Sarcolemma-localized nNOS is required to maintain activity after mild exercise
dc.contributor.author | Kobayashi, Yvonne M. | en_US |
dc.contributor.author | Rader, Erik P. | en_US |
dc.contributor.author | Crawford, Robert W. | en_US |
dc.contributor.author | Iyengar, Nikhil K. | en_US |
dc.contributor.author | Thedens, Daniel R. | en_US |
dc.contributor.author | Faulkner, John A. | en_US |
dc.contributor.author | Parikh, Swapnesh V. | en_US |
dc.contributor.author | Weiss, Robert M. | en_US |
dc.contributor.author | Chamberlain, Jeffrey S. | en_US |
dc.contributor.author | Moore, Steven A. | en_US |
dc.contributor.author | Campbell, Kevin P. | en_US |
dc.date.accessioned | 2009-06-01T17:40:53Z | |
dc.date.available | 2009-06-01T17:40:53Z | |
dc.date.issued | 2008-11-27 | en_US |
dc.identifier.citation | Kobayashi, Yvonne M.; Rader, Erik P.; Crawford, Robert W.; Iyengar, Nikhil K.; Thedens, Daniel R.; Faulkner, John A.; Parikh, Swapnesh V.; Weiss, Robert M.; Chamberlain, Jeffrey S.; Moore, Steven A.; Campbell, Kevin P.. (2008) "Sarcolemma-localized nNOS is required to maintain activity after mild exercise." Nature 456(7221): 511-515. <http://hdl.handle.net/2027.42/62850> | en_US |
dc.identifier.issn | 0028-0836 | en_US |
dc.identifier.uri | https://hdl.handle.net/2027.42/62850 | |
dc.identifier.uri | http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=retrieve&db=pubmed&list_uids=18953332&dopt=citation | en_US |
dc.description.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 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 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. | en_US |
dc.description.sponsorship | Paul D. Wellstone Muscular Dystrophy Cooperative Research Center Grant ; University of Iowa Cardiovascular Interdisciplinary Research ; National Research Service Award ; National Institute of Arthritis and Musculoskeletal and Skin Diseases ; National Institutes of Health ; Senator Paul D. Wellstone Fellowship ; Muscular Dystrophy Association Development Grant ; Howard Hughes Medical Institute | en_US |
dc.description.sponsorship | We thank M. Anderson and M. Henry for comments, and M. M. Kilburg, K. Uppal, B. J. Steinmann and S. Watkins and members of the Campbell laboratory for scientific contributions. This work was supported in part by a Paul D. Wellstone Muscular Dystrophy Cooperative Research Center Grant. Y.M.K. was supported by grants from the University of Iowa Cardiovascular Interdisciplinary Research/ National Research Service Award (NRSA) Fellowship, from an individual NRSA Fellowship from the National Institute of Arthritis and Musculoskeletal and Skin Diseases, from the National Institutes of Health (NIH), and from a Senator Paul D. Wellstone Fellowship. E.P.R. was supported by a Muscular Dystrophy Association Development Grant. R.M.W. was supported by the NIH. K.P.C. is an investigator of the Howard Hughes Medical Institute. | en_US |
dc.format.extent | 826467 bytes | |
dc.format.extent | 2489 bytes | |
dc.format.mimetype | application/pdf | |
dc.format.mimetype | text/plain | |
dc.publisher | Nature Publishing Group | en_US |
dc.source | Nature | en_US |
dc.title | Sarcolemma-localized nNOS is required to maintain activity after mild exercise | en_US |
dc.type | Article | en_US |
dc.subject.hlbtoplevel | Science | en_US |
dc.description.peerreviewed | Peer Reviewed | en_US |
dc.contributor.affiliationum | [Faulkner, John A.] Univ Michigan, Dept Mol & Integrat Physiol, Ann Arbor, MI 48109 USA | en_US |
dc.contributor.affiliationother | [Kobayashi, Yvonne M. | en_US |
dc.contributor.affiliationother | Rader, Erik P. | en_US |
dc.contributor.affiliationother | Crawford, Robert W. | en_US |
dc.contributor.affiliationother | Campbell, Kevin P.] Univ Iowa, Roy J & Lucille A Carver Coll Med, Howard Hughes Med Inst, Iowa City, IA 52242 USA | en_US |
dc.contributor.affiliationother | [Kobayashi, Yvonne M. | en_US |
dc.contributor.affiliationother | Rader, Erik P. | en_US |
dc.contributor.affiliationother | Crawford, Robert W. | en_US |
dc.contributor.affiliationother | Campbell, Kevin P.] Univ Iowa, Roy J & Lucille A Carver Coll Med, Dept Mol Physiol & Biophys, Iowa City, IA 52242 USA | en_US |
dc.contributor.affiliationother | [Kobayashi, Yvonne M. | en_US |
dc.contributor.affiliationother | Rader, Erik P. | en_US |
dc.contributor.affiliationother | Crawford, Robert W. | en_US |
dc.contributor.affiliationother | Campbell, Kevin P.] Univ Iowa, Roy J & Lucille A Carver Coll Med, Dept Neurol, Iowa City, IA 52242 USA | en_US |
dc.contributor.affiliationother | [Kobayashi, Yvonne M. | en_US |
dc.contributor.affiliationother | Rader, Erik P. | en_US |
dc.contributor.affiliationother | Crawford, Robert W. | en_US |
dc.contributor.affiliationother | Iyengar, Nikhil K. | en_US |
dc.contributor.affiliationother | Parikh, Swapnesh V. | en_US |
dc.contributor.affiliationother | Weiss, Robert M. | en_US |
dc.contributor.affiliationother | Campbell, Kevin P.] Univ Iowa, Roy J & Lucille A Carver Coll Med, Dept Internal Med, Iowa City, IA 52242 USA | en_US |
dc.contributor.affiliationother | [Thedens, Daniel R.] Univ Iowa, Roy J & Lucille A Carver Coll Med, Dept Radiol, Iowa City, IA 52242 USA | en_US |
dc.contributor.affiliationother | [Moore, Steven A.] Univ Iowa, Roy J & Lucille A Carver Coll Med, Dept Pathol, Iowa City, IA 52242 USA | en_US |
dc.contributor.affiliationother | [Chamberlain, Jeffrey S.] Univ Washington, Sch Med, Dept Neurol, Seattle, WA 98195 USA | en_US |
dc.identifier.pmid | 18953332 | en_US |
dc.description.bitstreamurl | http://deepblue.lib.umich.edu/bitstream/2027.42/62850/1/nature07414.pdf | |
dc.identifier.doi | http://dx.doi.org/10.1038/nature07414 | en_US |
dc.identifier.source | Nature | en_US |
dc.contributor.authoremail | kevin-campbell@uiowa.edu | en_US |
dc.owningcollname | Interdisciplinary and Peer-Reviewed |
Files in this item
Remediation of Harmful Language
The University of Michigan Library aims to describe library materials in a way that respects the people and communities who create, use, and are represented in our collections. Report harmful or offensive language in catalog records, finding aids, or elsewhere in our collections anonymously through our metadata feedback form. More information at Remediation of Harmful Language.
Accessibility
If you are unable to use this file in its current format, please select the Contact Us link and we can modify it to make it more accessible to you.