Muscle hypertrophy induced by myostatin inhibition : a new therapeutic approach of muscle atrophy

Increasing size and strength of skeletal muscle represents a promising therapeutic strategy for muscular disorders. One possible new tool is Myostatin (Mstn) because it plays a crucial role in regulating skeletal muscle mass. The first goal of our work was to determine whether Mstn inhibition could prevent muscle atrophy in catabolic states. As glucocorticoids play a major role in most muscle atrophy models, we assessed whether muscle atrophy caused by glucocorticoids in excess could be prevented by Mstn inhibition. This hypothesis was suggested by the fact that glucocorticoids increase muscle Mstn expression and that Mstn muscle overexpression is sufficient to cause muscle atrophy. Our work showed that deletion of Mstn gene protects skeletal muscle from glucocorticoid-induced atrophy, partially through inhibition of proteolysis. The identification of Mstn binding proteins able to inhibit Mstn activity has led to potential new approaches for postdevelopmental muscle mass enhancement. These Mstn binding proteins include Follistatin (FS) which shows a potent Mstn-inhibiting activity. The increase in muscle mass observed in transgenic mice overexpressing FS in muscle is even significantly larger than that observed in Mstn KO mice, suggesting that other ligands could contribute to the muscle hypertrophic effect of FS. The mechanisms involved in the FS effect are however relatively unknown. The second aim of this thesis was to investigate the contribution of satellite cells to the FS-induced muscle hypertrophy and to assess whether other FS ligands could act similarly to Mstn in controlling muscle growth. Our study showed that FS overexpression induces skeletal muscle hypertrophy via satellite cell activation and probably increased protein synthesis. Furthermore, our results indicate that FS-induced hypertrophy results not only from Mstn but also from Act inhibition. These observations therefore suggest that, besides Mstn, Act is a crucial player in the regulation of muscle mass. In conclusion, this work demonstrates the interest and the feasibility of Mstn inhibition as a potential therapeutic approach in muscle wasting disease. Since Mstn gene deletion prevents the muscle atrophy caused by dexamethasone and glucocorticoids are involved in muscle atrophy observed in many catabolic conditions, Mstn inhibition may be helpful in the treatment of disease-related muscle loss. Among Mstn inhibitors, FS seems to be a promising tool because of its powerful hypertrophic effect on skeletal muscle mass. As we showed, its anabolic action results from inhibition of both Mstn and Act, which negatively regulate muscle growth.(SBIM 3) -- UCL, 200