circulating levels of hormones and cytokines known to influence insulin signaling (), to determine if myostatin signaling acts directly on the insulin signaling pathway and glucose uptake we plan to conduct follow-up studies using liver and muscle cells in culture.
Like most members of the TGFβ family Myostatin is extensively regulated at the post-translational level, where it is cleaved into a chaperone-like pro-domain and an active peptide-dimer in the very stable cysteine knot conformation (23
). This is why some confusion persists about the appropriate molecular weight of the immunoreactive myostatin and why some prefer to study the mRNA levels alone. In fact, studies of Mstn mRNA have provided important information about the timeframe for the suppression of Mstn expression with aerobic exercise. The exercise-induced suppression of Mstn mRNA and protein occurs in as little as 1 hour and persists as long as 24 hours after a single exercise session (3
Like myostatin, insulin-like growth factor 1 (IGF-1) is an important component of the homeostatic mechanism linking muscle activity to hypertrophy and atrophy (4
). Exercise-induced IGF-1 signaling is mediated in part by the PI3K/PTEN/AKTpathway that promotes cell proliferation and myogenesis in both the heart and skeletal muscle. Opposing this mechanism, myostatin has been shown reduce IGF-1 stimulated AKT phosphorylation in a dose-dependant manner by blocking both PI3 Kinase and activating PTEN (13
). Interestingly, myostatin, IGF-1 and insulin all share the PI3K/Akt pathway, which is important for signaling a number of downstream substrates that play a role in cell growth and metabolism. In fact it has been demonstrated that the major growth inhibiting actions of myostatin are mediated through the attenuation of IGF-1 induced Akt phosphorylation (13
). Finally it has been shown that both insulin and IGF-1 inhibit the Mstn-induced degradation of p300, an important transcriptional coactivator regulating the expression of cyclin D1 (13
). Cumulatively, this suggests a plausible mechanism linking increased circulating myostatin with inactivity to the development of insulin resistance.
In summary, we found that Mstn protein levels decreased in matching muscle and plasma samples from insulin resistant men after six months of aerobic exercise training. Pre-training plasma myostatin correlated better with insulin sensitivity than lean or fat mass, suggesting a cause-effect relationship that was subsequently confirmed in myostatin-injected mice. The profound reduction in insulin sensitivity with modest increase in plasma myostatin levels was also characterized at the organ level where the insulin-stimulated phosphorylation of AKT was shown to be significantly reduced in both muscle and liver of myostatin treated mice. These unique observations imply a role for circulating Mstn in the pathophysiology of the insulin resistance syndromes. Finally, since moderate exercise is sufficient to both reduce circulating Mstn levels and improve insulin sensitivity, we believe that Mstn should be evaluated further as therapeutic benefit of exercise and a target for defining the optimal mode, dose and intensity of exercise for health benefits.