Effects of exosome-mediated delivery of myostatin propeptide on functional recovery of mdx mice
Effects of exosome-mediated delivery of myostatin propeptide on functional recovery of mdx mice
复制标题
外泌体介导的肌生成抑制素前肽对 mdx 小鼠功能恢复的影响
DOI：
10.1016/j.biomaterials.2020.119826
复制
发表时间：
2020-04-01
期刊：
影响因子：
14
通讯作者：
Yin, HaiFang
中科院分区：
文献类型：
--
作者：
Ran, Ning;Gao, Xianjun;Yin, HaiFang
杜氏肌营养不良症（DMD）是一种由功能性肌营养不良蛋白丢失引起的破坏性疾病，导致肌肉萎缩。通过抑制肌生长抑制素（一种负调节骨骼肌质量的生长因子）来增强肌肉生长是减缓疾病进展的有希望的方法。直接施用肌生长抑制素前肽（成熟肌生长抑制素的天然抑制剂）已经显示出有限的功效，这可能是由于低血清稳定性。在这里，我们证明了前肽的血清稳定性、递送效率和功效可以通过将肌生长抑制素前肽的抑制结构域融合到CD63的第二胞外环（EXOpro）中而将前肽锚定到外泌体表面来显著增强。EXOpro的重复给药加速肌肉再生和生长，导致mdx小鼠中肌肉质量和功能拯救显著增加，而没有任何可检测的毒性。重要的是，EXOpro部分修复了mdx小鼠的骨结构并促进了骨再生。我们的研究结果表明，锚定到外来体增加了前肽的递送和血清稳定性，并增强了肌生长抑制素前肽的抑制功效，从而为DMD中基于前肽的干预提供了递送平台。
Duchenne muscular dystrophy (DMD) is a devastating disorder caused by loss of functional dystrophin protein, resulting in muscle wasting. Enhancing muscle growth by inhibiting myostatin, a growth factor negatively regulating skeletal muscle mass, is a promising approach to slow disease progression. Direct administration of myostatin propeptide, a natural inhibitor of mature myostatin, has shown limited efficacy probably due to low serum stability. Here, we demonstrate that serum stability, delivery efficiency and efficacy of propeptide can be significantly enhanced by anchoring propeptide to the surface of exosomes by fusing the inhibitory domain of myosta tin propeptide into the second extracellular loop of CD63 (EXOpro). Repeated administrations of EXOpro accelerated muscle regeneration and growth, resulting in significantly increased muscle mass and functional rescue without any detectable toxicity in mdx mice. Importantly, EXOpro partially rehabilitated bone structure and promoted bone regeneration in mdx mice. Our findings demonstrate that anchoring to exosomes increased delivery and serum stability of propeptide and augmented the inhibitory efficacy of myostatin propeptide and thus provide a delivery platform for propeptide-based intervention in DMD.