Abnormal splicing switch of DMD's penultimate exon compromises muscle fibre maintenance in myotonic dystrophy

Nat Commun. 2015 May 28;6:7205. doi: 10.1038/ncomms8205.

Abstract

Myotonic Dystrophy type 1 (DM1) is a dominant neuromuscular disease caused by nuclear-retained RNAs containing expanded CUG repeats. These toxic RNAs alter the activities of RNA splicing factors resulting in alternative splicing misregulation and muscular dysfunction. Here we show that the abnormal splicing of DMD exon 78 found in dystrophic muscles of DM1 patients is due to the functional loss of MBNL1 and leads to the re-expression of an embryonic dystrophin in place of the adult isoform. Forced expression of embryonic dystrophin in zebrafish using an exon-skipping approach severely impairs the mobility and muscle architecture. Moreover, reproducing Dmd exon 78 missplicing switch in mice induces muscle fibre remodelling and ultrastructural abnormalities including ringed fibres, sarcoplasmic masses or Z-band disorganization, which are characteristic features of dystrophic DM1 skeletal muscles. Thus, we propose that splicing misregulation of DMD exon 78 compromises muscle fibre maintenance and contributes to the progressive dystrophic process in DM1.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Video-Audio Media

MeSH terms

  • Animals
  • Chromatography, Liquid
  • Dystrophin / genetics*
  • Dystrophin / metabolism
  • Exons
  • Gene Expression Regulation, Developmental*
  • Homeostasis
  • Humans
  • Immunohistochemistry
  • Immunoprecipitation
  • Membrane Proteins / genetics*
  • Membrane Proteins / metabolism
  • Mice
  • Microscopy, Electron
  • Muscle Fibers, Skeletal / metabolism*
  • Muscle Fibers, Skeletal / ultrastructure
  • Muscle Proteins / genetics*
  • Muscle Proteins / metabolism
  • Myotonic Dystrophy / genetics*
  • Myotonic Dystrophy / pathology
  • RNA Splicing / genetics*
  • RNA-Binding Proteins / genetics*
  • Real-Time Polymerase Chain Reaction
  • Sarcoplasmic Reticulum / ultrastructure
  • Tandem Mass Spectrometry
  • Zebrafish Proteins / genetics*
  • Zebrafish Proteins / metabolism

Substances

  • DMD protein, human
  • Dystrophin
  • MBNL1 protein, human
  • Membrane Proteins
  • Muscle Proteins
  • RNA-Binding Proteins
  • Zebrafish Proteins
  • apo-dystrophin 1
  • dmd protein, zebrafish