title: Apoptosis repressor with a CARD domain (ARC) restrains Bax-mediated pathogenesis in dystrophic skeletal muscle.
abstract: Myofiber wasting in muscular dystrophy has largely been ascribed to necrotic cell death, despite reports identifying apoptotic markers in dystrophic muscle. Here we set out to identify the contribution of canonical apoptotic pathways to skeletal muscle degeneration in muscular dystrophy by genetically deleting a known inhibitor of apoptosis, apoptosis repressor with a card domain (Arc), in dystrophic mouse models. Nol3 (Arc protein) genetic deletion in the dystrophic Sgcd or Lama2 null backgrounds showed exacerbated skeletal muscle pathology with decreased muscle performance compared with single null dystrophic littermate controls. The enhanced severity of the dystrophic phenotype associated with Nol3 deletion was caspase independent but dependent on the mitochondria permeability transition pore (MPTP), as the inhibitor Debio-025 partially rescued skeletal muscle pathology in Nol3 (-/-) Sgcd (-/-) double targeted mice. Mechanistically, Nol3 (-/-) Sgcd (-/-) mice showed elevated total and mitochondrial Bax protein levels, as well as greater mitochondrial swelling, suggesting that Arc normally restrains the cell death effects of Bax in skeletal muscle. Indeed, knockdown of Arc in mouse embryonic fibroblasts caused an increased sensitivity to cell death that was fully blocked in Bax Bak1 (genes encoding Bax and Bak) double null fibroblasts. Thus Arc deficiency in dystrophic muscle exacerbates disease pathogenesis due to a Bax-mediated sensitization of mitochondria-dependent death mechanisms.
authors: Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, United States of America.
authors: Jennifer
authors: J
authors: Davis
authors: Jennifer Q
authors: JQ
authors: Kwong
authors: Richard N
authors: RN
authors: Kitsis
authors: Jeffery D
authors: JD
authors: Molkentin
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015415:Biomarkers / Q000378:metabolism; D061945:Caspase Inhibitors / Q000494:pharmacology; D016572:Cyclosporine / Q000494:pharmacology; D003598:Cytoskeletal Proteins / Q000172:deficiency / Q000378:metabolism*; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D009136:Muscular Dystrophies / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D061945:Caspase Inhibitors; D003598:Cytoskeletal Proteins; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D009419:Nerve Tissue Proteins; C092069:activity regulated cytoskeletal-associated protein; D051028:bcl-2-Associated X Protein; D016572:Cyclosporine; C499715:alisporivir