title: Loss of miR-29 in myoblasts contributes to dystrophic muscle pathogenesis.
abstract: microRNAs (miRNAs) are noncoding RNAs that regulate gene expression in post-transcriptional fashion, and emerging studies support their importance in a multitude of physiological and pathological processes. Here, we describe the regulation and function of miR-29 in Duchenne muscular dystrophy (DMD) and its potential use as therapeutic target. Our results demonstrate that miR-29 expression is downregulated in dystrophic muscles of mdx mice, a model of DMD. Restoration of its expression by intramuscular and intravenous injection improved dystrophy pathology by both promoting regeneration and inhibiting fibrogenesis. Mechanistic studies revealed that loss of miR-29 in muscle precursor cells (myoblasts) promotes their transdifferentiation into myofibroblasts through targeting extracellular molecules including collagens and microfibrillar-associated protein 5 (Mfap5). We further demonstrated that miR-29 is under negative regulation by transforming growth factor-β (TGF-β) signaling. Together, these results not only identify TGF-β-miR-29 as a novel regulatory axis during myoblasts conversion into myofibroblasts which constitutes a novel contributing route to muscle fibrogenesis of DMD but also implicate miR-29 replacement therapy as a promising treatment approach for DMD.
authors.affiliation: Department of Obstetrics and Gynaecology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR, China.
authors.forename: Lijun
authors.initials: L
authors.lastname: Wang
authors.forename: Liang
authors.initials: L
authors.lastname: Zhou
authors.forename: Peiyong
authors.initials: P
authors.lastname: Jiang
authors.forename: Leina
authors.initials: L
authors.lastname: Lu
authors.forename: Xiaona
authors.initials: X
authors.lastname: Chen
authors.forename: Huiyao
authors.initials: H
authors.lastname: Lan
authors.forename: Denis C
authors.initials: DC
authors.lastname: Guttridge
authors.forename: Hao
authors.initials: H
authors.lastname: Sun
authors.forename: Huating
authors.initials: H
authors.lastname: Wang
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D054338:Cell Transdifferentiation; D002478:Cells, Cultured; D015536:Down-Regulation / Q000235:genetics; D005109:Extracellular Matrix / Q000235:genetics; D005355:Fibrosis / Q000235:genetics; D005786:Gene Expression Regulation; D051379:Mice; D018101:Mice, Inbred mdx; D035683:MicroRNAs / Q000008:administration & dosage / Q000235:genetics*; D008954:Models, Biological; D018482:Muscle, Skeletal / Q000378:metabolism; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics*; D032446:Myoblasts / Q000166:cytology / Q000378:metabolism*; D058628:Myofibroblasts / Q000166:cytology; D012038:Regeneration; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: C547014:MIRN29 microRNA, mouse; D035683:MicroRNAs; D016212:Transforming Growth Factor beta