1. Howard Hughes Medical Institute,
2. Department of Molecular Physiology and Biophysics,
3. Department of Neurology,
4. Department of Internal Medicine,
5. Department of Radiology,
6. Department of Pathology, University of Iowa, Roy J. and Lucille A. Carver College of Medicine, 4283 Carver Biomedical Research Building, 285 Newton Road, Iowa City, Iowa 52242-1101, USA
7. Department of Molecular and Integrative Physiology, University of Michigan, 2031 Biomedical Sciences Research Building, Ann Arbor, Michigan 48109-2200, USA
8. Department of Neurology, University of Washington School of Medicine, HSB, Room K243b, Seattle, Washington 98195-7720, USA

Correspondence to: Kevin P. Campbell^1,2,3,4 Correspondence and requests for materials should be addressed to K.P.C. (Email: kevin-campbell@uiowa.edu).

Abstract

Many neuromuscular conditions are characterized by an exaggerated exercise-induced fatigue response that is disproportionate to activity level. This fatigue is not necessarily correlated with greater central or peripheral fatigue in patients¹, and some patients experience severe fatigue without any demonstrable somatic disease². Except in myopathies that are due to specific metabolic defects, the mechanism underlying this type of fatigue remains unknown². With no treatment available, this form of inactivity is a major determinant of disability³. Here we show, using mouse models, that this exaggerated fatigue response is distinct from a loss in specific force production by muscle, and that sarcolemma-localized signalling by neuronal nitric oxide synthase (nNOS) in skeletal muscle is required to maintain activity after mild exercise. We show that nNOS-null mice do not have muscle pathology and have no loss of muscle-specific force after exercise but do display this exaggerated fatigue response to mild exercise. In mouse models of nNOS mislocalization from the sarcolemma, prolonged inactivity was only relieved by pharmacologically enhancing the cGMP signal that results from muscle nNOS activation during the nitric oxide signalling response to mild exercise. Our findings suggest that the mechanism underlying the exaggerated fatigue response to mild exercise is a lack of contraction-induced signalling from sarcolemma-localized nNOS, which decreases cGMP-mediated vasomodulation in the vessels that supply active muscle after mild exercise. Sarcolemmal nNOS staining was decreased in patient biopsies from a large number of distinct myopathies, suggesting a common mechanism of fatigue. Our results suggest that patients with an exaggerated fatigue response to mild exercise would show clinical improvement in response to treatment strategies aimed at improving exercise-induced signalling.

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