#apaperaday: Altered muscle niche contributes to myogenic deficit in the D2-mdx model of severe DMD

In today’s #apaperaday, Prof. Aartsma-Rus reads and comments on the paper titled: Altered muscle niche contributes to myogenic deficit in the D2-mdx model of severe DMD

Today’s pick is from BioRvix preprint 0.1101/2023.03.27.534413 – so a sneak preview of work that hopefully will be published. It is from Mazala et al on the nice of young and older d2/mdx mice and how this influences regeneration.

Duchenne is caused by lack of dystrophin. This leads to chronic muscle damage & inflammation, failed regeneration & replacement of muscle by fat & fibrosis. In mice lacking dystrophin (mdx mouse) regeneration is quite efficient. In d2/mdx mice however, regeneration seems impaired.

The authors & others (including my group) noticed something strange: young d2/mdx mice have severe necrosis & fibrosis, but adults do better.  Here authors aimed to study this in more detail in young (4-7 wk) & adult (~8 mo) d2/mdx mice using normal mdx (B10-mdx) as reference.

First authors noticed that old d2/mdx mice showed more centrally located fibers, suggesting more regeneration than in younger d2/mdx mice. They also studied regenerative capacity in wild types (with dystrophin) for B10 and d2 after muscle toxin injection and saw the same: the d2 background was less able to repair the muscle and there was less proliferation of muscle stem cells than for b10 background: 5% for d2 and 60% for b10 of muscle fibers showed central nuclei (repaired fibers) after 6 days.

Authors show that the young d2/mdx mice have more pro-inflammatory macrophages and that the fibro-adipogenic stem cells are less able to differentiate into muscle than for old d2/mdx mice and bl10/mdx mice. This is due to a niche effect (the muscle environment).

The ratio of macrophages that are pro-inflammatory and pro-regenerative changes to more regenerative in older d2/mdx mice. Young d2/mdx mice also have more macrophages and fibro-adipogenic progenitors than older mice.

Finally authors show that treatment with deflazacort in wild type d2 mice after muscle injury (with muscle toxin) improves the regeneration and repair. Authors show a lot of data and experiments, with beautiful figures. Looking forward to seeing the final form published.

Appreciate that the authors publish the work already as a preprint. Many people are working with the d2/mdx mice and it is important to be aware of the improved regeneration in adults when planning experiments (see also https://pubmed.ncbi.nlm.nih.gov/36336938/)