The dystrophinopathies: an alternative to the structural hypothesis

Abstract

Abnormal expression of the cytoskeletal protein dystrophin has deleterious consequences for skeletal muscle, cardiac muscle, and the central nervous system. A complete failure to express the protein produces Duchenne muscular dystrophy (DMD), in which there is extensive and progressive skeletal muscle necrosis, the development of a life-threatening dilated cardiomyopathy, and mild mental retardation. Dystrophin binds the F-actin cytoskeleton and is normally expressed in a complex of transmembrane proteins (the "dystrophin protein complex") that interact with external components of the basal lamina. One pathogenic model for DMD (the "structural hypothesis") suggests that this complex forms a structural bridge between the external basal lamina and the internal cytoskeleton and that the absence of dystrophin produces a defect in membrane structural support that renders skeletal muscle susceptible to plasmalemmal ruptures (or "tears") during the course of contractile activity. This review attempts to critically evaluate the structural hypothesis for DMD and presents an opposing model (the "channel aggregation model") that highlights the role of dystrophin in organizing the membrane cytoskeleton and the role of the cytoskeleton in aggregating ion channels and neurotransmitter receptors. Since ion channel aggregation is a process that is common across organ systems, the idea that channel function can be altered when aggregated ion channels interact with a dystrophic cytoskeleton has immediate implications for the expression of the dystrophinopathies in skeletal muscle, cardiac muscle, and the central nervous system.