PDF(Pubmed)
Abstract：
Duchenne muscular dystrophy (DMD) is a devastating genetic disorder that leads to compromised cellular membranes, caused by the absence of membrane-bound dystrophin protein. Muscle membrane leakage results in disrupted intracellular homeostasis, protein degradation, and muscle wasting. Improving muscle membrane integrity may delay disease progression and extend the lifespan of DMD patients. Here, we demonstrate that exosomes, membranous extracellular vesicles, can elicit functional improvements in dystrophic mice by improving muscle membrane integrity. Systemic administration of exosomes from different sources induced phenotypic rescue and mitigated pathological progression in dystrophic mice without detectable toxicity. Improved membrane integrity conferred by exosomes inhibited intracellular calcium influx and calcium-dependent activation of calpain proteases, preventing the degradation of the destabilized dystrophin-associated protein complex. We show that exosomes, particularly myotube-derived exosomes, induced functional improvements and alleviated muscle deterioration by stabilizing damaged muscle membrane in dystrophic mice. Our findings suggest that exosomes may have therapeutic implications for DMD and other diseases with compromised membranes.
摘要：
杜兴氏肌营养不良症（DMD）是一种破坏性的遗传性疾病，会导致细胞膜受损，由缺乏膜结合的肌营养不良蛋白引起。肌膜渗漏导致细胞内稳态破坏，蛋白质降解，肌肉萎缩。改善肌膜完整性可以延缓疾病进展并延长DMD患者的寿命。这里,我们证明了外泌体，膜状细胞外囊泡，可以通过改善肌膜完整性来引起营养不良小鼠的功能改善。来自不同来源的外泌体的全身施用在营养不良小鼠中诱导表型拯救并减轻病理进展而没有可检测的毒性。外泌体赋予的改善的膜完整性抑制了细胞内钙内流和钙蛋白酶的钙依赖性活化，防止不稳定的肌营养不良蛋白相关蛋白复合物的降解。我们证明外泌体，特别是肌管来源的外泌体，通过稳定营养不良小鼠受损的肌膜来诱导功能改善和减轻肌肉退化。我们的发现表明，外泌体可能对DMD和其他膜受损的疾病具有治疗意义。
