Journal article
Sarcolemma-localized nNOS is required to maintain activity after mild exercise
Nature (London), Vol.456(7221), pp.511-515
11/27/2008
DOI: 10.1038/nature07414
PMCID: PMC2588643
PMID: 18953332
Abstract
Many neuromuscular conditions are characterized by an exaggerated exercise-induced fatigue response that is disproportionate to activity level. This fatigue does not necessarily correlate with elevated central or peripheral fatigue in patients
1
, and some patients experience severe fatigue without any demonstrable somatic disease
2
. Except in myopathies that are due to specific metabolic defects, the mechanism underlying this type of fatigue remains unknown
2
. With no treatment available, this form of inactivity is a major determinant of disability
3
. 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 nNOS signaling in skeletal muscle is required to maintain activity after mild exercise. Of significance, 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 signaling response to mild exercise. Our findings suggest that the mechanism underlying the exaggerated fatigue response to mild exercise is a lack of contraction-induced signaling from sarcolemma-localized nNOS, which reduces cGMP-mediated vasomodulation in the vessels that supply active muscle after mild exercise. Notably, sarcolemmal nNOS was reduced 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 signaling.
Details
- Title: Subtitle
- Sarcolemma-localized nNOS is required to maintain activity after mild exercise
- Creators
- Yvonne M Kobayashi - Howard Hughes Medical Institute, 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 USAErik P Rader - Howard Hughes Medical Institute, 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 USARobert W Crawford - Howard Hughes Medical Institute, 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 USANikhil K Iyengar - Department of Internal Medicine, 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 USADaniel R Thedens - Department of Radiology, 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 USAJohn A Faulkner - Department of Molecular and Integrative Physiology, University of Michigan, 2031 Biomedical Sciences Research Building, Ann Arbor, Michigan 48109−2200Swapnesh V Parikh - Department of Internal Medicine, 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 USARobert M Weiss - Department of Internal Medicine, 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 USAJeffrey S Chamberlain - Department of Neurology, University of Washington School of Medicine, HSB, Room K243b, Seattle, Washington 98195−7720Steven A Moore - 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 USAKevin P Campbell - Howard Hughes Medical Institute, 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
- Resource Type
- Journal article
- Publication Details
- Nature (London), Vol.456(7221), pp.511-515
- DOI
- 10.1038/nature07414
- PMID
- 18953332
- PMCID
- PMC2588643
- ISSN
- 0028-0836
- eISSN
- 1476-4687
- Language
- English
- Date published
- 11/27/2008
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Neurology; Radiology; Electrical and Computer Engineering; Molecular Physiology and Biophysics; Pathology; Iowa Neuroscience Institute; Cardiovascular Medicine; Internal Medicine
- Record Identifier
- 9984020848302771
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