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Biophysical Reviews

, Volume 3, Issue 4, pp 209–217 | Cite as

nNOS regulation of skeletal muscle fatigue and exercise performance

  • Justin M. Percival
Review

Abstract

Neuronal nitric oxide synthases (nNOS) are Ca2+/calmodulin-activated enzymes that synthesize the gaseous messenger nitric oxide (NO). nNOSμ and the recently described nNOSβ, both spliced nNOS isoforms, are important enzymatic sources of NO in skeletal muscle, a tissue long considered to be a paradigmatic system for studying NO-dependent redox signaling. nNOS is indispensable for skeletal muscle integrity and contractile performance, and deregulation of nNOSμ signaling is a common pathogenic feature of many neuromuscular diseases. Recent evidence suggests that both nNOSμ and nNOSβ regulate skeletal muscle size, strength, and fatigue resistance, making them important players in exercise performance. nNOSμ acts as an activity sensor and appears to assist skeletal muscle adaptation to new functional demands, particularly those of endurance exercise. Prolonged inactivity leads to nNOS-mediated muscle atrophy through a FoxO-dependent pathway. nNOS also plays a role in modulating exercise performance in neuromuscular disease. In the mdx mouse model of Duchenne muscular dystrophy, defective nNOS signaling is thought to restrict contractile capacity of working muscle in two ways: loss of sarcolemmal nNOSμ causes excessive ischemic damage while residual cytosolic nNOSμ contributes to hypernitrosylation of the ryanodine receptor, causing pathogenic Ca2+ leak. This defect in Ca2+ handling promotes muscle damage, weakness, and fatigue. This review addresses these recent advances in the understanding of nNOS-dependent redox regulation of skeletal muscle function and exercise performance under physiological and neuromuscular disease conditions.

Keywords

Nitric oxide nNOS Ryanodine receptor Nitrosylation Dystrophin Fatigue 

Notes

Acknowledgments

I wish to thank Drs Kimberley Craven, Stanley Froehner, Marvin Adams, and Nicholas Whitehead for insightful discussions and critical comment. Funding sources include the Muscular Dystrophy Association (69075), Parent Project Muscular Dystrophy, and NIH grants R01 AR056221, R01 NS33145, and PO1 NS046788.

Conflict of Interest

None

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Copyright information

© International Union for Pure and Applied Biophysics (IUPAB) and Springer 2011

Authors and Affiliations

  1. 1.Department of Physiology & BiophysicsUniversity of WashingtonSeattleUSA

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