Abstract
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.
Highlights
Skeletal muscle weakness is a major feature of Duchenne muscular dystrophy (DMD) due to a deficiency in the protein dystrophin [1]
Brown and white adipose tissue mass were lower in mdx (P < 0.01 and P < 0.001; one-way analysis of variance (ANOVA) with Newman–Keuls post hoc test and Kruskal-Wallis with Dunn’s post hoc test; brown and white, respectively) compared with wild type
The major findings of the study are: (i) NAC supplementation improved mdx diaphragm functional capacity (ii) NAC supplementation reduced collagen deposition and immune cell infiltration in mdx diaphragm; (iii) NAC treatment reduced IL-1β and KC/GRO concentrations in mdx plasma samples; (iv) NAC increased Nrf2 mRNA expression in mdx diaphragm; (v) NAC had no adverse effect on ventilation, inspiratory pressure and respiratory muscle EMG or growth measures in mdx mice; (vi) NAC did not recover decreased respiratory muscle EMG activity in mdx mice during maximum activation
Summary
Skeletal muscle weakness is a major feature of Duchenne muscular dystrophy (DMD) due to a deficiency in the protein dystrophin [1]. Dystrophin has a structural role in supporting muscle fibres during repeated cycles of muscle contraction, acting to limit the mechanical stress applied to muscle fibres [2,3]. In the absence of dystrophin, such as in DMD, skeletal muscle fibres have increased fragility, resulting in fibre damage. Common pathological features of dystrophic muscle include myonecrosis, inflammation, and oxidative stress [4,5]. Due to profound muscle weakness and damage, children with DMD have difficulty with ambulation in their early years, necessitating assistive devices. Respiratory system morbidity occurs in DMD due to weakness of the respiratory musculature [6], the end effectors of breathing.
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