MicroRNA-33 inhibition ameliorates muscular dystrophy by enhancing skeletal muscle regeneration.

Muscular dystrophy is a group of diseases characterized by progressive weakness and degeneration of skeletal muscles, for which there is currently no cure. Here, we show that microRNA (miR)-33a/b play a crucial role in muscle regeneration. miR-33a was upregulated during myoblast differentiation and in skeletal muscles of mdx mice, a genetic model of Duchenne muscular dystrophy (DMD). miR-33a deficiency enhanced muscle regeneration response to cardiotoxin injury and attenuated muscle degeneration and fibrosis in mdx mice. Conversely, a humanized mouse model expressing miR-33a and miR-33b showed exacerbated muscle degeneration and fibrosis. Mechanistically, miR-33a/b inhibited satellite cell proliferation, leading to reduced muscle regeneration and increased fibrosis by targeting Cdk6, Fst, and Abca1. Local and systemic administration of anti-miRNA oligonucleotides targeting miR-33a/b ameliorated the dystrophic phenotype in mdx mice. Furthermore, miR-33b inhibition upregulated these target genes in myotubes differentiated from human induced pluripotent stem cells derived from a patient with DMD. These findings indicate that miR-33a/b are involved in muscle regeneration and their inhibition may represent a potential therapeutic strategy for muscular dystrophy.