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.

Circulating miRNAs are generic and versatile therapeutic monitoring biomarkers in muscular dystrophies

“…In addition to the dystromiRs, we quantified the muscle expression of three other miRNAs, miR-21, miR-31 and miR-142-3p, known to participate in three processes hallmark of MD. Indeed, the expression of miR-31 and miR-21 were shown to be upregulated in dystrophic muscle, in correlation with the formation of regenerating myoblasts for miR-3135 and the cellular fibrotic process for miR-213442. The miR-142-3P is highly expressing in monocytes43 and lymphocytes44, suggesting its enriched expression in muscle-invading inflammatory cells in MD (for a recent review see45).…”

Human microRNA expression in sporadic and FAP-associated desmoid tumors and correlation with beta-catenin mutations

“…The miR-21-3p is a positive regulator for L1CAM and COL1A1 [21, 22] and a negative regulator for MAT2A [23], while SERPINA3 and TSPAN3 are inversely correlated to miR-197-3p expression [24]. …”

Identification of miRNAs Potentially Involved in Bronchiolitis Obliterans Syndrome: A Computational Study

“…In addition, miR-21 upregulation has been demonstrated in fibroblast foci as well as in the serum of patients with idiopathic pulmonary fibrosis, with a significant correlation between serum levels and the degree of lung function impairment [56]. Besides its involvement in fibro-proliferative processes in several organs [54][56][57][58][59][60][61], miR-21 has been shown to play an important role in several other physiological and pathological processes [62]. Its up-regulation has been observed in solid tumors (breast, colon, lung, pancreas, prostate and stomach, ovarian, cervical, head and neck carcinomas), in leukemias and in a variety of other human proliferative disorders, implying a function in regulating cell growth [62].…”