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

Nature. 1999 Aug 5;400(6744):576-81. doi: 10.1038/23054.


Skeletal muscle hypertrophy and regeneration are important adaptive responses to both physical activity and pathological stimuli. Failure to maintain these processes underlies the loss of skeletal muscle mass and strength that occurs with ageing and in myopathies. 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3 Cells
  • Animals
  • Calcineurin / metabolism*
  • Calcium / metabolism*
  • Cardiomegaly / metabolism
  • Cell Differentiation
  • Cell Line
  • Cell Nucleus / metabolism
  • DNA-Binding Proteins / metabolism
  • Dexamethasone / pharmacology
  • Glycoproteins / pharmacology
  • Hypertrophy
  • Insulin / pharmacology
  • Insulin-Like Growth Factor I / genetics
  • Insulin-Like Growth Factor I / physiology
  • Mice
  • Muscle, Skeletal / drug effects
  • Muscle, Skeletal / metabolism*
  • Muscle, Skeletal / pathology*
  • NFATC Transcription Factors
  • Neuregulins
  • Nuclear Proteins*
  • Phosphoric Monoester Hydrolases / metabolism
  • Plasmids
  • Rats
  • Signal Transduction*
  • Transcription Factors / metabolism
  • Transfection


  • DNA-Binding Proteins
  • Glycoproteins
  • Insulin
  • NFATC Transcription Factors
  • Neuregulins
  • Nuclear Proteins
  • Transcription Factors
  • Insulin-Like Growth Factor I
  • Dexamethasone
  • calcineurin phosphatase
  • Calcineurin
  • Phosphoric Monoester Hydrolases
  • Calcium