Transcriptomic profiling of skeletal muscle in the DMDmdx rat model of Duchenne muscular dystrophy

This 2025 Scientific Reports paper by Ebrahimpour Gorji and colleagues, led by a group at Warsaw University of Life Sciences with collaborators in France, the UK, and Iran, presents a combined histopathological, biochemical, and transcriptomic characterisation of the Sprague-Dawley DMD^mdx rat model of Duchenne muscular dystrophy. The authors argue that this rat model is a better proxy for human DMD than the widely used mdx mouse, which shows unusually strong muscle regeneration and a milder phenotype, and they set out to map the molecular landscape of dystrophic muscle at an intermediate disease stage. Seven dystrophin-deficient rats and seven wild-type littermates were studied at roughly four months of age. Biceps femoris muscle was assessed histologically with H&E, Picrosirius red, and Koss staining, blood plasma was profiled across nineteen biochemical parameters, and muscle homogenates were tested for oxidative status markers including TAS, glutathione reductase, glutathione peroxidase, SOD, and TBARS. For the transcriptomic arm, RNA from four animals per genotype was sequenced and analysed using HISAT2 alignment, featureCounts quantification, DESeq2 differential expression, and GO/KEGG/Reactome enrichment.

The dystrophic rats showed the expected pathology: extensive multifocal myofiber necrosis, mononuclear inflammatory infiltration, reduced myofiber diameters, and dramatic interstitial fibrosis, with connective tissue occupying 44.3% of the muscle cross-section versus just 4.0% in wild-type controls. Plasma markers of muscle damage were sharply elevated (CPK, LDH, and ALT), alongside disturbances in calcium, sodium, phosphorus, magnesium, potassium, glucose, and urea. Antioxidant capacity was markedly impaired, with reduced TAS and lower glutathione reductase and peroxidase activity, though SOD activity was unchanged between groups. RNA-seq identified 3,615 differentially expressed genes (1,824 up, 1,791 down), enriched for actin cytoskeleton organisation, extracellular matrix organisation, calcium ion binding, and muscle contraction. Key structural and regenerative genes were downregulated, including Dmd, Actc1, Col6a1, Mmp2, Igf1, and the regeneration-linked myosins Myh3 and Myh8, while inflammatory and Wnt-inhibitory genes such as Tnfrsf19, Nos2, and Dkk1 were upregulated. KEGG analysis highlighted MAPK and calcium signalling, and Reactome emphasised immune and ECM pathways. The authors conclude that the rat model yields more DEGs and more severe pathology than mdx mice, making it a more translationally relevant platform, and they map their findings onto potential therapeutic targets including anti-fibrotic, anti-inflammatory, and PI3K/AKT-modulating strategies.