Dubinin Mikhail V, Stepanova Anastasia E, Mikheeva Irina B, Igoshkina Anastasia D, Kraeva Ekaterina N, Cherepanova Alena A, Talanov Eugeny Yu, Polikarpova Anna V, Astashev Maxim E, Loginov Vyacheslav A, Egorova Tatiana V
Department of Biochemistry, Cell Biology and Microbiology, Mari State University, pl. Lenina 1, 424001 Yoshkar-Ola, Russia.
Laboratory of Experimental Neurobiology, Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, 142290 Pushchino, Russia.
Int J Mol Sci. 2025 Sep 11;26(18):8845. doi: 10.3390/ijms26188845.
Duchenne muscular dystrophy (DMD) is a severe X-linked recessive disorder caused by mutations in the gene, leading to progressive muscle degeneration and fibrosis. A key pathological feature of DMD is mitochondrial dysfunction driven by calcium overload, which disrupts oxidative phosphorylation and triggers cell death pathways. This study shows the therapeutic potential of VBIT-4, a novel inhibitor of the mitochondrial voltage-dependent anion channel (VDAC), in two dystrophin-deficient mouse models: the mild and the severe D2.DMDel8-34 strains. VBIT-4 administration (20 mg/kg) reduced mitochondrial calcium overload, enhanced resistance to permeability transition pore induction, and improved mitochondrial ultrastructure in D2.DMDel8-34 mice, while showing negligible effects in mice. VBIT-4 suppressed mitochondrial and total calpain activity and reduced endoplasmic reticulum stress markers, suggesting a role in mitigating proteotoxic stress. However, it did not restore oxidative phosphorylation or reduce oxidative stress. Functional assays revealed limited improvements in muscle strength and fibrosis reduction, exclusively in the severe model. These findings underscore VDAC as a promising target for severe DMD and highlight the critical role of mitochondrial calcium homeostasis in DMD progression.
杜氏肌营养不良症（DMD）是一种严重的X连锁隐性疾病，由该基因的突变引起，导致进行性肌肉退化和纤维化。DMD的一个关键病理特征是由钙超载驱动的线粒体功能障碍，这会破坏氧化磷酸化并触发细胞死亡途径。本研究显示了线粒体电压依赖性阴离子通道（VDAC）的新型抑制剂VBIT-4在两种肌营养不良蛋白缺陷小鼠模型中的治疗潜力：轻度模型和严重的D2.DMDel8-34品系。给予VBIT-4（20mg/kg）可减少D2.DMDel8-34小鼠的线粒体钙超载，增强对通透性转换孔诱导的抗性，并改善线粒体超微结构，而在轻度模型小鼠中显示出可忽略不计的作用。VBIT-4抑制线粒体和总钙蛋白酶活性，并降低内质网应激标志物，表明其在减轻蛋白毒性应激中发挥作用。然而，它并未恢复氧化磷酸化或降低氧化应激。功能测定显示仅在严重模型中肌肉力量有有限改善且纤维化减少。这些发现强调了VDAC作为严重DMD的一个有前景的靶点，并突出了线粒体钙稳态在DMD进展中的关键作用。
