Apoptosis repressor with a CARD domain (ARC) restrains Bax-mediated pathogenesis in dystrophic skeletal muscle.

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 genetical...

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Autores principales:	Jennifer Davis, Jennifer Q Kwong, Richard N Kitsis, Jeffery D Molkentin
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/68cc6454da7d49518970c71b1d1886b4
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spelling	oai:doaj.org-article:68cc6454da7d49518970c71b1d1886b42021-11-18T08:43:53ZApoptosis repressor with a CARD domain (ARC) restrains Bax-mediated pathogenesis in dystrophic skeletal muscle.1932-620310.1371/journal.pone.0082053https://doaj.org/article/68cc6454da7d49518970c71b1d1886b42013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24312627/?tool=EBIhttps://doaj.org/toc/1932-6203Myofiber 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.Jennifer DavisJennifer Q KwongRichard N KitsisJeffery D MolkentinPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 12, p e82053 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Jennifer Davis Jennifer Q Kwong Richard N Kitsis Jeffery D Molkentin Apoptosis repressor with a CARD domain (ARC) restrains Bax-mediated pathogenesis in dystrophic skeletal muscle.
description	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.
format	article
author	Jennifer Davis Jennifer Q Kwong Richard N Kitsis Jeffery D Molkentin
author_facet	Jennifer Davis Jennifer Q Kwong Richard N Kitsis Jeffery D Molkentin
author_sort	Jennifer Davis
title	Apoptosis repressor with a CARD domain (ARC) restrains Bax-mediated pathogenesis in dystrophic skeletal muscle.
title_short	Apoptosis repressor with a CARD domain (ARC) restrains Bax-mediated pathogenesis in dystrophic skeletal muscle.
title_full	Apoptosis repressor with a CARD domain (ARC) restrains Bax-mediated pathogenesis in dystrophic skeletal muscle.
title_fullStr	Apoptosis repressor with a CARD domain (ARC) restrains Bax-mediated pathogenesis in dystrophic skeletal muscle.
title_full_unstemmed	Apoptosis repressor with a CARD domain (ARC) restrains Bax-mediated pathogenesis in dystrophic skeletal muscle.
title_sort	apoptosis repressor with a card domain (arc) restrains bax-mediated pathogenesis in dystrophic skeletal muscle.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/68cc6454da7d49518970c71b1d1886b4
work_keys_str_mv	AT jenniferdavis apoptosisrepressorwithacarddomainarcrestrainsbaxmediatedpathogenesisindystrophicskeletalmuscle AT jenniferqkwong apoptosisrepressorwithacarddomainarcrestrainsbaxmediatedpathogenesisindystrophicskeletalmuscle AT richardnkitsis apoptosisrepressorwithacarddomainarcrestrainsbaxmediatedpathogenesisindystrophicskeletalmuscle AT jefferydmolkentin apoptosisrepressorwithacarddomainarcrestrainsbaxmediatedpathogenesisindystrophicskeletalmuscle
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Apoptosis repressor with a CARD domain (ARC) restrains Bax-mediated pathogenesis in dystrophic skeletal muscle.

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