Liu Muchen, Chatterjee Somik, Wu Jianbo, Kashaniasl Zeinab, Kumar Ashok, Lin Chunru, Darabi Radbod
Institute of Muscle Biology and Cachexia (IMBC), University of Houston, Houston, TX, USA.
Department of Pharmaceutical and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX 77204, USA.
Mol Ther Methods Clin Dev. 2025 Jun 16;33(3):101515. doi: 10.1016/j.omtm.2025.101515. eCollection 2025 Sep 11.
Becker muscular dystrophy (BMD) is caused by in-frame mutations in dystrophin gene, leading to progressive muscle weakness, and cardiac and respiratory complications. Currently, there is no cure. We have recently identified the importance of poly-ubiquitination in regulating dystrophin stability through the binding of lncRNA H19 to the dystrophin C-terminal zinc-finger domain (ZNF), inhibiting TRIM63-mediated poly-ubiquitination. We also demonstrated that BMD mutations lead to conformational changes in ZNF domain, reduced lncRNA H19 binding and increased dystrophin ubiquitination. Here we used BMD iPSCs to investigate the myogenic potential of BMD myogenic cells, as well as and studies to evaluate the therapeutic efficacy of three candidate molecules targeting dystrophin ubiquitination pathway. assays indicated significant deficiencies in myogenic cell differentiation of BMD iPSCs, including reduced proliferation, cell-cycle arrest, increased apoptosis, senescence, and membrane damage, and impaired myotube formation. engraftment demonstrated significant improvement in BMD iPSC myogenic cell survival and dystrophin expression in the animals treated with two molecules: a TRIM63 inhibitor and an α-synuclein aggregation inhibitor. These findings provide promising evidence for the potential therapeutic efficacy of these ubiquitination pathway inhibitors to improve muscle progenitor cell survival and dystrophin expression in BMD patients.
贝克尔肌营养不良症（BMD）由肌营养不良蛋白基因的框内突变引起，导致进行性肌肉无力以及心脏和呼吸并发症。目前，尚无治愈方法。我们最近发现了多聚泛素化在通过长链非编码RNA H19与肌营养不良蛋白C末端锌指结构域（ZNF）结合来调节肌营养不良蛋白稳定性方面的重要性，从而抑制TRIM63介导的多聚泛素化。我们还证明，BMD突变会导致ZNF结构域的构象变化、长链非编码RNA H19结合减少以及肌营养不良蛋白泛素化增加。在此，我们使用BMD诱导多能干细胞（iPSC）来研究BMD成肌细胞的成肌潜力，并进行研究以评估三种靶向肌营养不良蛋白泛素化途径的候选分子的治疗效果。检测表明，BMD iPSC的成肌细胞分化存在明显缺陷，包括增殖减少、细胞周期停滞、凋亡增加、衰老以及膜损伤，并且肌管形成受损。移植实验表明，在用两种分子（一种TRIM63抑制剂和一种α-突触核蛋白聚集抑制剂）治疗的动物中，BMD iPSC成肌细胞的存活率和肌营养不良蛋白表达有显著改善。这些发现为这些泛素化途径抑制剂在改善BMD患者肌肉祖细胞存活率和肌营养不良蛋白表达方面的潜在治疗效果提供了有前景的证据。
