PDF(Pubmed)
Abstract：
Dynamin 2 (DNM2) is a ubiquitously expressed GTPase regulating membrane trafficking and cytoskeleton dynamics. Heterozygous dominant mutations in DNM2 cause centronuclear myopathy (CNM), associated with muscle weakness and atrophy and histopathological hallmarks as fiber hypotrophy and organelles mis-position. Different severities range from the severe neonatal onset form to the moderate form with childhood onset and to the mild adult onset form. No therapy is approved for CNM. Here we aimed to validate and rescue a mouse model for the moderate form of DNM2-CNM harboring the common DNM2 R369W missense mutation. Dnm2R369W/+ mice presented with increased DNM2 protein level in muscle and moderate CNM-like phenotypes with force deficit, muscle and fiber hypotrophy, impaired mTOR signaling, and progressive mitochondria and nuclei mis-position with age. Molecular analyses revealed a fiber type switch toward oxidative metabolism correlating with decreased force and alteration of mitophagy markers paralleling mitochondria structural defects. Normalization of DNM2 levels through intramuscular injection of AAV-shDnm2 targeting Dnm2 mRNA significantly improved histopathology and muscle and myofiber hypotrophy. These results showed that the Dnm2R369W/+ mouse is a faithful model for the moderate form of DNM2-CNM and revealed that DNM2 normalization after a short 4-week treatment is sufficient to improve the CNM phenotypes.
摘要：
Dynamin2（DNM2）是一种广泛表达的GTP酶，可调节膜运输和细胞骨架动力学。DNM2中的杂合显性突变导致中央核肌病（CNM），与肌肉无力和萎缩以及组织病理学标志相关，如纤维肥大和细胞器位置错误。不同的严重程度范围从严重的新生儿发作形式到儿童期发作的中度形式以及轻度的成人发作形式。没有批准用于CNM的疗法。在这里，我们旨在验证和挽救具有常见DNM2R369W错义突变的中等形式DNM2-CNM的小鼠模型。Dnm2R369W/+小鼠在肌肉和中度CNM样表型中呈现DNM2蛋白水平升高，并伴有力缺陷，肌肉和纤维肥大，mTOR信号受损，随着年龄的增长，线粒体和细胞核错位。分子分析显示，纤维类型向氧化代谢转变，与线粒体结构缺陷的减少和线粒体自噬标记的改变有关。通过肌内注射靶向Dnm2mRNA的AAV-shDnm2使DNM2水平正常化可显着改善组织病理学以及肌肉和肌纤维肥大。这些结果表明,Dnm2R369W/+小鼠是DNM2-CNM的中度形式的忠实模型,并且揭示在短4周治疗后DNM2正常化足以改善CNM表型。
