Role of IGF/Insulin pathway in the skeletal muscle hypertrophy induced by follistatin

Increasing size and strength of skeletal muscle represents a promising therapeutic strategy for muscular disorders. One possible tool is the inhibition of Myostatin (Mstn), a major inhibitor of skeletal muscle development. Among Mstn inhibitors, Follistatin (FS) induces the most dramatic effect on muscle mass growth. The molecular mechanisms involved in the FS effect are however relatively unknown. An interaction between Mstn and Insulin-like growth factor (IGF) pathways has been suggested by increased expression of IGFs and activation of its downstream pathway Akt/mTOR/S6K in the skeletal muscle when Mstn is inhibited. The aim of this thesis was to investigate the contribution of IGF-IR/Akt/mTOR/S6K pathway to the FS induced skeletal muscle hypertrophy. Our study shows that the hypertrophic action of FS requires the IGF-IR, Akt and, to some extent, mTORC1 but not S6K. As IGF-IR is activated either by IGFs or by insulin, we tend to delineate the role of each ligand. Our results indicate that the hypertrophic effect of FS requires the presence of insulin but does not seem to require the presence of IGFs. The present study connects the Mstn and the IGF-IR pathways, the two most important pathways that regulate muscle mass. Defining the key pathway for muscle hypertrophy is a crucial issue for the correct identification of drug targets to mitigate muscle wasting.