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

Antonio Musarò, Karl J A McCullagh, Francisco J. Naya, Eric N. Olson, Nadia Rosenthal

Research output: Contribution to journalArticle

515 Citations (Scopus)

Abstract

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 iso forms to activate gene expression programs.

Original languageEnglish (US)
Pages (from-to)581-585
Number of pages5
JournalNature
Volume400
Issue number6744
DOIs
StatePublished - Aug 5 1999

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Calcineurin
Skeletal Muscle Fibers
Somatomedins
Hypertrophy
Skeletal Muscle
Muscle Cells
GATA2 Transcription Factor
Gene Expression
Calcium Signaling
Muscular Atrophy
Cardiomegaly
Muscle Strength
Cyclosporine
Regeneration
Protein Isoforms
Transcription Factors
Growth

ASJC Scopus subject areas

  • General

Cite this

IGF-1 induces skeletal myocyte hypertrophy through calcineurin in association with GATA-2 and NF-ATc1. / Musarò, Antonio; McCullagh, Karl J A; Naya, Francisco J.; Olson, Eric N.; Rosenthal, Nadia.

In: Nature, Vol. 400, No. 6744, 05.08.1999, p. 581-585.

Research output: Contribution to journalArticle

Musarò, Antonio ; McCullagh, Karl J A ; Naya, Francisco J. ; Olson, Eric N. ; Rosenthal, Nadia. / IGF-1 induces skeletal myocyte hypertrophy through calcineurin in association with GATA-2 and NF-ATc1. In: Nature. 1999 ; Vol. 400, No. 6744. pp. 581-585.
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