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

Alyson A. Fiorillo, Christopher R. Heier, James S. Novak, Christopher B. Tully, Kristy J. Brown, Kitipong Uaesoontrachoon, Maria C. Vila, Peter P. Ngheim, Luca Bello, Joe N. Kornegay, Corrado Angelini, Terence A. Partridge, Kanneboyina Nagaraju, Eric P. Hoffman

Research output: Contribution to journalArticle

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. Fiorillo et al. find that miRNAs in muscle promote variable dystrophin levels in muscular dystrophies. Dystrophin-targeting miRNAs reduce dystrophin and increase with disease severity. Innate inflammatory pathways induce miRNAs, whereas NFκB inhibition dampens induction. These events initiate a self-sustaining feedback loop, exacerbating disease progression. Thus, miRNA inhibition in dystrophic muscle could provide therapeutic targets.

Original languageEnglish
Pages (from-to)1678-1690
Number of pages13
JournalCell Reports
Volume12
Issue number10
DOIs
Publication statusPublished - Sep 8 2015

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Dystrophin
Duchenne Muscular Dystrophy
MicroRNAs
Muscle
Muscles
Exons
Muscular Dystrophies
Disease Progression
Inbred mdx Mouse
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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Fiorillo, A. A., Heier, C. R., Novak, J. S., Tully, C. B., Brown, K. J., Uaesoontrachoon, K., ... Hoffman, E. P. (2015). TNF-α-Induced microRNAs Control Dystrophin Expression in Becker Muscular Dystrophy. Cell Reports, 12(10), 1678-1690. https://doi.org/10.1016/j.celrep.2015.07.066

TNF-α-Induced microRNAs Control Dystrophin Expression in Becker Muscular Dystrophy. / Fiorillo, Alyson A.; Heier, Christopher R.; Novak, James S.; Tully, Christopher B.; Brown, Kristy J.; Uaesoontrachoon, Kitipong; Vila, Maria C.; Ngheim, Peter P.; Bello, Luca; Kornegay, Joe N.; Angelini, Corrado; Partridge, Terence A.; Nagaraju, Kanneboyina; Hoffman, Eric P.

In: Cell Reports, Vol. 12, No. 10, 08.09.2015, p. 1678-1690.

Research output: Contribution to journalArticle

Fiorillo, AA, Heier, CR, Novak, JS, Tully, CB, Brown, KJ, Uaesoontrachoon, K, Vila, MC, Ngheim, PP, Bello, L, Kornegay, JN, Angelini, C, Partridge, TA, Nagaraju, K & Hoffman, EP 2015, 'TNF-α-Induced microRNAs Control Dystrophin Expression in Becker Muscular Dystrophy', Cell Reports, vol. 12, no. 10, pp. 1678-1690. https://doi.org/10.1016/j.celrep.2015.07.066
Fiorillo AA, Heier CR, Novak JS, Tully CB, Brown KJ, Uaesoontrachoon K et al. TNF-α-Induced microRNAs Control Dystrophin Expression in Becker Muscular Dystrophy. Cell Reports. 2015 Sep 8;12(10):1678-1690. https://doi.org/10.1016/j.celrep.2015.07.066
Fiorillo, Alyson A. ; Heier, Christopher R. ; Novak, James S. ; Tully, Christopher B. ; Brown, Kristy J. ; Uaesoontrachoon, Kitipong ; Vila, Maria C. ; Ngheim, Peter P. ; Bello, Luca ; Kornegay, Joe N. ; Angelini, Corrado ; Partridge, Terence A. ; Nagaraju, Kanneboyina ; Hoffman, Eric P. / TNF-α-Induced microRNAs Control Dystrophin Expression in Becker Muscular Dystrophy. In: Cell Reports. 2015 ; Vol. 12, No. 10. pp. 1678-1690.
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