Document Type
Journal Article
Publication Date
9-8-2015
Journal
Cell Reports
Volume
12
Issue
10
Inclusive Pages
1678-1690
DOI
10.1016/j.celrep.2015.07.066
Keywords
Dystrophin--genetics; MicroRNAs--genetics; Muscular Dystrophy, Duchenne--metabolism; Tumor Necrosis Factor-alpha--physiology
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.
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.
APA Citation
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, doi:10.1016/j.celrep.2015.07.066
Peer Reviewed
1
Open Access
1
Included in
Amino Acids, Peptides, and Proteins Commons, Genetics and Genomics Commons, Systems Biology Commons
Comments
Reproduced with permission of Elsevier B.V. Cell Reports.