Gorji Abdolvahab Ebrahimpour, Kliczkowska Katarzyna, Ollik Marcin, Le Guiner Caroline, Wilczak Jacek, Bielecki Wojciech, Ostaszewski Piotr, Shirali Masoud, Roudbari Zahra, Sadkowski Tomasz
Department of Physiological Sciences, Institute of Veterinary Medicine, Warsaw University of Life Sciences, Warsaw, 02-776, Poland.
Department of Pathology and Veterinary Diagnostics, Institute of Veterinary Medicine, Warsaw University of Life Sciences, Warsaw, 02-776, Poland.
Sci Rep. 2025 Aug 11;15(1):29312. doi: 10.1038/s41598-025-14756-9.
Duchenne muscular dystrophy (DMD) is a severe X-linked recessive disorder caused by a mutation in the Dmd gene, leading to progressive muscle degradation, increasing weakness, and typically resulting in death before the third decade of life. To investigate the pathobiology of DMD, this study employed the Sprague-Dawley Dmd-mutated rat model (DMD) and analyzed gene expression profiles and pathological molecular pathways. The methods used included histopathological, biochemical, and transcriptomic analyses of dystrophic skeletal muscle from DMD and wild-type (WT) individuals. Histological analysis of skeletal muscle tissue from DMD rats revealed multifocal necrosis, fibrosis, and inflammation, whereas WT rats displayed normal muscle architecture. Biochemical analysis revealed significant alterations in plasma markers of muscle damage and metabolism in DMD rats compared to WT controls, including elevated AST, ALT, ALP, CPK, and LDH levels. Additionally, oxidative status measurements showed reduced antioxidant capacity and increased lipid peroxidation in dystrophic skeletal muscle, as evidenced by lower TAS, GR, GPx, and SOD activities and higher TBARS levels. RNA-seq analysis identified 3,615 differentially expressed genes between the two groups, associated with muscle contraction, extracellular matrix (ECM) organization, and cytoskeleton organization. Notably, Dmd, Actc1, Col6a1, and Mmp2 were significantly downregulated. Gene ontology and pathway enrichment analyses indicated dystrophic changes in skeletal muscle, disruptions in calcium homeostasis, and alterations in actin cytoskeleton regulation. KEGG and Reactome pathway analyses revealed upregulation of the MAPK signaling and immune system pathways and downregulation of the ECM organization pathway. These findings support the hypothesis that targeting complex intracellular signaling pathways in DMD may represent a promising therapeutic strategy. Given that the DMD rat model closely mimics human DMD pathology compared to other animal models, it offers a more realistic platform for studying the molecular mechanisms of the disease and improving the translational potential of therapeutic approaches.
杜兴氏肌肉营养不良症（DMD）是一种严重的X连锁隐性疾病，由Dmd基因突变引起，导致进行性肌肉退化、肌无力加剧，通常在生命的第三个十年之前死亡。为了研究DMD的病理生物学，本研究采用了Sprague-Dawley Dmd突变大鼠模型（DMD），并分析了基因表达谱和病理分子途径。所使用的方法包括对DMD和野生型（WT）个体的营养不良性骨骼肌进行组织病理学、生化和转录组分析。对DMD大鼠骨骼肌组织的组织学分析显示多灶性坏死、纤维化和炎症，而WT大鼠显示正常的肌肉结构。生化分析显示，与WT对照组相比，DMD大鼠肌肉损伤和代谢的血浆标志物有显著改变，包括AST、ALT、ALP、CPK和LDH水平升高。此外，氧化状态测量显示营养不良性骨骼肌的抗氧化能力降低，脂质过氧化增加，TAS、GR、GPx和SOD活性降低以及TBARS水平升高证明了这一点。RNA测序分析确定了两组之间3615个差异表达基因，这些基因与肌肉收缩、细胞外基质（ECM）组织和细胞骨架组织有关。值得注意的是，Dmd、Actc1、Col6a1和Mmp2显著下调。基因本体和通路富集分析表明骨骼肌存在营养不良性变化、钙稳态破坏以及肌动蛋白细胞骨架调节改变。KEGG和Reactome通路分析显示MAPK信号通路和免疫系统通路上调，ECM组织通路下调。这些发现支持了这样一种假设，即针对DMD中复杂的细胞内信号通路可能是一种有前景的治疗策略。鉴于与其他动物模型相比，DMD大鼠模型更紧密地模拟了人类DMD病理，它为研究该疾病的分子机制和提高治疗方法的转化潜力提供了一个更现实的平台。
