IGF-1 induces skeletal myocyte hypertrophy through calcineurin in association with GATA-2 and NF-ATc1

Nature. 1999 Aug 5;400(6744):581-5. doi: 10.1038/23060.


Localized synthesis of insulin-like growth factors (IGFs) has been broadly implicated in skeletal muscle growth, hypertrophy and regeneration. Virally delivered IGF-1 genes induce local skeletal muscle hypertrophy and attenuate age-related skeletal muscle atrophy, restoring and improving muscle mass and strength in mice. Here we show that the molecular pathways underlying the hypertrophic action of IGF-1 in skeletal muscle are similar to those responsible for cardiac hypertrophy. Transfected IGF-1 gene expression in postmitotic skeletal myocytes activates calcineurin-mediated calcium signalling by inducing calcineurin transcripts and nuclear localization of calcineurin protein. Expression of activated calcineurin mimics the effects of IGF-1, whereas expression of a dominant-negative calcineurin mutant or addition of cyclosporin, a calcineurin inhibitor, represses myocyte differentiation and hypertrophy. Either IGF-1 or activated calcineurin induces expression of the transcription factor GATA-2, which accumulates in a subset of myocyte nuclei, where it associates with calcineurin and a specific dephosphorylated isoform of the transcription factor NF-ATc1. Thus, IGF-1 induces calcineurin-mediated signalling and activation of GATA-2, a marker of skeletal muscle hypertrophy, which cooperates with selected NF-ATc isoforms to activate gene expression programs.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Calcineurin / metabolism*
  • Calcineurin Inhibitors
  • Cardiomegaly / metabolism
  • Cell Line
  • Cyclosporine / pharmacology
  • DNA-Binding Proteins / metabolism*
  • GATA2 Transcription Factor
  • Gene Expression Regulation
  • Hypertrophy
  • Insulin-Like Growth Factor I / genetics
  • Insulin-Like Growth Factor I / physiology*
  • Mice
  • Mice, Transgenic
  • Muscle, Skeletal / pathology*
  • Myocardium / metabolism
  • NFATC Transcription Factors
  • Nuclear Proteins*
  • Signal Transduction
  • Transcription Factors / metabolism*


  • Calcineurin Inhibitors
  • DNA-Binding Proteins
  • GATA2 Transcription Factor
  • Gata2 protein, mouse
  • NFATC Transcription Factors
  • Nuclear Proteins
  • Transcription Factors
  • Insulin-Like Growth Factor I
  • Cyclosporine
  • Calcineurin