Apoptosis Repressor with a CARD Domain (ARC) Restrains Bax-Mediated Pathogenesis in Dystrophic Skeletal Muscle.docVIP

Apoptosis Repressor with a CARD Domain (ARC) Restrains Bax-Mediated Pathogenesis in Dystrophic Skeletal Muscle Jennifer Davis , Jennifer Q. Kwong , Richard N. Kitsis , Jeffery D. Molkentin 1 1 2 1,3* 1 Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, United States of America, 2 Department of Medicine and Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, Bronx, New York, United States of America, 3 Howard Hughes Medical Institute, Cincinnati, Ohio, United States of America 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 mice showed elevated total and mitochondrial Bax protein levels, as well -/- Sgcd -/- as greater mitochondrial swelling, suggesting that Arc normally restrains the cell death effects of Bax in skeletal muscle