NO more muscle fatigue
Ahlke Heydemann, Elizabeth McNally
Ahlke Heydemann, Elizabeth McNally
Published March 2, 2009; First published February 23, 2009
Citation Information: J Clin Invest. 2009;119(3):448-450. https://doi.org/10.1172/JCI38618.
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Commentary

NO more muscle fatigue

Abstract

NOS is a key enzyme in the production of NO, a molecule that directly regulates vasorelaxation and blood supply. Diverse forms of muscle disease have been clinically associated with unusual fatigue after exercise. The localization of neuronal NOS (nNOS) at the plasma membrane of muscle has recently been shown to prevent muscle fatigue after exercise. In this issue of the JCI, Lai et al. show that dystrophin — the structural protein missing in individuals with Duchenne muscular dystrophy — anchors nNOS to the sarcolemma through a direct interaction with dystrophin spectrin-like repeats 16 and 17 (see the related article beginning on page 624). Furthermore, in another recently reported study of mouse models of muscular dystrophy, phosphodiesterase 5A inhibitors were used to treat the downstream ischemia that is associated with nNOS mislocalization. Collectively, these findings significantly advance our understanding of exercise-induced muscle fatigue and its role in muscle disease.

Authors

Ahlke Heydemann, Elizabeth McNally

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Figure 1

Mechanism for the localization of nNOS to the plasma membrane of muscle.

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Mechanism for the localization of nNOS to the plasma membrane of muscle....
Sarcolemmal nNOS promotes vasodilation and improves blood flow into muscle. This blood flow is necessary to prevent early fatigue with exercise. In this issue of the JCI, Lai et al. show that a direct interaction between dystrophin and nNOS is mediated by spectrin-like repeats 16 and 17 in dystrophin (SR16/17) (14). It was previously shown that α-syntrophin could directly bind nNOS by way of its PDZ domain (15). Loss of dystrophin in humans with DMD or in mdx mice is associated with reduction in levels of dystrophin-associated proteins including α-syntrophin and nNOS (2). Work by Lai et al. (14) as well as recent reports by Kobayashi et al. (16) and Percival et al. (8) now clarify that loss of nNOS from the plasma membrane mediates muscle fatigue after minimal exercise and that this feature is present in diverse forms of muscle disease.