Chassagne Julie, Da Silva Nathalie, Akrouf Ines, Cadot Bruno, Julien Laura, Barthélémy Ines, Blot Stéphane, Le Guiner Caroline, Bui Mai Thao, Romero Norma B, Lainé Jeanne, Pietri-Rouxel France, Meunier Pierre, Mamchaoui Kamel, Lorain Stéphanie, Bitoun Marc, Benkhelifa-Ziyyat Sofia
Sorbonne Université, INSERM, Institute of Myology, Center of Research in Myology, Paris, France.
Biology of the Neuromuscular System Team, U955 Institut Mondor de Recherche Biomédicale, INSERM, University Paris-Est Créteil, Créteil, France; École Nationale Vétérinaire d'Alfort, Maisons-Alfort, France.
Am J Pathol. 2025 Sep;195(9):1627-1642. doi: 10.1016/j.ajpath.2025.05.007. Epub 2025 Jun 9.
Duchenne muscular dystrophy (DMD) is a lethal dystrophy characterized by the progressive loss of muscle fibers caused by mutations in DMD gene and absence of the dystrophin protein. Although autophagy and lysosome biogenesis defects have been described in DMD muscles, the endosomal pathway has never been studied. The current study revealed an association of impaired lysosome formation with altered acidification and reduced degradative function of the endolysosomal pathway in muscle cells derived from patients with DMD. Early endosomes were increased in these cells as well as in muscle biopsies from patients with DMD and two animal models of DMD, mdx mice and golden retriever muscular dystrophy dogs. These abnormalities occurred due to the lack of dystrophin per se and could be correlated with disease progression and severity. An abnormal up-regulation of the Rab5 GTPase protein, one key actor of early endosomal biogenesis and fusion, was identified in the three DMD models, which may underlie the endosomal defects. Finally, Rab5 knockdown in human DMD muscle cells as well as dystrophin restoration in golden retriever muscular dystrophy dogs normalized Rab5 expression levels and rescued endosomal abnormalities. This study unveiled a defect in a pathway essential for muscle homeostasis and for the efficacy of DMD therapies.
杜氏肌营养不良症（DMD）是一种致命的肌营养不良症，其特征是由于DMD基因突变导致肌纤维逐渐丧失，且缺乏抗肌萎缩蛋白。尽管已在DMD肌肉中描述了自噬和溶酶体生物发生缺陷，但内体途径从未被研究过。当前研究揭示了溶酶体形成受损与DMD患者来源的肌肉细胞中内溶酶体途径的酸化改变和降解功能降低之间的关联。在这些细胞以及来自DMD患者和两种DMD动物模型（mdx小鼠和金毛寻回犬型肌营养不良症犬）的肌肉活检中，早期内体均增加。这些异常是由于抗肌萎缩蛋白本身的缺乏所致，并且可能与疾病进展和严重程度相关。在三种DMD模型中均发现Rab5 GTPase蛋白异常上调，Rab5 GTPase蛋白是早期内体生物发生和融合的关键因子之一，这可能是内体缺陷的基础。最后，在人DMD肌肉细胞中敲低Rab5以及在金毛寻回犬型肌营养不良症犬中恢复抗肌萎缩蛋白可使Rab5表达水平正常化并挽救内体异常。这项研究揭示了对肌肉稳态和DMD治疗效果至关重要的一条途径中的缺陷。
