Reply from Gavin J. Pinniger, Jessica R. Terrill, Miranda D. Grounds and Peter G. Arthur

We are pleased with the attention garnered by our recent publication in The Journal of Physiology investigating the potential of N‐acetylcysteine (NAC) as a therapeutic treatment for Duchenne muscular dystrophy (DMD) (Pinniger et al. 2017). In brief, we showed that oral supplementation with NAC improved muscle function in young growing mdx mice and was associated with reduced markers of inflammation and oxidative stress. On these findings alone it appears that NAC has promising potential as a therapeutic treatment for DMD. We also note the impressive benefits of NAC in combating respiratory muscle dysfunction in animal models of hypoxia demonstrated in the substantial body of work published by O'Halloran and colleagues (e.g. Shortt et al. 2014; Lewis et al. 2016). However, our enthusiasm for NAC as a potential therapeutic treatment for DMD boys was tempered by the significant decrease in body mass and subsequent growth restriction that we observed in both young mdx mice and in non‐dystrophic wild‐type mice that received NAC in their drinking water for 6 weeks. Importantly, body mass significantly decreased, by almost 10% in the first week of treatment, at a time when untreated mice continued growing, and growth was severely restricted throughout the remainder of the treatment period for both strains. Also, to address the point that fluid and food intake may have been reduced in the first few days of supplementation due to acidification of the drinking water, mice in our untreated groups were given ‘control’ drinking water adjusted to ∼pH 2, and there was no difference in fluid intake between treated and untreated mice. Therefore, it is unlikely that the considerable drop in body mass in NAC‐treated mice was due to acidification. Additionally, while previous research suggests that NAC treatment reduces fat mass, mdx mice have a very low percentage of body fat (∼7%) (Radley‐Crabb et al. 2014); therefore the decrease in body mass observed in NAC‐treated mdx mice is unlikely to be due to loss of fat mass. While we are not convinced that the restriction in body weight gain was related to decreased water consumption, energy intake or loss of body fat, we agree with O'Halloran et al. that further metabolic studies are needed to determine the impact of NAC supplementation (and other interventions that can lead to increased cysteine levels) on energy balance.

We are concerned that growth restriction may reflect potential side effects of oral NAC treatment that are particularly evident in young growing mice. Therapies for DMD boys will most likely be lifelong treatments that are administered early, continue throughout critical stages of growth and be used in addition to corticosteroids. Therefore it is crucial that the effects of long‐term oral NAC treatment are fully investigated before treating DMD boys.

We are not saying ‘do not use NAC’ but instead suggest that full disclosure is needed when considering the use of any drug, since the balance of merits and disadvantages may differ depending on the specific condition being addressed. This is especially relevant when a drug that may be widely used in adults is proposed for very young growing children. This is further emphasised by our recent paper with taurine treatment of juvenile mice (Terrill et al. 2017) that emphasises the likely adverse effects of elevated cysteine levels, especially during growth. At the very least, our recent NAC paper illustrates the importance of monitoring for, and reporting, side effects and thoroughly evaluating the efficacy of potential DMD therapies in young growing individuals. Thus one does need to be aware and beware and tread carefully.

Additional information

Competing interests

None declared.

Author contributions

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