Duchenne Muscular Dystrophy (DMD) is an X-linked genetic disease caused by mutations in the dystrophin gene, resulting in severe muscle weakness, degeneration, and early death. Abnormal phenotypes seen in DMD muscle include inflammation, fibrosis, and dysregulated metabolism. Literature suggests microRNA-146a (miR-146a) targets each of these phenotypes: inflammation via nuclear factor-kappa B, fibrosis via transforming growth factor-beta, and metabolism via peroxisome proliferator-activated receptor (Ppar)-alpha, Ppar-gamma, and peroxisome proliferator-activated receptor gamma coactivator 1-alpha. We therefore hypothesize that overexpression of miR-146a will reduce muscle inflammation and fibrosis in dystrophic mice and improve muscle metabolic defects, resulting in a stabilized muscle environment. We generated a cohort of dystrophin-deficient (mdx4cv) mice overexpressing miR-146a (mdx4cv;miR-146aKI/WT) and analyzed muscle histology at 3 and 7 months of age compared to mdx4cv mice. Data show reduced myofiber degeneration in skeletal muscle of mdx4cv;miR-146aKI/WT mice at 3 months of age and reduced cumulative muscle damage in the diaphragm muscle of mdx4cv;miR-146aKI/WT mice by 7 months of age. We performed spatial transcriptomics on diaphragm muscles of 7-month-old dystrophic mice and demonstrated that genes responsible for inflammation are downregulated with miR-146a overexpression, whereas driver genes for pathways involved in muscle function and oxidative phosphorylation (metabolism) are upregulated. Collectively, our data show an exciting potential for miR-146a as a therapeutic to protect muscle from deleterious downstream effects of dystrophin-deficiency. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
Oyebode et al. (Fri,) studied this question.