Musecle cell dysfunction caused by disturbed cell adhesion and signal transduction

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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.