Costamere Defects in Muscular Dystrophies

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): Costameres are subsarcolemmal protein assemblies in striated muscle cells that physically couple force-generating sarcomeres with the sarcolemma. Costameres are clearly important for normal muscle function because several constituent proteins are the primary sites of defect in human muscular dystrophies and dilated cardiomyopathies. We previously demonstrated that the costameric cytoskeleton is enriched in non-muscle "cytoplasmic" ?cyto-actin and that muscle-specific ablation of ?cyto-actin causes a novel form of progressive myopathy. The major objective of this renewal is to elucidate the important, but poorly understood functions of both ¿cyto- and ?cyto-actin isoforms in skeletal muscle. We will make use of novel conditional animal models and isoform-specific reagents generated by my group during the original project period to address several fundamental questions about cytoplasmic actins in normal skeletal muscle function and in human diseases of skeletal muscle tissue. In aim 1, we will investigate the specific contribution of ?cyto-actin to the mechanical function of skeletal muscle, which may also shed light into the mechanism of contraction-induced injury of normal and dystrophin-deficient muscle. In aim 2, the distinct and overlapping roles of ¿cyto- and ?cyto- actins in developing and adult skeletal muscle, particularly in costameres, will be investigated through the characterization of mouse lines in which either ¿cyto-actin, or ¿cyto- and ?cyto-actins have been knocked out specifically in skeletal muscle. In aim 3, we will test the hypothesized role for aberrant ¿cyto-actin localization in the pathogenesis of spinal muscular atrophy both in vivo and in vitro. The results of the proposed studies will most definitively address the unique and important contributions of cytoplasmic actin isoforms to the function of normal and diseased skeletal muscle.