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 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 mice. Eight-week-old male wild type ( = 10) and ( = 20) mice were studied; a subset of ( = 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 compared with wild type. Diaphragm muscle remodelling was observed in , characterized by increased muscle fibrosis, immune cell infiltration, and central myonucleation. NAC supplementation rescued diaphragm function. Collagen content and immune cell infiltration were decreased in + NAC compared with diaphragms. The cytokines IL-1β, IL-6 and KC/GRO were increased in plasma and diaphragm compared with wild type; NAC decreased systemic IL-1β and KC/GRO concentrations in mice. We reveal that NAC treatment improved 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.