| First Author | Li D | Year | 2011 |
| Journal | J Pathol | Volume | 223 |
| Issue | 1 | Pages | 88-98 |
| PubMed ID | 21125668 | Mgi Jnum | J:167308 |
| Mgi Id | MGI:4867784 | Doi | 10.1002/path.2799 |
| Citation | Li D, et al. (2011) Nitrosative stress elicited by nNOSmicro delocalization inhibits muscle force in dystrophin-null mice. J Pathol 223(1):88-98 |
| abstractText | 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 micro (nNOSmicro), a major source of muscle nitric oxide, is lost from the sarcolemma in DMD muscle. We hypothesize that nNOSmicro delocalization contributes to force reduction in DMD. To test this hypothesis, we generated dystrophin/nNOSmicro double knockout mice. Genetic elimination of nNOSmicro 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 nNOSmicro delocalization and muscle force was less compromised. Annihilation of nNOSmicro did not improve their force either. To determine whether nNOSmicro delocalization itself inhibited force, we corrected muscle disease in dystrophin-null mice with micro-dystrophins that either restored or did not restore sarcolemmal nNOSmicro. Similar muscle force was obtained irrespective of nNOSmicro localization. Additional studies suggest that nNOSmicro 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 nNOSmicro delocalization is an important mechanism underlying force loss in DMD. |
