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.
Highlights
Muscular dystrophy is an inherited disorder characterized by skeletal muscle weakness and wasting that typically results in loss of ambulation with aging and premature death due to cardiac and respiratory dysfunction
The desensitization of mitochondrial permeability transition pore (MPTP) formation by both genetic deletion and pharmacologic inhibition of cyclophilin D (CypD) in several mouse models of muscular dystrophy showed reduced pathology and less muscle fiber death associated with this disease [11,16,17]
Given Arc’s strong antagonistic relationship with Bax, we found that Nol3 Sgcd double null mice had increased total and mitochondrial levels of Bax in muscle, as well as greater mitochondrial swelling. shRNAmediated knockdown of Arc sensitized mouse embryonic fibroblasts (MEFs) to cell death stimuli, a result that was fully blocked in fibroblasts lacking Bax and Bak
Summary
Muscular dystrophy is an inherited disorder characterized by skeletal muscle weakness and wasting that typically results in loss of ambulation with aging and premature death due to cardiac and respiratory dysfunction. The most common mutations fall within genes encoding structural or membrane proteins that are part of or influence the dystrophin-glycoprotein complex, which links the contractile apparatus within the cell to the extracellular matrix and in so doing, provides stability to the sarcolemma (plasma membrane of a skeletal muscle fiber) The loss of these structural components or their proper function renders the sarcolemma more susceptible to contraction induced permeation or rupture, which permits unrestrained Ca2+ entry [1,2,3]. The desensitization of mitochondrial permeability transition pore (MPTP) formation by both genetic deletion and pharmacologic inhibition of cyclophilin D (CypD) in several mouse models of muscular dystrophy showed reduced pathology and less muscle fiber death associated with this disease [11,16,17] These studies demonstrate that a substantial proportion of muscle fiber wasting can be ascribed to a mitochondrialdependent necrotic cell death process. To date the relative contribution of apoptotic versus necrotic cell death mechanisms to skeletal muscular dystrophy still remains inconclusive, aspects of both molecular programs are clearly involved
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call