Exosomes and exosomal miRNAs from muscle-derived fibroblasts promote skeletal muscle fibrosis

We investigated in vitro and in vivo the pro-fibrotic role of exosomes released by muscle-derived fibroblasts of Duchenne muscular dystrophy (DMD) patients, and of miRNAs carried by exosomes. We found that exosomes from DMD fibroblasts, but not from myoblasts, had significantly higher levels of miR-199a-5p, a miRNA up-regulated in fibrotic conditions, compared to control exosomes. In control fibroblasts, exposure to DMD fibroblast-derived exosomes induced a myofibroblastic phenotype with increase in α-smooth actin, collagen and fibronectin transcript and protein expression, soluble collagen production and deposition, cell proliferation, and activation of Akt and ERK signalling, while exposure to control exosomes did not. These findings were related to transfer of high levels of miR-199a-5p and to reduction of its target caveolin-1. Finally, injection of DMD fibroblast-derived exosomes into mouse tibialis anterior muscle after cardiotoxin-induced necrosis, produced greater fibrosis than control exosomes. Our findings indicate that exosomes produced by local fibroblasts in the DMD muscle are able to induce phenotypic conversion of normal fibroblasts to myofibroblasts thereby increasing the fibrotic response; and suggest miR-199a-5p and caveolin-1as potential therapeutic targets.