#apaperaday: Six weeks of N-acetylcysteine antioxidant in drinking water decreases pathological fiber branching in MDX mouse dystrophic fast-twitch skeletal muscle

In today’s #apaperaday, Prof. Aartsma-Rus reads and comments on the paper titled: Six weeks of N-acetylcysteine antioxidant in drinking water decreases pathological fiber branching in MDX mouse dystrophic fast-twitch skeletal muscle.

Today’s pick is from Frontiers in Medicine Physiology by Redwan et al on the use of antioxidant NAC in mdx mice. Doi: 10.3389/fphys.2023.1109587

Oxidative stress plays a role in Duchenne pathology. Due to chronic inflammation there is an excess of free radicals, which have a purpose when battling e.g. a bacterium but not when the damage occurs due to a genetic defect.

Also, because nitric oxide synthase enzyme is mislocalized lacking dystrophin, the NO radical is produced in the wrong place (at the right place it causes vasodilation, in the wrong place oxidative stress). The free radicals cause damage of proteins thus exacerbating pathology.

As such, antioxidants make sense as a therapeutic approach for Duchenne. NAC (N-acetylcysteine) is one such antioxidant, that is already approved for human use and that scavenges free radicals and increases levels of glutathione, one of the body’s own antioxidants.

Previous studies have already shown that NAC treatment can reduce oxidative stress in mdx mice, but that this is associated with reduced body mass. Here authors tested NAC treatment in mdx and wild type mice, focusing on weight and branched fibers.

Authors used heterogyzous breeding, to generate male wild type and mdx littermates, that were used in this study. So wild types are genetically and epigenetically as similar as they can be. Animals were treated for 6 weeks with NAC in drinking water (age 3-9 weeks).

NAC is acidic. To avoid animals drinking less due to this taste, artificial flavoring was added (banana caramel – no information on which flavoring mice liked best – note that (artificial) sweeteners are also used in sodas to get humans to drink them (sodas are very acidic).

Back to the study: animals drank equal amounts of water and NAC water so the flavoring trick worked. However, both wild type and mdx mice drinking NAC water had a lower body weight. This means that the reduced weight is not only due to less hypertrophy in mdx mice.

Authors discuss that other studies have shown NAC does not only affect lean mass (muscle and bone) but also reduces fat, and increases energy expenditure. As such, the weight loss is not unexpected. Authors saw that the EDL of NAC treated mdx mice was lighter (not for wild type).

However, there were no differences in EDL force or resistance to damage during normal and eccentric contraction for mdx or wild type mice. Authors did see the expected reduced force and increased force drop after eccentric exercise for mdx compared to wild type.