The Sarcoglycan Complex in Skeletal Muscle Mechanotransduction

点击翻译按钮获取中文摘要

 DESCRIPTION (provided by applicant): Physical activity imposes changes in load to skeletal muscle, which adapts through acute changes in biochemical signaling pathways and longer-term alterations in protein expression. One important mechanical sensor is the sarcoglycan (SG) complex, which is lost from the muscle membrane (sarcolemma) in both Duchenne and Limb Girdle muscular dystrophies (LGMD). Absence of γ-SG loss induces severe muscle degeneration and signaling defects in response to mechanical load without causing susceptibility to contractile damage, suggesting that LGMD pathology arises in part through disruption of normal mechanotransduction signaling through the SG complex. In a recent advance, the applicants have discovered that archvillin, a muscle-specific isoform of supervillin, is a γ-SG- and dystrophin-interacting protein and that archvillin association with phosphorylated ERK1/2 (P-ERK) increases dramatically, if and only if γ-SG is present, following eccentric contraction of muscle. Aim 1 is to determine the molecular bases for the associations of archvillin with γ-SG and P-ERK at rest and following stretch. Aim 2 is to determine the consequences of archvillin loss upon mechanical signal transduction in normal and dystrophic muscles. Aim 3 is to use drugs in clinical trials for other diseases to determine how up- or down-regulation of the molecular pathways identified in preliminary studies and in Aim 1 affects the progression of muscle pathology in gsg-/- mice, a model for human LGMD2C. Completion of these aims will elucidate the role of archvillin in mechanochemical signal transduction in muscle, identify new proteins in SG-mediated signaling, and determine whether modulation of the identified pathways has therapeutic potential.