|Ph.D Student||Volodin Alexandra|
|Subject||Molecular Mechanisms of Skeletal Muscle Adaptation to|
|Department||Department of Biology||Supervisor||Professor Shenhav Cohen|
|Full Thesis text|
A hallmark of muscle atrophy is the accelerated degradation of muscle proteins, especially the contractile myofibrils, by the ubiquitin proteasome system, and the destruction of organelles by autophagy. Insulin Receptor-PI3K-Akt signaling is the central growth pathway in muscle and all cells, and its inhibition during fasting, or metabolic disorders (e.g. diabetes, obesity) causes muscle atrophy. We identified a new regulator of this pathway in skeletal muscle, the desmosomal component plakoglobin that by linking the Insulin Receptor to the dystrophin-glycoprotein complex (DGC), promotes insulin receptor activity and skeletal muscle integrity. DGC is essential for muscle architecture, and its dissociation during aging or disease largely contributes to the development of atrophy. To date, it is unclear what triggers DGC dissociation. Here, we demonstrate that during the rapid atrophy induced by fasting, plakoglobin association with the principal DGC component, β-Dystroglycan, is reduced, which correlated with Plakoglobin-β-Dystroglycan-Insulin Receptor colocalization with the autophagy marker, LC3. Consequently, this protein co-assembly is targeted to lysosomes, where β-dystroglycan is de-glycosylated by a mechanism involving the glucosidase alpha-N-acetylglucosaminidase (NAGLU). Surprisingly, plakoglobin overexpression alone was sufficient to prevent Plakoglobin-β-Dystroglycan-Insulin Receptor internalization, β-Dystroglycan de-glycosylation and degradation by the lysosome, and resulted in accumulation of this multiprotein assembly on the muscle membrane. This beneficial effect by plakoglobin overexpression seem to result from a protective effect conferred by plakoglobin, which masks LC3-interactin regions (LIR) on β-Dystroglycan and prevents its recognition by LC3 and the autophagy machinery. Thus, plakoglobin-β-Dystroglycan dissociation appears to be a critical key step in cellular adaptation to fasting, and inhibition of this dissociation may enhance sensitivity to insulin and block wasting in aging or disease.