Reduced levels of myostatin spur greater muscle growth, and there are animal lineages and even a few individual humans with myostatin loss of function mutations. The amount of evidence and experience in the scientific community working with this genetic alteration makes it a promising compensatory therapy for age-related loss of muscle mass and strength. Indeed, trials have already been held for the use of antibodies to reduce myostatin activity, and gene therapies are a possibility for the near future once tissue coverage issues have been solved. This study quantifies some of the differences between genetic loss of myostatin and antibody therapy for suppression of myostatin. As might be expected the results are similar in character but quite different at the detailed level, showing that genetic engineering for lifelong loss of myostatin produces superior results to an adult therapy. A further comparison with gene therapy carried out in adults remains to be conducted, but the outcomes will probably fall somewhere in the middle between these two examples.
Pharmacologic blockade of the myostatin (Mstn)/activin receptor pathway is being pursued as a potential therapy for several muscle wasting disorders. The functional benefits of blocking this pathway are under investigation, in particular given the findings that greater muscle hypertrophy results from Mstn deficiency arising from genetic ablation compared to post-developmental Mstn blockade. Using high-resolution mass spectrometry coupled with SILAC mouse technology, we quantitated the relative proteomic changes in gastrocnemius muscle from Mstn knockout (Mstn-/-) and mice treated for 2-weeks with REGN1033, an anti-Mstn antibody.
Relative to wild-type animals, Mstn-/- mice had a two-fold greater muscle mass and a greater than 1.5-fold change in expression of 12.0% of 1137 quantified muscle proteins. In contrast, mice treated with REGN1033 had minimal changes in muscle proteome (0.7% of 1510 proteins with more than a 1.5-fold change, similar to biological difference 0.5% of 1310) even though the treatment induced significant 20% muscle mass increase. Functional annotation of the altered proteins in Mstn-/- mice corroborates the mutiple physiological changes including slow-to-fast fiber type switch. Thus, the proteome-wide protein expression differs between Mstn-/- mice and mice subjected to specific Mstn blockade post-developmentally, providing molecular-level insights to inform mechanistic hypotheses to explain the observed functional differences.