Publication Date:
2008-10-28
Description:
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, and some patients experience severe fatigue without any demonstrable somatic disease. Except in myopathies that are due to specific metabolic defects, the mechanism underlying this type of fatigue remains unknown. With no treatment available, this form of inactivity is a major determinant of disability. 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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2588643/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2588643/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉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 -- F32 AR048742-01/AR/NIAMS NIH HHS/ -- F32 AR048742-02/AR/NIAMS NIH HHS/ -- K26 RR017369/RR/NCRR NIH HHS/ -- K26 RR017369-01A1/RR/NCRR NIH HHS/ -- K26 RR017369-02/RR/NCRR NIH HHS/ -- K26 RR017369-03/RR/NCRR NIH HHS/ -- K26 RR017369-04/RR/NCRR NIH HHS/ -- K26 RR017369-05/RR/NCRR NIH HHS/ -- R01 AG033610/AG/NIA NIH HHS/ -- R01 AR051199/AR/NIAMS NIH HHS/ -- R01 AR051199-01/AR/NIAMS NIH HHS/ -- T32 HL007121/HL/NHLBI NIH HHS/ -- T32 HL007121-26/HL/NHLBI NIH HHS/ -- T32 HL007121-27/HL/NHLBI NIH HHS/ -- U54 NS053672/NS/NINDS NIH HHS/ -- U54 NS053672-01/NS/NINDS NIH HHS/ -- U54 NS053672-02/NS/NINDS NIH HHS/ -- U54 NS053672-02S1/NS/NINDS NIH HHS/ -- U54 NS053672-03/NS/NINDS NIH HHS/ -- U54 NS053672-04/NS/NINDS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2008 Nov 27;456(7221):511-5. doi: 10.1038/nature07414. Epub 2008 Oct 26.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉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.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18953332" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Cyclic GMP/metabolism
;
Cyclic Nucleotide Phosphodiesterases, Type 5
;
*Disease Models, Animal
;
Edema/drug therapy/etiology/prevention & control
;
Enzyme Activation
;
Exercise/*physiology
;
Fatigue/pathology/*physiopathology
;
Hemodynamics/drug effects
;
Humans
;
Mice
;
Mice, Inbred C57BL
;
Mice, Inbred mdx
;
Muscle, Skeletal/blood supply/cytology/enzymology/physiopathology
;
Muscular Diseases/enzymology/pathology
;
Nitric Oxide/metabolism
;
Nitric Oxide Synthase Type I/deficiency/genetics/*metabolism
;
Phosphodiesterase 5 Inhibitors
;
Protein Transport
;
Sarcolemma/*enzymology
;
Signal Transduction
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
Permalink