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

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.

Pubmed ID: 18953332

Authors

  • Kobayashi YM
  • Rader EP
  • Crawford RW
  • Iyengar NK
  • Thedens DR
  • Faulkner JA
  • Parikh SV
  • Weiss RM
  • Chamberlain JS
  • Moore SA
  • Campbell KP

Journal

Nature

Publication Data

November 27, 2008

Associated Grants

  • Agency: NIAMS NIH HHS, Id: F32 AR048742-01
  • Agency: NIAMS NIH HHS, Id: F32 AR048742-02
  • Agency: NCRR NIH HHS, Id: K26 RR017369
  • Agency: NCRR NIH HHS, Id: K26 RR017369-01A1
  • Agency: NCRR NIH HHS, Id: K26 RR017369-02
  • Agency: NCRR NIH HHS, Id: K26 RR017369-03
  • Agency: NCRR NIH HHS, Id: K26 RR017369-04
  • Agency: NCRR NIH HHS, Id: K26 RR017369-05
  • Agency: NIA NIH HHS, Id: R01 AG033610
  • Agency: NIAMS NIH HHS, Id: R01 AR051199
  • Agency: NIAMS NIH HHS, Id: R01 AR051199-01
  • Agency: NHLBI NIH HHS, Id: T32 HL007121
  • Agency: NHLBI NIH HHS, Id: T32 HL007121-26
  • Agency: NHLBI NIH HHS, Id: T32 HL007121-27
  • Agency: NINDS NIH HHS, Id: U54 NS053672
  • Agency: NINDS NIH HHS, Id: U54 NS053672-01
  • Agency: NINDS NIH HHS, Id: U54 NS053672-02
  • Agency: NINDS NIH HHS, Id: U54 NS053672-02S1
  • Agency: NINDS NIH HHS, Id: U54 NS053672-03
  • Agency: NINDS NIH HHS, Id: U54 NS053672-04
  • Agency: Howard Hughes Medical Institute, Id:
  • Agency: Howard Hughes Medical Institute, Id:

Mesh Terms

  • Animals
  • Cyclic GMP
  • Cyclic Nucleotide Phosphodiesterases, Type 5
  • Disease Models, Animal
  • Edema
  • Enzyme Activation
  • Exercise
  • Fatigue
  • Hemodynamics
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred mdx
  • Muscle, Skeletal
  • Muscular Diseases
  • Nitric Oxide
  • Nitric Oxide Synthase Type I
  • Phosphodiesterase 5 Inhibitors
  • Protein Transport
  • Sarcolemma
  • Signal Transduction