Impaired skeletal muscle stem cell (MuSC) function has long been suspected to contribute to the pathogenesis of muscular dystrophy (MD). Here, we showed that defects in the endothelial cell (EC) compartment of the vascular stem cell niche in mouse models of Duchenne MD, laminin α2–related MD, and collagen VI–related myopathy were associated with inefficient mobilization of MuSCs after tissue damage. Using chemoinformatic analysis, we identified the 13–amino acid form of the peptide hormone apelin (AP-13) as a candidate for systemic stimulation of skeletal muscle ECs. Systemic administration of AP-13 using osmotic pumps generated a pro-proliferative EC-rich niche that supported MuSC function through angiocrine factors and markedly improved tissue regeneration and muscle strength in all three dystrophic mouse models. Moreover, EC-specific knockout of the apelin receptor led to regenerative defects that phenocopied key pathological features of MD, including vascular defects, fibrosis, muscle fiber necrosis, impaired MuSC function, and reduced force generation. Together, these studies provide in vivo proof of concept that enhancing endogenous skeletal muscle repair by targeting the vascular niche is a viable therapeutic avenue for MD and characterized AP-13 as a candidate for further study for the systemic treatment of MuSC dysfunction.

中文翻译：

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Apelin 刺激血管骨骼肌干细胞生态位增强营养不良小鼠的内源性修复

长期以来，骨骼肌干细胞（MuSC）功能受损一直被怀疑与肌营养不良症（MD）的发病机制有关。在这里，我们发现，在 Duchenne MD、层粘连蛋白 α2 相关 MD 和胶原 VI 相关肌病小鼠模型中，血管干细胞生态位的内皮细胞 (EC) 区室的缺陷与组织损伤后 MuSC 的低效动员有关。通过化学信息学分析，我们确定了肽激素 apelin (AP-13) 的 13 个氨基酸形式作为骨骼肌 EC 全身刺激的候选者。使用渗透泵全身施用 AP-13 产生了富含 EC 的促增殖生态位，该生态位通过血管分泌因子支持 MuSC 功能，并在所有三种营养不良小鼠模型中显着改善组织再生和肌肉力量。此外，EC特异性敲除apelin受体会导致再生缺陷，这些缺陷与MD的关键病理特征相似，包括血管缺陷、纤维化、肌纤维坏死、MuSC功能受损和力量产生减少。总之，这些研究提供了体内概念证明，即通过靶向血管生态位来增强内源性骨骼肌修复是 MD 的可行治疗途径，并将 AP-13 定性为进一步研究系统性治疗 MuSC 功能障碍的候选药物。