Sander M, Chavoshan B, Harris S A, Iannaccone S T, Stull J T, Thomas G D, Victor R G
Copenhagen Muscle Research Center, Rigshospitalet, DK-2200, Copenhagen N, Denmark.
Proc Natl Acad Sci U S A. 2000 Dec 5;97(25):13818-23. doi: 10.1073/pnas.250379497.
Duchenne muscular dystrophy (DMD) is a fatal disease caused by mutation of the gene encoding the cytoskeletal protein dystrophin. Despite a wealth of recent information about the molecular basis of DMD, effective treatment for this disease does not exist because the mechanism by which dystrophin deficiency produces the clinical phenotype is unknown. In both mouse and human skeletal muscle, dystrophin deficiency results in loss of neuronal nitric oxide synthase, which normally is localized to the sarcolemma as part of the dystrophin-glycoprotein complex. Recent studies in mice suggest that skeletal muscle-derived nitric oxide may play a key role in the regulation of blood flow within exercising skeletal muscle by blunting the vasoconstrictor response to alpha-adrenergic receptor activation. Here we report that this protective mechanism is defective in children with DMD, because the vasoconstrictor response (measured as a decrease in muscle oxygenation) to reflex sympathetic activation was not blunted during exercise of the dystrophic muscles. In contrast, this protective mechanism is intact in healthy children and those with polymyositis or limb-girdle muscular dystrophy, muscle diseases that do not result in loss of neuronal nitric oxide synthase. This clinical investigation suggests that unopposed sympathetic vasoconstriction in exercising human skeletal muscle may constitute a heretofore unappreciated vascular mechanism contributing to the pathogenesis of DMD.
杜兴氏肌肉营养不良症（DMD）是一种由编码细胞骨架蛋白肌营养不良蛋白的基因突变引起的致命疾病。尽管最近有大量关于DMD分子基础的信息，但由于肌营养不良蛋白缺乏产生临床表型的机制尚不清楚，因此目前尚无针对该疾病的有效治疗方法。在小鼠和人类骨骼肌中，肌营养不良蛋白缺乏都会导致神经元型一氧化氮合酶的丧失，该酶通常作为肌营养不良蛋白-糖蛋白复合物的一部分定位于肌膜。最近对小鼠的研究表明，骨骼肌衍生的一氧化氮可能通过减弱对α-肾上腺素能受体激活的血管收缩反应，在运动的骨骼肌内的血流调节中起关键作用。在此我们报告，这种保护机制在DMD患儿中存在缺陷，因为在营养不良肌肉运动期间，对反射性交感神经激活的血管收缩反应（以肌肉氧合减少来衡量）并未减弱。相比之下，这种保护机制在健康儿童以及患有多发性肌炎或肢带型肌肉营养不良症的儿童中是完整的，这些肌肉疾病不会导致神经元型一氧化氮合酶的丧失。这项临床研究表明，运动的人类骨骼肌中无对抗的交感神经血管收缩可能构成一种迄今为止未被认识的血管机制，促成了DMD的发病机制。
