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

Abstract

Localized synthesis of insulin-like growth factors (IGFs) has been broadly implicated in skeletal muscle growth, hypertrophy and regeneration1. 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 mice2. 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.

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Figure 1: Calcineurin expression and subcellular localization are responsive to postmitotic IGF-1 expression in myogenic cell cultures.
Figure 2: Perturbation of calcineurin action affects hypertrophy in myogenic cell cultures.
Figure 3: Activation of GATA-2 expression in hypertrophic myocytes.
Figure 4: GATA-2 interacts with NF-ATc1 to induce myocyte hypertrophy.

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Acknowledgements

We thank L. Sweeney, F. McKeon, C. Marks, and members of the Rosenthal laboratory for helpful discussion; A. Rao and G. Crabtree for advice and gifts of NF-AT antibodies; M. McGrew, C.Semsarian and R. Graham for sharing unpublished data; and J. Florini for his original concept and continued insights into the properties of IGF. The study was supported by grants to N.R. from the NIA and NASA, to A.M. from the MDA, and to E.N.O. from the NIH. F.N. was supported by an NIH postdoctoral fellowship.

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Musarò, A., McCullagh, K., Naya, F. et al. IGF-1 induces skeletal myocyte hypertrophy through calcineurin in association with GATA-2 and NF-ATc1. Nature 400, 581–585 (1999). https://doi.org/10.1038/23060

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