Institute of Human Genetics, International Centre for Life, University of Newcastle, Newcastle-upon-Tyne NE1 3BZ, UK.
Muscle Nerve. 2010 Feb;41(2):166-73. doi: 10.1002/mus.21166.
Mutations in the dysferlin gene cause limb-girdle muscular dystrophy type 2B, Miyoshi myopathy, and distal anterior compartment myopathy. Dysferlin mainly localizes to the sarcolemma in mature skeletal muscle where it is implicated in membrane fusion and repair. In different forms of muscular dystrophy, a predominantly cytoplasmic localization of dysferlin can be observed in regenerating myofibers, but the subcellular compartment responsible for this labeling pattern is not yet known. We have previously demonstrated an association of dysferlin with the developing T-tubule system in vitro. To investigate the role of dysferlin in adult skeletal muscle regeneration, we studied dysferlin localization at high resolution in a rat model of regeneration and found that the subcellular labeling of dysferlin colocalizes with the developing T-tubule system. Furthermore, ultrastructural analysis of dysferlin-deficient muscle revealed primary T-tubule anomalies similar to those seen in caveolin-3-deficient muscle. These findings indicate that dysferlin is necessary for correct T-tubule formation, and dysferlin-deficient skeletal muscle is characterized by abnormally configured T-tubules.
肌营养不良蛋白基因突变会导致 2B 型肢带型肌营养不良症、宫泽肌病和远端前间隔肌病。肌营养不良蛋白主要定位于成熟骨骼肌的肌膜，在那里它参与膜融合和修复。在不同形式的肌肉营养不良中，可以观察到再生肌纤维中肌营养不良蛋白的主要细胞质定位，但负责这种标记模式的亚细胞隔室尚不清楚。我们之前已经证明肌营养不良蛋白与体外发育中的 T 小管系统有关。为了研究肌营养不良蛋白在成年骨骼肌再生中的作用，我们在大鼠再生模型中对肌营养不良蛋白的定位进行了高分辨率研究，发现肌营养不良蛋白的亚细胞标记与发育中的 T 小管系统共定位。此外，对肌营养不良蛋白缺陷肌肉的超微结构分析显示，主要 T 小管异常类似于 caveolin-3 缺陷肌肉中观察到的异常。这些发现表明肌营养不良蛋白对于正确的 T 小管形成是必要的，并且肌营养不良蛋白缺陷的骨骼肌的特点是 T 小管异常排列。
