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

Cell Rep. 2015 Sep 8;12(10):1678-90. doi: 10.1016/j.celrep.2015.07.066. Epub 2015 Aug 28.


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 microRNAs 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. TNF-α increases microRNA levels in vitro whereas 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • 3' Untranslated Regions
  • Animals
  • Base Sequence
  • Binding Sites
  • Dogs
  • Dystrophin / genetics*
  • Dystrophin / metabolism
  • Gene Expression
  • Humans
  • Mice, Inbred C57BL
  • MicroRNAs / genetics*
  • MicroRNAs / metabolism
  • Muscle, Skeletal / metabolism
  • Muscle, Skeletal / pathology
  • Muscular Dystrophy, Duchenne / genetics
  • Muscular Dystrophy, Duchenne / immunology
  • Muscular Dystrophy, Duchenne / metabolism*
  • RNA Interference
  • Transcriptional Activation
  • Tumor Necrosis Factor-alpha / physiology*


  • 3' Untranslated Regions
  • Dystrophin
  • MicroRNAs
  • TNF protein, human
  • Tumor Necrosis Factor-alpha