Abnormal Ion Homeostasis and Cell Damage in Muscular Dystrophy

Disruption of cytoskeletal organization caused by genetic defects in the components of the dystrophin-glycoprotein complex (DGC) results in muscular dystrophy and/or cardiomyopathy in human patients and animal models. Accumulating evidence obtained from studies by using skeletal muscle fibers, cultured myotubes, and cardiac muscle preparations from dystrophic animals suggest that defects in DGC components cause altered membrane properties in the sarcolemma of myocytes. For example, disruption of the DGC can cause increased susceptibility to mechanical stress or increased permeability to ions such as Ca2+ and Na+, leading to a chronic increase in the concentrations of intracellular Ca2+ ([Ca2+]i) and Na+ ([Na+]i). Abnormal ion homeostasis, especially under conditions of mechanical stress, is thought to be a key molecular event in the pathology of muscular dysgenesis. In this chapter, we will review the stretch-induced cell damage pathways that result in abnormal Ca2+ and Na+ concentrations. In particular, we will focus on stretchactivated channels, transient receptor potential cation channels, and Na+-dependent ion transporters, which have been reported to be of critical pathological significance. We will also discuss the therapeutic potential of these ion handling membrane proteins for the treatment of muscular dystrophy.