Common micro‐RNA signature in skeletal muscle damage and regeneration induced by Duchenne muscular dystrophy and acute ischemia

Abstract

The aim of this work was to identify micro-RNAs (miRNAs) involved in the pathological pathways activated in skeletal muscle damage and regeneration by both dystrophin absence and acute ischemia. Eleven miRNAs were deregulated both in MDX mice and in Duchenne muscular dystrophy patients (DMD signature). Therapeutic interventions ameliorating the mdx-phenotype rescued DMD-signature alterations. The significance of DMD-signature changes was characterized using a damage/regeneration mouse model of hind-limb ischemia and newborn mice. According to their expression, DMD-signature miRNAs were divided into 3 classes. 1) Regeneration miRNAs, miR-31, miR-34c, miR-206, miR-335, miR-449, and miR-494, which were induced in MDX mice and in DMD patients, but also in newborn mice and in newly formed myofibers during postischemic regeneration. Notably, miR-206, miR-34c, and miR-335 were up-regulated following myoblast differentiation in vitro. 2) Degenerative-miRNAs, miR-1, miR-29c, and miR-135a, that were down-modulated in MDX mice, in DMD patients, in the degenerative phase of the ischemia response, and in newborn mice. Their down-modulation was linked to myofiber loss and fibrosis. 3) Inflammatory miRNAs, miR-222 and miR-223, which were expressed in damaged muscle areas, and their expression correlated with the presence of infiltrating inflammatory cells. These findings show an important role of miRNAs in physiopathological pathways regulating muscle response to damage and regeneration.

Non-coding RNAs in muscle differentiation and musculoskeletal disease

“…miRNA profiles of different skeletal muscle disorders (16)(17)(18)(19)(20)(21) revealed that, despite their heterogeneity, these disorders share a common set of deregulated miRNAs, which generally includes myomiRs.…”

Histone Deacetylase Inhibitors in the Treatment of Muscular Dystrophies: Epigenetic Drugs for Genetic Diseases

“…miRNAs are emerging as important regulators of muscle development, homeo-stasis and regeneration, and several studies reported on altered levels of miRNAs in muscular dystrophies and other muscular disorders (56,57). A number of muscle-specific and nonspecific miRNAs are induced during myogenesis, and many genes controlling myoblast proliferation and differentiation are the targets of miRNAs (58).…”

Regulation of IRS1/Akt insulin signaling by microRNA-128a during myogenesis

“…MiRNAs are from 17 to 24 nucleotides in length and are known to interact with 39-untranslated regions (39 UTRs) of target mRNAs, resulting in the repression of mRNA translation and/or stability (Bartel, 2004). Since miRNAs can repress multiple target mRNAs, miRNA expression patterns and their predicted target mRNAs might represent a novel regulatory network (Eisenberg et al, 2007;Greco et al, 2009;Williams et al, 2009). MiRNAs are involved in the process of regeneration and hypertrophy/atrophy in skeletal muscle.…”