Patching Things Up

Abstract

Bansal et al. investigated the mechanism whereby loss of dysferlin, a protein linked to two forms of muscular dystrophy, caused muscle damage and discovered that, unlike other proteins implicated in muscular dystrophy, dysferlin deficiency led to defects in membrane repair. The muscular dystrophies are a group of diseases in which muscles waste away. Various genes are associated with different forms of the disease; many of these encode proteins comprising the dystrophin-glycoprotein complex (DGC), which links the extracellular matrix with the muscle cell cytoskeleton. DGC disruption increases the likelihood of muscle injury. Bansal et al. generated mice lacking dysferlin, a protein that shows Ca2+-dependent binding to phospholipids and is homologous to a Caenorhabditis elegans protein involved in vesicle fusion to the plasma membrane, and discovered that they developed muscular dystrophy. The authors used immunofluorescent and Western analysis to demonstrate normal DGC expression in the mutant mice. Assessment of membrane damage following a treadmill exercise indicated that these mice were not more susceptible to muscle injury. Following injury, muscle fibers from wild-type mice developed dysferlin-enriched patches at wound sites and regained membrane integrity through a Ca2+-dependent process. In contrast, muscle fibers from dystophin-deficient mice accumulated vesicles at the injury site and behaved like wild-type fibers damaged in the absence of Ca2+, failing to regain membrane integrity. The authors proposed that dysferlin mediates Ca2+-dependent fusion of vesicles to the plasma membrane during membrane repair and speculated that related genes may be involved in other human diseases. Ellis discusses the background and implications of this research.D. Bansal, K. Miyake, S. S. Vogel, S. Groh, C.-C. Chen, R. Williamson, P. L. McNell, K. P. Campbell, Defective membrane repair in dysferlin-deficient muscular dystrophy. Nature 423, 168-172 (2003). [Online Journal]J. A. Ellis, Patches for wounded muscle, Nature 423, 129-131 (2003). [Online Journal]