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. Here, it was shown that impaired lysosome formation is associated with altered acidification and reduced degradative function of the endolysosomal pathway in muscle cells derived from patients with DMD. The data demonstrated that early endosomes are 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. It was determined that these abnormalities are due to the lack of dystrophin per se and could be correlated with disease progression and severity. We further identified an abnormal up-regulation of the Rab5 GTPase protein, one key actor of early endosomal biogenesis and fusion, in the three DMD models, which may underlie the endosomal defects. Finally, we demonstrated that Rab5 knockdown in human DMD muscle cells as well as dystrophin restoration in golden retriever muscular dystrophy dogs normalize Rab5 expression levels and rescue endosomal abnormalities. This study unveils a defect in a pathway essential for muscle homeostasis and for the efficacy of DMD therapies.