Mechanisms of Duchenne and Miyoshi Myopathy
The laboratory is also interested in understanding the molecular mechanisms that underlie skeletal muscle degeneration in muscular dystrophy (MD). A longstanding hypothesis in MD research is that loss of membrane integrity is a primary event leading to the degeneration of skeletal muscle fibers resulting in disease. A large number of characterized mutations in humans that cause MD result from alterations in structural attachment proteins that "rivit" the underlying contractile proteins to the basal lamina, providing rigidity to the skeletal muscle cell membrane, or in proteins that directly stabilize or repair the cell membrane, such as dysferlin. Intermittent tears in the cell membrane permits influx of calcium that then functions as a primary inducer of cellular degeneration and necrosis of whole muscle fibers. For example, loss of dystrophin (Duchenne Muscular Dystrophy) or any one of the sarcoglycans leads to destabilization of the skeletal muscle cell membrane, permitting calcium influx and cellular necrosis. The laboratory is currently investigating the hypothesis that unregulated calcium entry associated with an unstable sarcolemma is a central mediator of skeletal muscle fiber degeneration and MD pathogenesis.
