TNF-α-Induced microRNAs Control Dystrophin Expression in Becker Muscular Dystrophy

Abstract

Summary The amount and distribution of dystrophin protein in myofibers and muscle is highly variable in Becker muscular dystrophy and in exon-skipping trials for Duchenne muscular dystrophy. Here, we investigate a molecular basis for this variability. In muscle from Becker patients sharing the same exon 45–47 in-frame deletion, dystrophin levels negatively correlate with microRNAs predicted to target dystrophin. Seven miRNAs inhibit dystrophin expression in vitro, and three are validated in vivo (miR-146b/miR-374a/miR-31). microRNAs are expressed in dystrophic myofibers and increase with age and disease severity. In exon-skipping treated mdx mice, microRNAs are significantly higher in muscles with low dystrophin rescue. TNFα increases microRNA levels in vitro while NFκB inhibition blocks this in vitro and in vivo. Collectively, these data show that microRNAs contribute to variable dystrophin levels in muscular dystrophy. Our findings suggest a model where chronic inflammation in distinct microenvironments induces pathological microRNAs, initiating a self-sustaining feedback loop that exacerbates disease progression.

Lack of muscle mTOR kinase activity causes early onset myopathy and compromises whole‐body homeostasis

“…Fiorillo et al . recently published pathological contexts in which muscle atrophy and regeneration are associated with inflammatory pathways inducing down‐regulation of dystrophin via dystrophin‐targeting miRNA . Such mechanisms may therefore mask dystrophin activation by the mTORki mutant protein.…”

Derepressing muscleblind expression by miRNA sponges ameliorates myotonic dystrophy-like phenotypes in Drosophila

“…In this study we aimed to upregulate endogenous muscleblind expression by silencing defined miRNAs, which regulate it in muscle. miRNAs have been extensively associated with several neuromuscular disorders in valuable in-vivo systems, which highlights the importance of studying miRNA-based regulation of dystrophy-associated genes as potential therapeutic strategy4849505152. Specifically, we used miRNA sponge constructs, which are transgenes, containing multiple, tandem binding sites of a microRNA of interest, expressed from strong promoters.…”

Non-coding RNAs in muscle differentiation and musculoskeletal disease

“…More recently, other miRNAs (miR-146b, -223, and -374a) were found to target dystrophin mRNA and to increase in dystrophic myofibers, paralleling disease severity (45). Interestingly, miR-146b and miR-223 are activated during inflammation processes in dystrophic muscles through TNF-α-induced NF-κB signaling.…”

“…Even though the roles of miR-1 and miR-206 in RMS are still not well defined, several studies suggest that they play an important role in the pathogenesis of this cancer. For instance, the RTK oncogene MET is targeted by microvesicles (45). These miRNAs are also increased in a wide variety of muscle disorders, such as myositis, Miyoshi myopathy, and limb-girdle muscular dystrophy (16,17,46), suggesting that inflammatory miRNAs can be a common signature of muscle diseases where chronic inflammation is present.…”

“…These miRNAs are also increased in a wide variety of muscle disorders, such as myositis, Miyoshi myopathy, and limb-girdle muscular dystrophy (16,17,46), suggesting that inflammatory miRNAs can be a common signature of muscle diseases where chronic inflammation is present. Targeting of such miRNAs could be effectively combined with other therapeutic strategies, such as the exon skipping approach in DMD (45).…”