miR‐31 modulates dystrophin expression: new implications for Duchenne muscular dystrophy therapy

Abstract

Duchenne muscular dystrophy (DMD)-which is caused by mutations in the dystrophin gene-is one of the most severe myopathies. Among therapeutic strategies, exon skipping allows the rescue of dystrophin synthesis through the production of a shorter but functional messenger RNA. Here, we report the identification of a microRNA-miR-31-that represses dystrophin expression by targeting its 3 0 untranslated region. In human DMD myoblasts treated with exon skipping, we demonstrate that miR-31 inhibition increases dystrophin rescue. These results indicate that interfering with miR-31 activity can provide an ameliorating strategy for those DMD therapies that are aimed at efficiently recovering dystrophin synthesis.

Novel Long Noncoding RNAs (lncRNAs) in Myogenesis: a miR-31 Overlapping lncRNA Transcript Controls Myoblast Differentiation

“…C 2 C 12 cells were cultured as previously described (7). For differentiation, cells maintained under confluent conditions were switched to a low serum concentration (0.5% fetal bovine serum [FBS]).…”

“…Among lncRNAs expressed in proliferating myoblasts, an interesting candidate was lnc-31, since it harbors precursor sequences for miR-31, a relevant miRNA known to play a crucial role in muscle regeneration (7,17) and to be associated to many processes linked to cell proliferation (16). Moreover, aberrant high levels of miR-31, found in both human and murine dystrophic myoblasts, contribute to the pathology by compromising the normal progression of satellite cell activation to enter the differentiation program.…”

“…Among the selected lncRNAs, we found a few species overlapping with miRNA genomic loci: pre-miR125b-1 was found in the lnc-254 unique intron, pre-let7c2 and pre-let7b were found in the last exon of lnc-023, and pre-miR-31 was found in the third exon of lnc-31. Since miR-31 was previously shown to play an important role in muscle regeneration and to be deregulated in myopathies (7,17,41), lnc-31 was selected for further studies. Moreover, a transcript overlapping miR-31 also originates from the syntenic human HG31 genomic region at chromosome 9p21.3 (42); however, in contrast with mouse (43), whereas miR-31 maps inside the third exon of lnc-31 (Fig.…”

“…Advancement in the field was stimulated by the identification of regulatory small noncoding RNAs (sncRNAs) and long noncoding RNAs (lncRNAs) as critical orchestrators of muscle specification (5,6). Among sncRNAs, the characterization of miR-1/miR-206 and miR-133 microRNA (miRNA) families in both muscle physiology and diseases was of primary interest (7)(8)(9)(10). Besides characterizing miRNAs, a number of studies also focused on the participation of lncRNAs in muscular circuitries (11)(12)(13).…”

Non-coding RNAs in muscle differentiation and musculoskeletal disease

“…While SMYD1 was upregulated, likely as a consequence of MYOD activation mediated by miR-206 (39), G6PD was downregulated and has been shown to be a direct target of miR-206 (38). miR-31 provides an interesting link between miRNAs and skeletal muscle pathologies because it is strongly enriched in dystrophic muscles and associated with delay of the muscle differentiation program (40,41). Notably, miR-31 plays a dual role in dystrophic muscles.…”