Law D J, Allen D L, Tidball J G
Department of Physiological Science, University of California, Los Angeles 90024-1527.
J Cell Sci. 1994 Jun;107 ( Pt 6):1477-83. doi: 10.1242/jcs.107.6.1477.
Duchenne muscular dystrophy (DMD) and the myopathy seen in the mdx mouse both result from absence of the protein dystrophin. Structural similarities between dystrophin and other cytoskeletal proteins, its enrichment at myotendinous junctions, and its indirect association with laminin mediated by a transmembrane glycoprotein complex suggest that one of dystrophin's functions in normal muscle is to form one of the links between the actin cytoskeleton and the extracellular matrix. Unlike Duchenne muscular dystrophy patients, mdx mice suffer only transient muscle necrosis, and are able to regenerate damaged muscle tissue. The present study tests the hypothesis that mdx mice partially compensate for dystrophin's absence by upregulating one or more dystrophin-independent mechanisms of cytoskeleton-membrane association. Quantitative analysis of immunoblots of adult mdx muscle samples showed an increase of approximately 200% for vinculin and talin, cytoskeletal proteins that mediate thin filament-membrane interactions at myotendinous junctions. Blots also showed an increase (143%) in the dystrophin-related protein called utrophin, another myotendinous junction constituent, which may be able to substitute for dystrophin directly. Muscle samples from 2-week-old animals, a period immediately preceding the onset of muscle necrosis, showed no significant differences in protein concentration between mdx and controls. Quantitative analyses of confocal images of myotendinous junctions from mdx and control muscles show significantly higher concentrations of talin and vinculin at the myotendinous junctions of mdx muscle. These findings indicate that mdx mice may compensate in part for the absence of dystrophin by increased expression of other molecules that subsume dystrophin's mechanical function.
杜兴氏肌肉营养不良症（DMD）以及mdx小鼠中出现的肌病均由抗肌萎缩蛋白缺失所致。抗肌萎缩蛋白与其他细胞骨架蛋白在结构上具有相似性，在肌-腱连接处高度富集，并且通过跨膜糖蛋白复合物与层粘连蛋白间接关联，这表明抗肌萎缩蛋白在正常肌肉中的功能之一是形成肌动蛋白细胞骨架与细胞外基质之间的连接之一。与杜兴氏肌肉营养不良症患者不同，mdx小鼠仅经历短暂的肌肉坏死，并且能够再生受损的肌肉组织。本研究检验了以下假设：mdx小鼠通过上调一种或多种与抗肌萎缩蛋白无关的细胞骨架-膜关联机制来部分补偿抗肌萎缩蛋白的缺失。对成年mdx肌肉样本免疫印迹的定量分析显示，纽蛋白和踝蛋白增加了约200%，这两种细胞骨架蛋白在肌-腱连接处介导细肌丝与膜的相互作用。印迹还显示，另一种肌-腱连接成分、与抗肌萎缩蛋白相关的蛋白——抗肌萎缩蛋白聚糖增加了143%，它可能能够直接替代抗肌萎缩蛋白。来自2周龄动物（恰好在肌肉坏死开始之前的时期）的肌肉样本显示，mdx小鼠和对照小鼠在蛋白质浓度上没有显著差异。对mdx小鼠和对照小鼠肌-腱连接处共聚焦图像的定量分析显示，mdx小鼠肌-腱连接处的踝蛋白和纽蛋白浓度显著更高。这些发现表明，mdx小鼠可能通过增加表达其他承担抗肌萎缩蛋白机械功能的分子来部分补偿抗肌萎缩蛋白的缺失。
