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Mediation of IGF-1-induced skeletal myotube hypertrophy by PI(3)K/Akt/mTOR and PI(3)K/Akt/GSK3 pathways

Nature Cell Biology volume 3, pages 1009–1013 (2001)Cite this article

Abstract

Skeletal muscle is composed of multinucleated fibres, formed after the differentiation and fusion of myoblast precursors1. Skeletal muscle atrophy and hypertrophy refer to changes in the diameter of these pre-existing muscle fibres. The prevention of atrophy would provide an obvious clinical benefit; insulin-like growth factor 1 (IGF-1) is a promising anti-atrophy agent2,3,4,5 because of its ability to promote hypertrophy. However, the signalling pathways by which IGF-1 promotes hypertrophy remain unclear, with roles suggested for both the calcineurin/NFAT (nuclear factor of activated T cells) pathway6,7 and the PtdIns-3-OH kinase (PI(3)K)/Akt pathway8. Here we employ a battery of approaches to examine these pathways during the hypertrophic response of cultured myotubes to IGF-1. We report that Akt promotes hypertrophy by activating downstream signalling pathways previously implicated in activating protein synthesis: the pathways downstream of mammalian target of rapamycin (mTOR) and the pathway activated by phosphorylating and thereby inhibiting glycogen synthase kinase 3 (GSK3). In contrast, in addition to demonstrating that calcineurin does not mediate IGF-1-induced hypertrophy, we show that IGF-1 unexpectedly acts via Akt to antagonize calcineurin signalling during myotube hypertrophy.

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Figure 1: Schematic overview of a signalling network downstream of the growth factor IGF-1, emphasizing the primary role of the PI(3)K/Akt/mTOR cascade, linking receptor tyrosine kinase derived signals to growth regulatory mechanisms.
Figure 2: Signalling pathways activated by IGF-1 or the calcium ionophore A23187 (Ca-I) in C2C12 differentiated myotubes.
Figure 3: IGF-1 induces skeletal myotube hypertrophy via the PI(3)K/Akt/mTOR kinase cascade, independently of calcineurin activity.
Figure 4: Direct or indirect Akt activation results in p70S6 kinase activation.

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Acknowledgements

We thank L. S. Schleifer and P. R. Vagelos for enthusiastic support, along with the rest of the Regeneron community; T. Salomon and J. McCormick for expert assistance with the FACS; S. Staton and E. Burrows for graphics work; A. Bellacosa, P. Tsichlis and J. Blenis for providing reagents and advice; J. Wodgett for the dominant negative GSK3β; and E. Hafen for sharing results before publication.

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  1. Regeneron Pharmaceuticals, 777 Old Saw Mill River Road, Tarrytown, 10591-6707, NY, USA

    Christian Rommel, Sue C. Bodine, Brian A. Clarke, Roni Rossman, Lorna Nunez, Trevor N. Stitt, George D. Yancopoulos & David J. Glass

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  1. Christian Rommel
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Correspondence to David J. Glass.

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Rommel, C., Bodine, S., Clarke, B. et al. Mediation of IGF-1-induced skeletal myotube hypertrophy by PI(3)K/Akt/mTOR and PI(3)K/Akt/GSK3 pathways. Nat Cell Biol 3, 1009–1013 (2001). https://doi.org/10.1038/ncb1101-1009

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