IGF-1 induces skeletal myocyte hypertrophy through calcineurin in association with GATA-2 and NF-ATc1.
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.
Musarò
A
A
Cardiovascular Research Center, Massachusetts General Hospital-East, Charlestown 02129, USA.
McCullagh
K J
KJ
Naya
F J
FJ
Olson
E N
EN
Rosenthal
N
N
D000818:Animals; D019703:Calcineurin / Q000378:metabolism*; D065095:Calcineurin Inhibitors; D006332:Cardiomegaly / Q000378:metabolism; D002460:Cell Line; D016572:Cyclosporine / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D050989:GATA2 Transcription Factor; D005786:Gene Expression Regulation; D006984:Hypertrophy; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000473:pathology*; D009206:Myocardium / Q000378:metabolism; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism*
D065095:Calcineurin Inhibitors; D004268:DNA-Binding Proteins; D050989:GATA2 Transcription Factor; C494712:Gata2 protein, mouse; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D014157:Transcription Factors; D007334:Insulin-Like Growth Factor I; D016572:Cyclosporine; D019703:Calcineurin