Julie Chassagne , Nathalie Da Silva , Ines Akrouf , Bruno Cadot , Laura Julien , Ines Barthélémy , Stéphane Blot , Caroline Le Guiner , Mai Thao Bui , Norma B. Romero , Jeanne Lainé , France Pietri-Rouxel , Pierre Meunier , Kamel Mamchaoui , Stéphanie Lorain , Marc Bitoun , Sofia Benkhelifa-Ziyyat
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引用次数: 0
Abstract
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.
期刊介绍:
The American Journal of Pathology, official journal of the American Society for Investigative Pathology, published by Elsevier, Inc., seeks high-quality original research reports, reviews, and commentaries related to the molecular and cellular basis of disease. The editors will consider basic, translational, and clinical investigations that directly address mechanisms of pathogenesis or provide a foundation for future mechanistic inquiries. Examples of such foundational investigations include data mining, identification of biomarkers, molecular pathology, and discovery research. Foundational studies that incorporate deep learning and artificial intelligence are also welcome. High priority is given to studies of human disease and relevant experimental models using molecular, cellular, and organismal approaches.