Proteolysis of β-dystroglycan in muscular diseases

Abstract α-Dystroglycan is a cell surface peripheral membrane protein which binds to the extracellular matrix (ECM), while β-dystroglycan is a type I integral membrane protein which anchors α-dystroglycan to the cell membrane via the N-terminal extracellular domain. The complex composed of α-and β-dystroglycan is called the dystroglycan complex. We reported previously a matrix metalloproteinase (MMP) activity that disrupts the dystroglycan complex by cleaving the extracellular domain of β-dystroglycan. This MMP creates a characteristic 30 kDa fragment of β-dystroglycan that is detected by the monoclonal antibody 43DAG/8D5 directed against the C-terminus of β-dystroglycan. We also reported that the 30 kDa fragment of β-dystroglycan was increased in the skeletal and cardiac muscles of cardiomyopathic hamsters, the model animals of sarcoglycanopathy, and that this resulted in the disruption of the link between the ECM and cell membrane via the dystroglycan complex. In this study, we investigated the proteolysis of β-dystroglycan in the biopsied skeletal muscles of various human muscular diseases, including sarcoglycanopathy, Duchenne muscular dystrophy (DMD), Becker muscular dystrophy, Fukuyama congenital muscular dystrophy, Miyoshi myopathy, LGMD2A, facioscapulohumeral muscular dystrophy, myotonic dystrophy and dermatomyositis/polymyositis. We show that the 30 kDa fragment of β-dystroglycan is increased significantly in sarcoglycanopathy and DMD, but not in the other diseases. We propose that the proteolysis of β-dystroglycan may contribute to skeletal muscle degeneration by disrupting the link between the ECM and cell membrane in sarcoglycanopathy and DMD.