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Open AccessArticle

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

1
Department of Physiology, School of Medicine, College of Medicine and Health, University College Cork, T12 XF62 Cork, Ireland
2
Department of Physiology, School of Medicine, Trinity Biomedical Sciences Institute, Trinity College Dublin, the University of Dublin, D02 R590 Dublin, Ireland
*
Author to whom correspondence should be addressed.
Antioxidants 2019, 8(12), 581; https://doi.org/10.3390/antiox8120581
Received: 30 August 2019 / Revised: 10 November 2019 / Accepted: 21 November 2019 / Published: 24 November 2019
(This article belongs to the Special Issue Redox Modulation of Respiratory Muscles in Health and Disease)
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.
Keywords: antioxidant; N-acetylcysteine; DMD; mdx; diaphragm; intercostal; interleukin-6; interleukin-1β; fibrosis antioxidant; N-acetylcysteine; DMD; mdx; diaphragm; intercostal; interleukin-6; interleukin-1β; fibrosis
MDPI and ACS Style

Burns, D.P.; Drummond, S.E.; Bolger, D.; Coiscaud, A.; Murphy, K.H.; Edge, D.; O’Halloran, K.D. N-acetylcysteine Decreases Fibrosis and Increases Force-Generating Capacity of mdx Diaphragm. Antioxidants 2019, 8, 581.

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