Disatnik M H, Dhawan J, Yu Y, Beal M F, Whirl M M, Franco A A, Rando T A
Department of Veterans Affairs, Palo Alto, CA, USA.
J Neurol Sci. 1998 Nov 26;161(1):77-84. doi: 10.1016/s0022-510x(98)00258-5.
Considerable evidence indicates that free radical injury may underlie the pathologic changes in muscular dystrophies from mammalian and avian species. We have investigated the role of oxidative injury in muscle necrosis in mice with a muscular dystrophy due to a defect in the dystrophin gene (the mdx strain). In order to avoid secondary consequences of muscle necrosis, all experiments were done on muscle prior to the onset of the degenerative process (i.e. during the 'pre-necrotic' phase) which lasted up to 20 days of age in the muscles examined. In pre-necrotic mdx muscle, there was an induction of expression of genes encoding antioxidant enzymes, indicative of a cellular response to oxidative stress. In addition, the levels of lipid peroxidation were greater in mdx muscle than in the control. Since the free radical nitric oxide (NO*) has been shown to mediate oxidative injury in various disease states, and because dystrophin has been shown to form a complex with the enzyme nitric oxide synthase, we examined pre-necrotic mdx muscle for evidence of NO*-mediated injury by measuring cellular nitrotyrosine formation. By both immunohistochemical and electrochemical analyses, no evidence of increased nitrotyrosine levels in mdx muscle was detected. Therefore, although no relationship with NO*-mediated toxicity was found, we found evidence of increased oxidative stress preceding the onset of muscle cell death in dystrophin-deficient mice. These results lend support to the hypothesis that free radical-mediated injury may contribute to the pathogenesis of muscular dystrophies.
大量证据表明，自由基损伤可能是哺乳动物和鸟类肌肉营养不良病理变化的基础。我们研究了氧化损伤在因抗肌萎缩蛋白基因缺陷（mdx品系）导致肌肉营养不良的小鼠肌肉坏死中的作用。为了避免肌肉坏死的继发后果，所有实验均在肌肉退化过程开始之前（即在“坏死前期”）进行，在所检查的肌肉中，该阶段可持续到20日龄。在坏死前期的mdx肌肉中，编码抗氧化酶的基因表达被诱导，这表明细胞对氧化应激有反应。此外，mdx肌肉中的脂质过氧化水平高于对照组。由于自由基一氧化氮（NO*）已被证明在各种疾病状态下介导氧化损伤，并且由于抗肌萎缩蛋白已被证明与一氧化氮合酶形成复合物，我们通过测量细胞中硝基酪氨酸的形成，检查坏死前期的mdx肌肉中是否存在NO介导损伤的证据。通过免疫组织化学和电化学分析，均未检测到mdx肌肉中硝基酪氨酸水平升高的证据。因此，虽然未发现与NO介导的毒性有关，但我们发现了抗肌萎缩蛋白缺陷小鼠肌肉细胞死亡开始前氧化应激增加的证据。这些结果支持了自由基介导的损伤可能导致肌肉营养不良发病机制的假说。
