Noncoding RNAs in Duchenne and Becker muscular dystrophies: role in pathogenesis and future prognostic and therapeutic perspectives

Abstract

Noncoding RNAs (ncRNAs), such as miRNAs and long noncoding RNAs, are key regulators of gene expression at the post-transcriptional level and represent promising therapeutic targets and biomarkers for several human diseases, including Duchenne and Becker muscular dystrophies (DMD/BMD). A role for ncRNAs in the pathogenesis of muscular dystrophies has been suggested, even if it is still incompletely understood. Here, we discuss current progress leading towards the clinical utility of ncRNAs for DMD/BMD. Long and short noncoding RNAs are differentially expressed in DMD/BMD and have a mechanism of action via targeting mRNAs. A subset of muscle-enriched miRNAs, the so-called myomiRs (miR-1, miR-133, and miR-206), are increased in the serum of patients with DMD and in dystrophin-defective animal models. Interestingly, myomiRs might be used as biomarkers, given that their levels can be corrected after dystrophin restoration in dystrophic mice. Remarkably, further evidence demonstrates that ncRNAs also play a role in dystrophin expression; thus, their modulations might represent a potential therapeutic strategy with the aim of upregulating the dystrophin protein in combination with other oligonucleotides/gene therapy approaches.

Anti-Inflammatory and General Glucocorticoid Physiology in Skeletal Muscles Affected by Duchenne Muscular Dystrophy: Exploration of Steroid-Sparing Agents

“…miRNA-142-3p is increased in inflammatory cells and is suspected to be increased in invading inflammatory cells in DMD muscles. It interacts with glycoprotein 130 (gp130), a component of interleukin-6 receptor [ 15 , 19 , 20 , 21 , 22 , 23 , 24 ]. The muscle-enriched miRNA-206, which belongs to the so-called myomiRNAs, is increased in the serum and muscle of DMD patients [ 23 ].…”

“…It interacts with glycoprotein 130 (gp130), a component of interleukin-6 receptor [ 15 , 19 , 20 , 21 , 22 , 23 , 24 ]. The muscle-enriched miRNA-206, which belongs to the so-called myomiRNAs, is increased in the serum and muscle of DMD patients [ 23 ]. It activates components involved in skeletal muscle growth and differentiation such as histone deacetylase 4 (HDAC4), polypirimidine tract-binding protein (PTB), utrophin, follistatin-like 1 (Fstl1), connexin 43 (Cx43), and the tissue inhibitor of metalloproteinases 3 (TIMP3).…”

Progressive Skeletal Muscle Atrophy in Muscular Dystrophies: A Role for Toll-Like Receptor-Signaling in Disease Pathogenesis

“…Multiple mediators that regulate further immune cell recruitment are released; however, the tissue does not succeed to fully regenerate. In muscular dystrophy, dysregulated expression of regulatory non-coding RNAs is involved in the failing muscle regeneration [ 17 , 18 ] and represents relevant biomarkers for the evaluation of disease progression and therapeutic effects. Certain miRs have repeatedly been reported elevated in muscular dystrophy patients, hence are termed dystromiRs.…”

Multi-Omics Identifies Circulating miRNA and Protein Biomarkers for Facioscapulohumeral Dystrophy

“…In addition to myomiRs, inflammatory miRNAs such as miR-146a, miR-146b, miR-221 and miR-155 have been found to be dysregulated in multiple forms of muscular dystrophies [29][30][31]. These two classes of miRNA show potential as pharmacodynamic biomarkers, with myomiRs proposed for muscle-stabilizing treatments such as gene therapy [32,33], and inflammatory microRNAs proposed for current steroids [34,35] as well as newly emerging dissociative anti-inflammatory drugs such as vamorolone [36][37][38] or edasalonexent [39,40]. In parallel to development of miRNA monitoring biomarkers, new advances in whole exome sequencing are enabling clinicians to diagnose novel mutations in over 60 genes known to be responsible for muscular dystrophies such as FSHD and limb-girdle muscular dystrophy (LGMD) [41][42][43][44].…”