miR-23b and miR-218 silencing increase Muscleblind-like expression and alleviate myotonic dystrophy phenotypes in mammalian models

Nat Commun. 2018 Jun 26;9(1):2482. doi: 10.1038/s41467-018-04892-4.

Abstract

Functional depletion of the alternative splicing factors Muscleblind-like (MBNL 1 and 2) is at the basis of the neuromuscular disease myotonic dystrophy type 1 (DM1). We previously showed the efficacy of miRNA downregulation in Drosophila DM1 model. Here, we screen for miRNAs that regulate MBNL1 and MBNL2 in HeLa cells. We thus identify miR-23b and miR-218, and confirm that they downregulate MBNL proteins in this cell line. Antagonists of miR-23b and miR-218 miRNAs enhance MBNL protein levels and rescue pathogenic missplicing events in DM1 myoblasts. Systemic delivery of these "antagomiRs" similarly boost MBNL expression and improve DM1-like phenotypes, including splicing alterations, histopathology, and myotonia in the HSALR DM1 model mice. These mammalian data provide evidence for therapeutic blocking of the miRNAs that control Muscleblind-like protein expression in myotonic dystrophy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions
  • Alternative Splicing
  • Animals
  • Cell Line
  • Disease Models, Animal
  • Gene Silencing
  • HeLa Cells
  • Humans
  • Male
  • Mice
  • Mice, Transgenic
  • MicroRNAs / genetics*
  • Muscle, Skeletal / metabolism
  • Muscle, Skeletal / pathology
  • Myoblasts, Skeletal / metabolism
  • Myoblasts, Skeletal / pathology
  • Myotonic Dystrophy / genetics*
  • Myotonic Dystrophy / physiopathology
  • Myotonic Dystrophy / therapy*
  • Phenotype
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • RNA-Binding Proteins / antagonists & inhibitors*
  • RNA-Binding Proteins / genetics*
  • Up-Regulation

Substances

  • 3' Untranslated Regions
  • MBNL1 protein, human
  • MBNL2 protein, human
  • MIRN218 microRNA, human
  • MIRN23a microRNA, human
  • MicroRNAs
  • RNA, Messenger
  • RNA-Binding Proteins