Sarcolemma-localized nNOS is required to maintain activity after mild exercise

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Abstract
Many neuromuscular conditions, such as Duchenne muscular dystrophy, involve an exaggerated exercise-induced fatigue response. Experiments in mice have identified a potential cause of this fatigue: when neuronal nitric oxide synthase (nNOS) is missing from its normal location on the muscle membrane, the blood vessels that supply the muscles fail to relax normally and the animals experience post-exercise fatigue. Sarcolemmal nNOS was found to be reduced in biopsies from patients with a range of distinct myopathies pointing towards a common mechanism of fatigue. These results suggest that patients with an exaggerated fatigue response to mild exercise may respond to treatment that improves exercise-induced signalling. Many neuromuscular conditions are characterized by an exaggerated exercise-induced fatigue response. This form of inactivity is a major determinant of disability. The mechanism underlying this type of fatigue remains unknown. It is shown in mice that such exaggerated fatigue is due to a lack of contraction-induced signalling from sarcolemma-localized nNOS. In addition, in patient biopsies from a large number of distinct myopathies, sarcolemmal nNOS is reduced—pointing towards a common mechanism of fatigue. 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.