Extracellular vesicles from serum and muscle cells of muscular dystrophy patients inhibit muscle differentiation and increase fibrosis
2Department of Neurology, Talpiot Medical Leadership Program, Chaim Sheba Medical Center, Ramat-Gan, and Sackler Faculty of Medicine, Israel
Duchenne muscular dystrophy (DMD) is a recessive, X-linked disease. DMD is caused by mutations in the dystrophin gene that can be either spontaneous or inherited. The dystrophin protein plays a critical role in the maintenance, integrity and normal functions of muscle cells, as well as the asymmetric division of satellite cells. Therefore, muscle differentiation and regeneration are impaired in DMD which results in fibrotic and fat tissues.
Extracellular vesicles (EVs) are membrane‐bound secreted nanovesicles that contain a diverse cargo which reflects the pathophysiological status of the cells. EVs play major roles in cell-cell interactions and have recently emerged as circulating biomarkers and disease mediators in various pathological conditions. Here, we analyzed the effects EVs isolated from serum and skeletal muscle cultures of muscular dystrophy patients on the myogenic and fibrogenic differentiation of human skeletal muscle cells. DMD and BMD serum EVs inhibited the proliferation of satellite cells but did not exert a significant effect on their differentiation. In contrast, EVs isolated from cultured DMD muscle cells inhibited the myogenic differentiation of the cells while increasing their fibrogenic phenotype. The DMD muscle EVs expressed higher levels of miR-21 and the lncRNA TALNEC2 and lower expression of H19, miR-145 and miR-29c compared with healthy control muscle EVs. Using silencing experiments, we found that miR-21 and TALNEC2 mediated some of the DMD muscle EV effects. In summary, EVs of serum and muscle muscular dystrophy patients deliver specific non-coding RNAs that act as mediators of disease progression and represent novel therapeutic targets.