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

Christopher Semsarian, Ming-Jie Wu, Yue-Kun Ju, Tadeusz Marciniec, Thomas Yeoh, David G. Allen, Richard P. Harvey and Robert M. Graham ()
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Christopher Semsarian: Victor Chang Cardiac Research Institute, St Vincent's Hospital
Ming-Jie Wu: Victor Chang Cardiac Research Institute, St Vincent's Hospital
Yue-Kun Ju: University of Sydney
Tadeusz Marciniec: Victor Chang Cardiac Research Institute, St Vincent's Hospital
Thomas Yeoh: Victor Chang Cardiac Research Institute, St Vincent's Hospital
David G. Allen: University of Sydney
Richard P. Harvey: Victor Chang Cardiac Research Institute, St Vincent's Hospital
Robert M. Graham: Victor Chang Cardiac Research Institute, St Vincent's Hospital

Nature, 1999, vol. 400, issue 6744, 576-581

Abstract: Abstract Skeletal muscle hypertrophy and regeneration are important adaptive responses to both physical activity and pathological stimuli1. Failure to maintain these processes underlies the loss of skeletal muscle mass and strength that occurs with ageing and in myopathies2. Here we show that stable expression of a gene encoding insulin-like growth factor 1 (IGF-1) in C2C12 skeletal muscle cells, or treatment of these cells with recombinant IGF-1 or with insulin and dexamethasone, results in hypertrophy of differentiated myotubes and a switch to glycolytic metabolism. Treatment with IGF-1 or insulin and dexamethasone mobilizes intracellular calcium, activates the Ca2+/calmodulin-dependent phosphatase calcineurin, and induces the nuclear translocation of the transcription factor NF-ATc1. Hypertrophy is suppressed by the calcineurin inhibitors cyclosporin A or FK506, but not by inhibitors of the MAP-kinase or phosphatidylinositol-3-OH kinase pathways. Injecting rat latissimus dorsi muscle with a plasmid encoding IGF-1 also activates calcineurin, mobilizes satellite cells and causes a switch to glycolytic metabolism. We propose that growth-factor-induced skeletal-muscle hypertrophy and changes in myofibre phenotype are mediated by calcium mobilization and are critically regulated by the calcineurin/NF-ATc1 signalling pathway.

Date: 1999
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DOI: 10.1038/23054

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