Abstract
Skeletal muscle atrophy occurs in aging and pathological conditions, including cancer, diabetes and AIDS1. Treatment of atrophy is based on either preventing protein-degradation pathways, which are activated during atrophy, or activating protein-synthesis pathways, which induce muscle hypertrophy2. Here we show that neuronal nitric oxide synthase (nNOS) regulates load-induced hypertrophy by activating transient receptor potential cation channel, subfamily V, member 1 (TRPV1). The overload-induced hypertrophy was prevented in nNOS-null mice. nNOS was transiently activated within 3 min after overload. This activation promoted formation of peroxynitrite, a reaction product of nitric oxide with superoxide3, which was derived from NADPH oxidase 4 (Nox4). Nitric oxide and peroxynitrite then activated Trpv1, resulting in an increase of intracellular Ca2+ concentration ([Ca2+]i) that subsequently triggered activation of mammalian target of rapamycin (mTOR). Notably, administration of the TRPV1 agonist capsaicin induced hypertrophy without overload and alleviated unloading- or denervation-induced atrophy. These findings identify nitric oxide, peroxynitrite and [Ca2+]i as the crucial mediators that convert a mechanical load into an intracellular signaling pathway and lead us to suggest that TRPV1 could be a new therapeutic target for treating muscle atrophy.
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Acknowledgements
We thank M. Kotlikoff (Department of Biomedical Science, College of Veterinary Medicine, Cornell University, Ithaca, New York, USA) for providing pCAGGS-GCaMP2 mice, K.-H. Krause (Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland) for Nox4-null mice, Y. Ono for the technical support to isolate satellite cells and GenKyoTex (Geneva, Switzerland) for supplying GKT136901. We also thank D. Glass, I. Kii, V. Ullrich, B. Gähwiler and Y. Aoki for reading the manuscript and contributing to valuable discussions. This work was supported by a Grant-in-Aid for Scientific Research (B), a Grant-in-Aid for Japan Society for the Promotion of Science Fellows and a grant from the Association Française contre les Myopathies (AFM, France).
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N.I. conceived and performed the experiments. A.K., Y.M.-S., U.T.R. and S.T. conducted and supervised the experiments. N.I. and U.T.R. designed the experiments and wrote the manuscript, and all authors discussed the results and commented on the manuscript.
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Ito, N., Ruegg, U., Kudo, A. et al. Activation of calcium signaling through Trpv1 by nNOS and peroxynitrite as a key trigger of skeletal muscle hypertrophy. Nat Med 19, 101–106 (2013). https://doi.org/10.1038/nm.3019
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DOI: https://doi.org/10.1038/nm.3019
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