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Akt/mTOR pathway is a crucial regulator of skeletal muscle hypertrophy and can prevent muscle atrophy in vivo

Abstract

Skeletal muscles adapt to changes in their workload by regulating fibre size by unknown mechanisms1,2. The roles of two signalling pathways implicated in muscle hypertrophy on the basis of findings in vitro3,4,5,6, Akt/mTOR (mammalian target of rapamycin) and calcineurin/NFAT (nuclear factor of activated T cells), were investigated in several models of skeletal muscle hypertrophy and atrophy in vivo. The Akt/mTOR pathway was upregulated during hypertrophy and downregulated during muscle atrophy. Furthermore, rapamycin, a selective blocker of mTOR7, blocked hypertrophy in all models tested, without causing atrophy in control muscles. In contrast, the calcineurin pathway was not activated during hypertrophy in vivo, and inhibitors of calcineurin, cyclosporin A and FK506 did not blunt hypertrophy. Finally, genetic activation of the Akt/mTOR pathway was sufficient to cause hypertrophy and prevent atrophy in vivo, whereas genetic blockade of this pathway blocked hypertrophy in vivo. We conclude that the activation of the Akt/mTOR pathway and its downstream targets, p70S6K and PHAS-1/4E-BP1, is requisitely involved in regulating skeletal muscle fibre size, and that activation of the Akt/mTOR pathway can oppose muscle atrophy induced by disuse.

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Figure 1: Muscle hypertrophy is not blocked by CsA.
Figure 2: Muscle hypertrophy is associated with activation of the Akt/mTOR pathway and is blocked by rapamycin.
Figure 3: Recovery of muscle weight after HLS is blocked by rapamycin, but not cyclosporin.
Figure 4: Expression of activated Akt in normal and denervated muscle fibres induces hypertrophy.

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Acknowledgements

We thank L. S. Schleifer and P. R. Vagelos and the rest of the Regeneron community for their support, particularly E. Burrows for graphics work and C. Rommel for insightful discussions.

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Correspondence to Sue C. Bodine or George D. Yancopoulos.

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Bodine, S., Stitt, T., Gonzalez, M. et al. Akt/mTOR pathway is a crucial regulator of skeletal muscle hypertrophy and can prevent muscle atrophy in vivo. Nat Cell Biol 3, 1014–1019 (2001). https://doi.org/10.1038/ncb1101-1014

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