Skeletal muscle hypertrophy is mediated by a Ca2+-dependent calcineurin signalling pathway

Skeletal muscle hypertrophy and regeneration are important adaptive respons es to both physical activity and pathological stimuli(1). Failure to mainta in these processes underlies the loss of skeletal muscle mass and strength that occurs with ageing and in myopathies(2). Here we show that stable expr ession of a gene encoding insulin-like growth factor 1 (IGF-1) in C2C12 ske letal muscle cells, or treatment of these cells with recombinant IGF-1 or w ith insulin and dexamethasone, results in hypertrophy of differentiated myo tubes and a switch to glycolytic metabolism. Treatment with IGF-1 or insuli n and dexamethasone mobilizes intracellular calcium, activates the Ca2+/cal modulin-dependent phosphatase calcineurin, and induces the nuclear transloc ation of the transcription factor NF-ATc1. Hypertrophy is suppressed by the calcineurin inhibitors cyclosporin A or FK506, but not by inhibitors of th e MAP-kinase or phosphatidylinositol-3-OH kinase pathways. Injecting rat la tissimus dorsi muscle with a plasmid encoding IGF-1 also activates calcineu rin, mobilizes satellite cells and causes a switch to glycolytic metabolism . We propose that growth-factor-induced skeletal-muscle hypertrophy and cha nges in myofibre phenotype are mediated by calcium mobilization and are cri tically regulated by the calcineurin/NF-ATc1 signalling pathway.