title: Suppression of GSK-3β activation by M-cadherin protects myoblasts against mitochondria-associated apoptosis during myogenic differentiation.
abstract: Apoptosis occurs concurrently with differentiation of muscle progenitor cells (MPCs) before they fuse to form myotubes. Dysregulated apoptosis in MPCs contributes to the low regeneration capability in aged muscle and decreases the survival rate of donor cells in stem cell-based therapies for muscular dystrophies. This study investigated the role of the M-cadherin/PI3K/Akt/GSK-3β signaling pathway in regulating apoptosis during differentiation of MPCs. Disruption of M-cadherin-dependent cell-cell adhesion by M-cadherin RNA interference in confluent C2C12 myoblasts sensitized the cells to mitochondria-associated intrinsic apoptosis induced by cell confluence or serum starvation. Further investigation of this pathway revealed that M-cadherin-mediated signaling suppressed GSK-3β activation by enhancing the PI3K/AKT-dependent inhibitory phosphorylation of Ser9 in GSK-3β. Overexpression of wild-type GSK-3β in confluent C2C12 myoblasts exacerbated the apoptosis, whereas chemical inhibition of GSK-3β using TDZD-8, or forced expression of constitutively active Akt (myrAkt), or a kinase-deficient GSK-3β mutant [GSK-3β(K85R)], attenuated apoptosis and rescued the impaired myogenic differentiation that is caused by M-cadherin RNA interference. These data suggest that M-cadherin-mediated signaling prevents acceleration of mitochondria-associated intrinsic apoptosis in MPCs by suppressing GSK-3β activation during myogenic differentiation.
authors: Laboratory of Muscle Biology and Sarcopenia, Division of Exercise Physiology, and Center for Cardiovascular and Respiratory Sciences, Robert C. Byrd Health Sciences Center, West Virginia University School of Medicine, Morgantown, West Virginia 26506,  USA.
authors: Yan
authors: Y
authors: Wang
authors: Yanlei
authors: Y
authors: Hao
authors: Stephen E
authors: SE
authors: Alway
mesh_terms: D000818:Animals; D017209:Apoptosis; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation; D002460:Cell Line; D002478:Cells, Cultured; D015536:Down-Regulation; D004789:Enzyme Activation; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D032446:Myoblasts / Q000166:cytology* / Q000201:enzymology / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D015820:Cadherins; C070896:M-cadherin; D019869:Phosphatidylinositol 3-Kinases; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3