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

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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.

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Figure 1: Induction and calcineurin-dependence of IGF-1-mediated hypertrophy in C2C12 cells.
Figure 2: Calcineurin phosphatase (CnPP) activity.
Figure 3: Induction and calcineurin-dependence of C2C12 cell myotube hypertrophy resulting from I/D treatment.
Figure 4: IGF-1-induced transformation of rat latissimus dorsi muscle (LDM).


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Supported in part by funds donated in memory of Diana, Princess of Wales. We thank P. Poronnik and C. Lee for IGF-1 expression vector reagents; N. Rosenthal for sharing unpublished data; P. Gunning for C2C12 cells; M. Fujioka (Fujisawa) for supplying FK506; C. Klee for the ‘Free Calcium’ program; K. Walsh, E. Hardeman, A. Gualberto and P. Sutrave for helpful discussions; and E.Martin and N. Groves for preparation for this manuscript. This work was supported by NH and MRC Medical Research Scholarships (to C.S. and T.Y.).

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Correspondence to Robert M. Graham.

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Semsarian, C., Wu, M., Ju, Y. et al. Skeletal muscle hypertrophy is mediated by a Ca2+-dependent calcineurin signalling pathway. Nature 400, 576–581 (1999) doi:10.1038/23054

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