title: Opposing roles of miR-21 and miR-29 in the progression of fibrosis in Duchenne muscular dystrophy.
abstract: Excessive extracellular matrix deposition progressively replacing muscle fibres is the endpoint of most severe muscle diseases. Recent data indicate major involvement of microRNAs in regulating pro- and anti-fibrotic genes. To investigate the roles of miR-21 and miR-29 in muscle fibrosis in Duchenne muscle dystrophy, we evaluated their expression in muscle biopsies from 14 patients, and in muscle-derived fibroblasts and myoblasts. In Duchenne muscle biopsies, miR-21 expression was significantly increased, and correlated directly with COL1A1 and COL6A1 transcript levels. MiR-21 expression was also significantly increased in Duchenne fibroblasts, more so after TGF-β1 treatment. In Duchenne fibroblasts the expression of miR-21 target transcripts PTEN (phosphatase and tensin homolog deleted on chromosome 10) and SPRY-1 (Sprouty homolog 1) was significantly reduced; while collagen I and VI transcript levels and soluble collagen production were significantly increased. MiR-29a and miR-29c were significantly reduced in Duchenne muscle and myoblasts, and miR-29 target transcripts, COL3A1, FBN1 and YY1, significantly increased. MiR-21 silencing in mdx mice reduced fibrosis in the diaphragm muscle and in both Duchenne fibroblasts and mdx mice restored PTEN and SPRY-1 expression, and significantly reduced collagen I and VI expression; while miR-29 mimicking in Duchenne myoblasts significantly decreased miR-29 target transcripts. These findings indicate that miR-21 and miR-29 play opposing roles in Duchenne muscle fibrosis and suggest that pharmacological modulation of their expression has therapeutic potential for reducing fibrosis in this condition.
authors.affiliation: Neuromuscular Diseases and Neuroimmunology Unit, Foundation IRCCS Neurological Institute C. Besta, Milano, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Zanotti
authors.affiliation: Neuromuscular Diseases and Neuroimmunology Unit, Foundation IRCCS Neurological Institute C. Besta, Milano, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Gibertini
authors.affiliation: Neuromuscular Diseases and Neuroimmunology Unit, Foundation IRCCS Neurological Institute C. Besta, Milano, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Curcio
authors.affiliation: Neuromuscular Diseases and Neuroimmunology Unit, Foundation IRCCS Neurological Institute C. Besta, Milano, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Savadori
authors.affiliation: Neuromuscular Diseases and Neuroimmunology Unit, Foundation IRCCS Neurological Institute C. Besta, Milano, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Pasanisi
authors.affiliation: Neuromuscular Diseases and Neuroimmunology Unit, Foundation IRCCS Neurological Institute C. Besta, Milano, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Morandi
authors.affiliation: Neuromuscular Diseases and Neuroimmunology Unit, Foundation IRCCS Neurological Institute C. Besta, Milano, Italy.
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Cornelio
authors.affiliation: Neuromuscular Diseases and Neuroimmunology Unit, Foundation IRCCS Neurological Institute C. Besta, Milano, Italy.
authors.forename: Renato
authors.initials: R
authors.lastname: Mantegazza
authors.affiliation: Neuromuscular Diseases and Neuroimmunology Unit, Foundation IRCCS Neurological Institute C. Besta, Milano, Italy. Electronic address: mmora@istituto-besta.it.
authors.forename: Marina
authors.initials: M
authors.lastname: Mora
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D016022:Case-Control Studies; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D000090602:Collagen Type I, alpha 1 Chain; D024142:Collagen Type VI / Q000235:genetics / Q000378:metabolism; D000071838:Fibrillin-1; D000071837:Fibrillins; D005347:Fibroblasts / Q000378:metabolism; D005355:Fibrosis / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007223:Infant; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018101:Mice, Inbred mdx; D035683:MicroRNAs / Q000235:genetics*; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D032446:Myoblasts / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D050986:YY1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D054392:Adipokines
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D024142:Collagen Type VI; D000071838:Fibrillin-1; D000071837:Fibrillins; D008565:Membrane Proteins; D035683:MicroRNAs; D008840:Microfilament Proteins; D051059:PTEN Phosphohydrolase; D010750:Phosphoproteins; D012333:RNA, Messenger; D050986:YY1 Transcription Factor; C540085:Col6a1 protein, mouse; C000605722:FBN1 protein, human; D054392:Adipokines; C000605724:Fbn1 protein, mouse; C531950:MIRN21 microRNA, mouse; C547014:MIRN29 microRNA, mouse; C425468:Spry1 protein, mouse; C494699:Yy1 protein, mouse
keywords: Duchenne muscular dystrophy; Fibroblast; Fibrosis; MiR-21; MiR-29; Myoblast; mdx mouse