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N-acetylcysteine Decreases Fibrosis and Increases Force-Generating Capacity of mdx Diaphragm

Respiratory muscle weakness occurs due to dystrophin deficiency in Duchenne muscular dystrophy (DMD). The mdx mouse model of DMD shows evidence of impaired respiratory muscle performance with attendant inflammation and oxidative stress. We examined the effects of N-acetylcysteine (NAC) supplementati...

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Autores principales: Burns, David P., Drummond, Sarah E., Bolger, Dearbhla, Coiscaud, Amélie, Murphy, Kevin H., Edge, Deirdre, O’Halloran, Ken D.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6943616/
https://www.ncbi.nlm.nih.gov/pubmed/31771272
http://dx.doi.org/10.3390/antiox8120581
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author Burns, David P.
Drummond, Sarah E.
Bolger, Dearbhla
Coiscaud, Amélie
Murphy, Kevin H.
Edge, Deirdre
O’Halloran, Ken D.
author_facet Burns, David P.
Drummond, Sarah E.
Bolger, Dearbhla
Coiscaud, Amélie
Murphy, Kevin H.
Edge, Deirdre
O’Halloran, Ken D.
author_sort Burns, David P.
collection PubMed
description Respiratory muscle weakness occurs due to dystrophin deficiency in Duchenne muscular dystrophy (DMD). The mdx mouse model of DMD shows evidence of impaired respiratory muscle performance with attendant inflammation and oxidative stress. We examined the effects of N-acetylcysteine (NAC) supplementation on respiratory system performance in mdx mice. Eight-week-old male wild type (n = 10) and mdx (n = 20) mice were studied; a subset of mdx (n = 10) received 1% NAC in the drinking water for 14 days. We assessed breathing, diaphragm, and external intercostal electromyogram (EMG) activities and inspiratory pressure during ventilatory and non-ventilatory behaviours. Diaphragm muscle structure and function, cytokine concentrations, glutathione status, and mRNA expression were determined. Diaphragm force-generating capacity was impaired in mdx compared with wild type. Diaphragm muscle remodelling was observed in mdx, characterized by increased muscle fibrosis, immune cell infiltration, and central myonucleation. NAC supplementation rescued mdx diaphragm function. Collagen content and immune cell infiltration were decreased in mdx + NAC compared with mdx diaphragms. The cytokines IL-1β, IL-6 and KC/GRO were increased in mdx plasma and diaphragm compared with wild type; NAC decreased systemic IL-1β and KC/GRO concentrations in mdx mice. We reveal that NAC treatment improved mdx diaphragm force-generating capacity associated with beneficial anti-inflammatory and anti-fibrotic effects. These data support the potential use of NAC as an adjunctive therapy in human dystrophinopathies.
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spelling pubmed-69436162020-01-10 N-acetylcysteine Decreases Fibrosis and Increases Force-Generating Capacity of mdx Diaphragm Burns, David P. Drummond, Sarah E. Bolger, Dearbhla Coiscaud, Amélie Murphy, Kevin H. Edge, Deirdre O’Halloran, Ken D. Antioxidants (Basel) Article Respiratory muscle weakness occurs due to dystrophin deficiency in Duchenne muscular dystrophy (DMD). The mdx mouse model of DMD shows evidence of impaired respiratory muscle performance with attendant inflammation and oxidative stress. We examined the effects of N-acetylcysteine (NAC) supplementation on respiratory system performance in mdx mice. Eight-week-old male wild type (n = 10) and mdx (n = 20) mice were studied; a subset of mdx (n = 10) received 1% NAC in the drinking water for 14 days. We assessed breathing, diaphragm, and external intercostal electromyogram (EMG) activities and inspiratory pressure during ventilatory and non-ventilatory behaviours. Diaphragm muscle structure and function, cytokine concentrations, glutathione status, and mRNA expression were determined. Diaphragm force-generating capacity was impaired in mdx compared with wild type. Diaphragm muscle remodelling was observed in mdx, characterized by increased muscle fibrosis, immune cell infiltration, and central myonucleation. NAC supplementation rescued mdx diaphragm function. Collagen content and immune cell infiltration were decreased in mdx + NAC compared with mdx diaphragms. The cytokines IL-1β, IL-6 and KC/GRO were increased in mdx plasma and diaphragm compared with wild type; NAC decreased systemic IL-1β and KC/GRO concentrations in mdx mice. We reveal that NAC treatment improved mdx diaphragm force-generating capacity associated with beneficial anti-inflammatory and anti-fibrotic effects. These data support the potential use of NAC as an adjunctive therapy in human dystrophinopathies. MDPI 2019-11-24 /pmc/articles/PMC6943616/ /pubmed/31771272 http://dx.doi.org/10.3390/antiox8120581 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Burns, David P.
Drummond, Sarah E.
Bolger, Dearbhla
Coiscaud, Amélie
Murphy, Kevin H.
Edge, Deirdre
O’Halloran, Ken D.
N-acetylcysteine Decreases Fibrosis and Increases Force-Generating Capacity of mdx Diaphragm
title N-acetylcysteine Decreases Fibrosis and Increases Force-Generating Capacity of mdx Diaphragm
title_full N-acetylcysteine Decreases Fibrosis and Increases Force-Generating Capacity of mdx Diaphragm
title_fullStr N-acetylcysteine Decreases Fibrosis and Increases Force-Generating Capacity of mdx Diaphragm
title_full_unstemmed N-acetylcysteine Decreases Fibrosis and Increases Force-Generating Capacity of mdx Diaphragm
title_short N-acetylcysteine Decreases Fibrosis and Increases Force-Generating Capacity of mdx Diaphragm
title_sort n-acetylcysteine decreases fibrosis and increases force-generating capacity of mdx diaphragm
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6943616/
https://www.ncbi.nlm.nih.gov/pubmed/31771272
http://dx.doi.org/10.3390/antiox8120581
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