Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, USA.
Am J Pathol. 2009 Nov;175(5):1817-23. doi: 10.2353/ajpath.2009.090107. Epub 2009 Oct 15.
Mutations in the gene DYSF, which codes for the protein dysferlin, underlie Miyoshi myopathy and limb-girdle muscular dystrophy 2B in humans and produce a slowly progressing skeletal muscle degenerative disease in mice. Dysferlin is a Ca(2+)-sensing, regulatory protein that is involved in membrane repair after injury. To assess the function of dysferlin in healthy and dystrophic skeletal muscle, we generated skeletal muscle-specific transgenic mice with threefold overexpression of this protein. These mice were phenotypically indistinguishable from wild-type, and more importantly, the transgene completely rescued the muscular dystrophy (MD) disease in Dysf-null A/J mice. The dysferlin transgene rescued all histopathology and macrophage infiltration in skeletal muscle of Dysf(-/-) A/J mice, as well as promoted the rapid recovery of muscle function after forced lengthening contractions. These results indicate that MD in A/J mice is autonomous to skeletal muscle and not initiated by any other cell type. However, overexpression of dysferlin did not improve dystrophic symptoms or membrane instability in the dystrophin-glycoprotein complex-lacking Scgd (delta-sarcoglycan) null mouse, indicating that dysferlin functionality is not a limiting factor underlying membrane repair in other models of MD. In summary, the restoration of dysferlin in skeletal muscle fibers is sufficient to rescue the MD in Dysf-deficient mice, although its mild overexpression does not appear to functionally enhance membrane repair in other models of MD.
基因突变的 dysf 基因，这是为蛋白质 dysferlin 编码，是肌营养不良症和肢带型肌营养不良症 2B 的基础在人类和生产一个缓慢的进行性骨骼肌退行性疾病在老鼠。肌营养不良蛋白是一个 Ca(2+)-感觉，调节蛋白，参与损伤后的膜修复。为了评估 dysferlin 在健康和萎缩性骨骼肌中的功能，我们生成了骨骼肌特异性转基因小鼠三倍过表达这种蛋白质。这些老鼠表型与野生型没有区别，更重要的是，转基因完全拯救了 Dysf 缺失 A/J 小鼠的肌肉营养不良症（MD）。肌营养不良蛋白转基因拯救了所有的组织病理学和巨噬细胞浸润在 Dysf(-/-) A/J 小鼠的骨骼肌，以及促进肌肉功能的快速恢复后，强迫延长收缩。这些结果表明，A/J 小鼠的 MD 是自主的骨骼肌，而不是由任何其他细胞类型引发的。然而，肌营养不良蛋白的过表达并没有改善缺乏 dystrophin-糖蛋白复合物的 Scgd (δ-肌聚糖) 缺失型 null 小鼠的萎缩症状或膜不稳定，表明肌营养不良蛋白的功能不是其他 MD 模型中膜修复的限制因素。总之，在 Dysf 缺陷型小鼠骨骼肌纤维中恢复肌营养不良蛋白足以拯救 MD，尽管其轻度过表达似乎并没有在其他 MD 模型中功能性地增强膜修复。
