Pre-clinical evaluation of N-Acetylcysteine reveals side effects in the mdx mouse model of Duchenne muscular dystrophy

Abstract

Duchenne Muscular Dystrophy (DMD) is a fatal X-linked muscle wasting disease characterised by severe muscle weakness, necrosis, inflammation and oxidative stress. The antioxidant N-acetylcysteine (NAC) has been proposed as a potential therapeutic intervention for DMD boys. We investigated the capacity of NAC to improve dystrophic muscle function in the mdx mouse model of DMD. Young (6 w old) mdx and non-dystrophic C57 mice receiving 2% NAC in drinking water for 6 w were compared with untreated mice. Grip strength and body weight were measured weekly, before the 12 w old mice were anaesthetized and extensor digitorum longus (EDL) muscles excised for functional analysis and tissues sampled for biochemical analyses. Compared to untreated mice, the mean (SD) normalised grip strength was significantly greater in NAC treated mdx [3.13 (0.58) cf. 4.87 (0.78) g bw⁻¹; P < 0.001] and C57 mice [3.90 (0.32) cf. 5.32 (0.60) g bw⁻¹; P < 0.001]. Maximum specific force was significantly greater in NAC treated mdx muscles [9.80 (2.27) cf. 13.07 (3.37) N·cm⁻²; P = 0.038]. Increased force in mdx mice was associated with reduced thiol oxidation and inflammation in fast muscles, and increased citrate synthase activity in slow muscle. Importantly, NAC significantly impaired body weight gain in both strains of young growing mice, reduced liver weight in C57 mice and muscle weight in mdx mice. These potentially adverse effects of NAC emphasise the need for caution when interpreting improvements in muscle function based on normalised force measures, and that careful consideration be given to these effects when proposing NAC as a potential treatment for young DMD boys.

This article is protected by copyright. All rights reserved

from Physiology via xlomafota13 on Inoreader http://ift.tt/2gSebt6
via IFTTT