Exploring miR-146a As A Potential Therapeutic For Duchenne Muscular Dystrophy

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 pathways; 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 hypothesized 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-146a KI/WT ) and analyzed muscle histology at 3 and 7 months of age compared to mdx4Cv mice. Data show reduced inflammation (macrophages) in skeletal muscle of mdx4Cv;miR-146a KI/WT mice at 3 months of age and reduced cumulative muscle damage (7.8% recovery toward wild-type) in the diaphragm muscle of mdx4Cv;miR-146a KI/WT mice by 7 months of age. We additionally performed spatial transcriptomics on diaphragm muscles of 7-month-old dystrophic mice and demonstrated reduced inflammatory gene expression and enhanced metabolic and structural muscle gene expression with miR-146a overexpression. Collectively our data demonstrate an exciting potential for miR-146a as a therapeutic to protect muscle from deleterious downstream effects of dystrophin-deficiency. This project was supported by a deArce-Koch Memorial Endowment Fund award through The University of Toledo This abstract was presented at the American Physiology Summit 2025 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.