Musecle cell dysfunction caused by disturbed cell adhesion and signal transduction

肌营养不良蛋白聚糖（dystroglycan，DG）复合物由αDG和βDG两个亚基组成，与肌聚糖复合物相互作用形成肌营养不良蛋白-糖蛋白复合物。αDG是一种与细胞外基质成分结合的细胞表面外周膜蛋白，而βDG是一种I型整合膜蛋白，通过N-末端胞外结构域将αDG锚定在细胞膜上。在这项研究中，我们已经调查了DG复合物的缺陷导致肌细胞功能障碍的机制。(1)我们已经表征了基质金属蛋白酶（MMP）的活性，该活性通过切割βDG的胞外结构域来破坏DG复合物，并发现该MMP在心肌病仓鼠（肌聚糖病的模型动物）的骨骼肌和心肌中被激活。结果提高了抑制MMP活性的药物的治疗潜力，以减缓肌聚糖病中的肌肉变性。(2)我们与大坂大学的Tatsushi户田教授合作，开发并分析了fukutin缺陷嵌合小鼠。这些动物表现出与FCMD相似的脑、眼和骨骼肌严重异常。在脑和骨骼肌中，αDG的糖基化和层粘连蛋白结合受到干扰。这些动物将有助于进一步阐明FCMD的发病机制。(3)我们发现，αDG的糖基化和层粘连蛋白的结合在营养不良的鸡脑和骨骼肌中受到干扰。这些动物将有助于进一步阐明α-肌营养不良聚糖病的发病机制。

The dystroglycan (DG) complex, composed of two subunits αDG and βDG, interacts with the sarcoglycan complex to form the dystrophin-glycoprotein complex. αDG is a cell surface peripheral membrane protein which binds to the components of the extracellular matrix, while βDG is a type I integral membrane protein which anchors αDG to the cell membrane via the N-terminal extracellular domain. In this study, we have investigated the mechanisms by which the defects of the DG complex causes muscle cell dysfunction.(1) We have characterized the matrix metalloproteinase (MMP) activity that disrupts the DG complex by cleaving the extracellular domain of βDG and found that this MMP is activated in the skeletal and cardiac muscles of cardiomyopathic hamsters, the model animal of sarcoglycanopathy. The results raise a therapeutic potential of the 'drugs that inhibit, this MMP activity to decelerate muscle degeneration in sarcoglycanopathy.(2) In collaboration with Professor Tatsushi Toda (University of Osaka), we have developed and analyzed fukutin-deficient chimeric mice. These animals showed severe abnormalities of brain, eye and skeletal muscle, similar to FCMD. In the brain and skeletal muscle, glycosylation and laminin-binding of αDG were disturbed. These animals will be useful for further elucidation of FCMD pathogenesis.(3) We have found that glycosylation and laminin-binding of αDG are disturbed in the brain and skeletal muscle of dystrophy chicken. These animals will be useful for further elucidation of pathogenesis of α-dystroglycanopathy.