Rosen H Grace, Berger Nicolas J, Hodge Shantel N, Fujishiro Atsutaro, Lourie Jared, Kapadia Vrusti, Duzz Tessa, Linden Melissa A, Jee Eunbin, Kim Jonghan, Kim Yuho, Zou Kai
Department of Biology, University of Massachusetts Boston, Boston, Massachusetts, United States.
Department of Exercise and Health Sciences, University of Massachusetts Boston, Boston, Massachusetts, United States.
Am J Physiol Cell Physiol. 2025 Jul 1;329(1):C307-C324. doi: 10.1152/ajpcell.01009.2024. Epub 2025 Jun 16.
Although current treatments for Duchenne muscular dystrophy (DMD) have proven to be effective in delaying myopathy, there remains a strong need to identify novel targets to develop additional therapies. Mitochondrial dysfunction is an early pathological feature of DMD. A fine balance of mitochondrial dynamics (fission and fusion) is crucial to maintain mitochondrial function and skeletal muscle health. Excessive activation of dynamin-related protein 1 (Drp1)-mediated mitochondrial fission was reported in animal models of DMD. However, whether Drp1-mediated mitochondrial fission is a viable target for treating myopathy in DMD remains unknown. Here, we treated a D2.B10-/J (D2-mdx) model of DMD (9-10 wk old) with mitochondrial division inhibitor 1 (Mdivi-1), a selective Drp1 inhibitor, every other day (intraperitoneal injection) for 5 wk. We demonstrated that Mdivi-1 effectively improved skeletal muscle strength and reduced serum creatine kinase concentration. Mdivi-1 treatment also effectively inhibited mitochondrial fission regulatory protein markers, Drp1(Ser616) phosphorylation, and mitochondrial fission protein 1 (Fis1) in skeletal muscles from D2-mdx mice, which resulted in reduced content of damaged and fragmented mitochondria. Furthermore, Mdivi-1 treatment attenuated lipid peroxidation product, 4-hydroxynonenal (4-HNE), in skeletal muscle from D2-mdx mice, which was inversely correlated with muscle grip strength. Finally, we revealed that Mdivi-1 treatment downregulated the expression of markers of fibrosis [alpha 1 type I collagen (Col1a1), metalloproteinases 2 and 9 (MMP2 and MMP9)] and inflammation [IL-6, monocyte chemoattractant protein-1 (MCP1), and CXC motif chemokine ligand 12 (CXCL12)]. In summary, these results demonstrate that inhibition of Drp1-mediated mitochondrial fission by Mdivi-1 is effective in improving muscle strength and alleviating muscle damage in D2-mdx mice. These improvements are associated with improved skeletal muscle mitochondrial integrity, leading to attenuated lipid peroxidation. The therapeutic potential of targeting mitochondrial dynamics in treating myopathy in Duchenne muscular dystrophy (DMD) remains unknown. This study is the first to target Drp1-mediated mitochondrial fission to alleviate myopathy in DMD. We reported that Mdivi-1, a pharmacological inhibitor targeting Drp1-mediated mitochondrial fission, was effective in reducing muscle damage and improving skeletal muscle strength in D2-mdx mice. These responses were associated with improved mitochondrial morphology and reduced lipid peroxidation.
尽管目前用于治疗杜氏肌营养不良症（DMD）的疗法已被证明在延缓肌病方面有效，但仍迫切需要确定新的靶点以开发更多疗法。线粒体功能障碍是DMD的早期病理特征。线粒体动力学（裂变和融合）的精细平衡对于维持线粒体功能和骨骼肌健康至关重要。在DMD动物模型中，已报道发动蛋白相关蛋白1（Drp1）介导的线粒体裂变过度激活。然而，Drp1介导的线粒体裂变是否是治疗DMD肌病的可行靶点仍不清楚。在此，我们每隔一天（腹腔注射）用线粒体分裂抑制剂1（Mdivi-1，一种选择性Drp1抑制剂）治疗DMD的D2.B10-/J（D2-mdx）模型（9-10周龄），持续5周。我们证明Mdivi-1有效改善了骨骼肌力量并降低了血清肌酸激酶浓度。Mdivi-1治疗还有效抑制了D2-mdx小鼠骨骼肌中的线粒体裂变调节蛋白标志物、Drp1（Ser616）磷酸化和线粒体裂变蛋白1（Fis1），这导致受损和碎片化线粒体的含量减少。此外，Mdivi-1治疗减轻了D2-mdx小鼠骨骼肌中脂质过氧化产物4-羟基壬烯醛（4-HNE）的水平，其与肌肉握力呈负相关。最后，我们发现Mdivi-1治疗下调了纤维化标志物[I型α1胶原蛋白（Col1a1）、金属蛋白酶2和9（MMP2和MMP9）]和炎症标志物[白细胞介素-6、单核细胞趋化蛋白-1（MCP1）和CXC基序趋化因子配体12（CXCL12）]的表达。总之，这些结果表明，Mdivi-1抑制Drp1介导的线粒体裂变可有效改善D2-mdx小鼠的肌肉力量并减轻肌肉损伤。这些改善与骨骼肌线粒体完整性的改善相关，从而导致脂质过氧化减轻。靶向线粒体动力学治疗杜氏肌营养不良症（DMD）肌病的治疗潜力仍不清楚。本研究首次靶向Drp1介导的线粒体裂变以减轻DMD中的肌病。我们报道，作为靶向Drp1介导的线粒体裂变的药理学抑制剂，Mdivi-1在减轻D2-mdx小鼠肌肉损伤和改善骨骼肌力量方面有效。这些反应与线粒体形态的改善和脂质过氧化的减少有关。
