{'fraction_non_alphanumeric': 0.02120141342756184, 'fraction_numerical': 0.009769278736229474, 'mean_word_length': 5.185089974293059, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Antioxidant therapy in a mouse model of Duchenne muscular dystrophy: some promising results but with a weighty caveat

Antioxidants have been proposed as potential therapies for a host of cardiac and neuromuscular conditions. Disappointingly, despite the involvement of many patients in placebo-controlled based clinical trials, the results have been mostly negative (Steinhubl, 2008). In boys with Duchenne muscular dystrophy (DMD) trials of antioxidants in the 1970s and 1980s showed few beneficial effects. In this issue of The Journal of Physiology, Pinniger and colleagues (2017) using the mdx mouse model of DMD demonstrated some significant improvements in muscle function from treating mdx mice with a 2% solution of N-acetylcysteine in their drinking water for a period of 6 weeks. N-Acetylcysteine is one of the few antioxidants that has produced some promising results and importantly it’s approved for use in humans for treatment of paracetamol overdose (Dodd et al. 2008), expediting any future translational applications to boys with DMD. Pinniger and colleagues (2017) showed N-acetylcysteine compensated for the dystrophic hypertrophy normally seen in mdx extensor digitorum longus (EDL) fasttwitch muscles, resulting in a dystrophic muscle with a lower weight approaching normal wild-type values. Despite their smaller mass the N-acetylcysteine-treated dystrophic muscles produced a greater force per cross-sectional area compared with non-treated dystrophic muscles, good correlative evidence that N-acetylcysteine is preventing some of the dystrophic pathology in this fast-twitch muscle. They also demonstrated that N-acetylcysteine improved grip strength in dystrophic animals. One of the main muscles involved in grip strength is flexor digitorum brevis, another primarily fast-twitch muscle, so it seems that N-acetylcysteine improves the force output of dystrophic fast-twitch muscle. In the slow-twitch dystrophic soleus N-acetylcysteine increased mitochondrial function and there was evidence of an anti-inflammatory effect in the gastrocnemius muscle. These are promising findings suggesting that N-acetylcysteine may indeed be an effective therapy in DMD. The current results build on earlier work from David Allen’s laboratory (Whitehead et al. 2008) where they showed that 1% N-acetylcysteine in the drinking water of mdx mice for 6 weeks reduced the damage caused by eccentric contractions in the EDL muscle. Additionally, work from some of the authors on the present paper (Terrill et al. 2012) demonstrated that addition of Nacetylcysteine to the drinking water of mdx mice abolished treadmill exercise-induced necrosis. The only fly in the ointment of the present study is alluded to by my referral in the title to a ‘weighty caveat’. Antioxidant treatment produced a very significant decrease of body weight in both control and dystrophic mice. This reduction in body weight was somewhat surprising and has not been reported in earlier murine studies; however, these earlier studies either used a 1% N-acetylcysteine solution in the drinking water for around 6 weeks or used a higher percentage for a shorter period. Is this body weight reduction likely to be a serious impediment for translational studies? I believe the answer is most likely no, as oral administration is well tolerated in humans, with only mild gastric distress reported, typically doses of up to 2 g a day are well tolerated and furthermore most clinical trials have reported only benign side effects without significant weight loss (Dodd et al. 2008). The present study appears to be the first to report a very significant loss of body mass and it’s possible the effect may have been exacerbated because Pinniger et al. 2017 used young mice during their peak growth phase. Clearly, the current report of a correlation between oral administration of N-acetylcysteine and significant weight loss requires further confirmatory investigation. It also has to be taken into consideration that the reported reduction in body mass may contribute to some of the beneficial muscle effects seen in the mdx mice; grip strength and greater force production, as forces acting on the muscle will be proportionally reduced in relation to the body weight reduction, meaning that there will be less damage in the treated mdx. Indeed, there have been recommendations that DMD boys maintain an ideal body weight to help reduce muscle damage. Taking into account the positive findings of earlier studies and the results presented in this issue of The Journal of Physiology by Pinninger and colleagues, it is evident that oral administration of N-acetylcysteine warrants further research as a potential therapy for DMD with the important caveat that close attention must be paid to any N-acetylcysteine-associated weight loss.