Nitrosative stress elicited by nNOSµ delocalization inhibits muscle force in dystrophin‐null mice
Nitrosative stress elicited by nNOSµ delocalization inhibits muscle force in dystrophin‐null mice
复制标题
nNOSμ 离域引起的亚硝化应激抑制肌营养不良蛋白缺失小鼠的肌肉力量
作者：
Dejia Li;Y. Yue;Yi Lai;Chady H. Hakim;D. Duan
杜氏肌营养不良症（DMD）是一种营养不良蛋白缺乏的致死性疾病，其力量减少的机制尚不完全清楚。一氧化氮调节肌肉力量。有趣的是，神经元一氧化氮合酶µ（nNOSµ）是肌肉一氧化氮的主要来源，在DMD肌肉的肌膜中丢失。我们假设nNOS微离域有助于DMD的力降低。为了验证这一假设，我们产生了dystrophin/nNOSµ双敲除小鼠。基因消除nNOSµ可显著增强肌营养不良蛋白缺失小鼠的力。药理抑制nNOS产生了类似的结果。为了进一步验证我们的假设，我们研究了δ -肌聚糖缺失小鼠，一种肢带肌营养不良模型。这些小鼠的肌上皮nNOS脱位最小，肌肉力量受损较小。歼灭nNOSµ也没有改善他们的力量。为了确定nNOS μ脱位本身是否会抑制力，我们用微肌营养不良蛋白修复或不恢复肌层nNOS μ的微肌营养不良蛋白来纠正肌营养不良蛋白缺失小鼠的肌肉疾病。无论nNOS定位如何，均可获得相似的肌肉力。其他研究表明，nNOS脱位通过亚硝化应激选择性地抑制肌营养不良蛋白缺失小鼠的肌力。总之，我们首次证明了nNOS微离域引起的亚硝化应力是DMD中力损失的重要机制。版权所有©2010英国和爱尔兰病理学会。约翰·威利父子有限公司出版。
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 µ (nNOSµ), a major source of muscle nitric oxide, is lost from the sarcolemma in DMD muscle. We hypothesize that nNOSµ delocalization contributes to force reduction in DMD. To test this hypothesis, we generated dystrophin/nNOSµ double knockout mice. Genetic elimination of nNOSµ significantly enhanced force in dystrophin‐null mice. Pharmacological inhibition of nNOS yielded similar results. To further test our hypothesis, we studied δ‐sarcoglycan‐null mice, a model of limb‐girdle muscular dystrophy. These mice had minimal sarcolemmal nNOSµ delocalization and muscle force was less compromised. Annihilation of nNOSµ did not improve their force either. To determine whether nNOSµ delocalization itself inhibited force, we corrected muscle disease in dystrophin‐null mice with micro‐dystrophins that either restored or did not restore sarcolemmal nNOSµ. Similar muscle force was obtained irrespective of nNOSµ localization. Additional studies suggest that nNOSµ 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 nNOSµ delocalization is an important mechanism underlying force loss in DMD. Copyright © 2010 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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影响因子：
5.5
作者：
BROOKS, SV;FAULKNER, JA
通讯作者：
FAULKNER, JA
影响因子：
15.9
作者：
Percival, Justin M.;Anderson, Kendra N. E.;Froehner, Stanley C.
通讯作者：
Froehner, Stanley C.
影响因子：
33.6
作者：
Powers SK;Jackson MJ
通讯作者：
Jackson MJ
DOI：
10.1073/pnas.90.8.3710
发表时间：
1993-04-15
影响因子：
11.1
作者：
PETROF, BJ;SHRAGER, JB;SWEENEY, HL
通讯作者：
SWEENEY, HL