期刊
JOURNAL OF PATHOLOGY
卷 223, 期 1, 页码 88-98出版社
WILEY
DOI: 10.1002/path.2799
关键词
dystrophin; Duchenne muscular dystrophy; nitrosative stress; nitrotyrosination; nNOS; delta-sarcoglycan; mdx; mdx4cv; ryanodine receptor 1; S-nitrosylation
资金
- National Institutes of Health [AR-49419]
- Muscular Dystrophy Association
- NIH [T90DK70105]
- NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES [R01AR049419] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [T90DK070105] Funding Source: NIH RePORTER
The mechanism of force reduction is not completely understood in Duchenne muscular dystrophy (DMD), a dystrophin-deficient lethal disease. Nitric oxide regulates muscle force. Interestingly, neuronal nitric oxide synthase mu (nNOS mu), a major source of muscle nitric oxide, is lost from the sarcolemma in DMD muscle. We hypothesize that nNOS mu delocalization contributes to force reduction in DMD. To test this hypothesis, we generated dystrophin/nNOS mu double knockout mice. Genetic elimination of nNOS mu significantly enhanced force in dystrophin-null mice. Pharmacological inhibition of nNOS yielded similar results. To further test our hypothesis, we studied delta-sarcoglycan-null mice, a model of limb-girdle muscular dystrophy. These mice had minimal sarcolemmal nNOS mu delocalization and muscle force was less compromised. Annihilation of nNOS mu did not improve their force either. To determine whether nNOS mu delocalization itself inhibited force, we corrected muscle disease in dystrophin-null mice with micro-dystrophins that either restored or did not restore sarcolemmal nNOS mu. Similar muscle force was obtained irrespective of nNOS mu localization. Additional studies suggest that nNOS mu delocalization selectively inhibits muscle force in dystrophin-null mice via nitrosative stress. In summary, we have demonstrated for the first time that nitrosative stress elicited by nNOS mu delocalization is an important mechanism underlying force loss in DMD. Copyright (C) 2010 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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