Mediation of IGF-1-induced skeletal myotube hypertrophy by PI(3)K/Akt/mTORand PI(3)K/Akt/GSK3 pathways

Skeletal muscle is composed of multinucleated fibres, formed after the diff erentiation and fusion of myoblast precursors'. Skeletal muscle atrophy and hypertrophy refer to changes in the diameter of these pre-existing muscle fibres. The prevention of atrophy would provide an obvious clinical benefit ; insulin-like growth factor 1 (IGF-1) is a promising anti-atrophy agent(2- 5) because of its ability to promote hypertrophy. However, the signalling p athways by which IGF-1 promotes hypertrophy remain unclear, with roles sugg ested for both the calcineurin/NFAT (nuclear factor of activated T cells) p athway(6,7) and the Ptdlns-3-OH kinase (PI(3)K)/Akt pathway(8). Here we emp loy a battery of approaches to examine these pathways during the hypertroph ic response of cultured myotubes to IGF-1, We report that Akt promotes hype rtrophy by activating downstream signalling pathways previously implicated in activating protein synthesis: the pathways downstream of mammalian targe t of rapamycin (mTOR) and the, pathway activated by phosphorylating and the reby inhibiting glycogen synthase kinase 3 (GSK3). In contrast, in addition to demonstrating that calcineurin does not mediate IGF-1-induced hypertrop hy, we show that IGF-1 unexpectedly acts via Akt to antagonize calcineurin signalling during myotube hypertrophy.