Early Endosome Disturbance and Endolysosomal Pathway Dysfunction in Duchenne Muscular Dystrophy.

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.