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

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

Author information

1
Center for Genetic Medicine Research, Children's National Medical Center, Washington, DC 20010, USA.
2
Center for Genetic Medicine Research, Children's National Medical Center, Washington, DC 20010, USA; Department of Integrative Systems Biology, George Washington University School of Medicine and Health Sciences, Washington, DC 20010, USA.
3
Center for Genetic Medicine Research, Children's National Medical Center, Washington, DC 20010, USA; Fondazione Ospedale S. Camillo, IRCCS, Lido Venice 30126, Italy.
4
Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, TX 77845, USA.
5
Fondazione Ospedale S. Camillo, IRCCS, Lido Venice 30126, Italy.
6
Center for Genetic Medicine Research, Children's National Medical Center, Washington, DC 20010, USA; Department of Integrative Systems Biology, George Washington University School of Medicine and Health Sciences, Washington, DC 20010, USA. Electronic address: ehoffman@childrensnational.org.

Abstract

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.

PMID:
26321630
PMCID:
PMC4757433
DOI:
10.1016/j.celrep.2015.07.066
[Indexed for MEDLINE]
Free PMC Article
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