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

• DOI: 10.1016/j.celrep.2015.07.066
• Publication Date: 2015-08-28T21:49:50Z
• Authors: Alyson A. Fiorillo; Christopher R. Heier; James S. Novak; Christopher B. Tully; Kristy J. Brown; Kitipong Uaesoont...; Maria C. Vila; Peter P. Ngheim; Luca Bello; Joe N. Kornegay; Corrado Angelini; Terence A. Partridge; Kanneboyina Nagaraju; Eric P. Hoffman
• Keywords: Transcriptional Activation; 0303 health sciences; Binding Sites; Base Sequence; QH301-705.5; Tumor Necrosis Factor-alpha; 3' Untranslated Regions; Animals; Base Sequence; Binding Sites; Dogs; Dystrophin; Gene Expression; Humans; Mice, Inbred C57BL; MicroRNAs; Muscle, Skeletal; Muscular Dystrophy, Duchenne; RNA Interference; Transcriptional Activation; Tumor Necrosis Factor-alpha; Biochemistry, Genetics and Molecular Biology (all); Gene Expression; Dystrophin; Mice, Inbred C57BL; Muscular Dystrophy, Duchenne; MicroRNAs; 03 medical and health sciences; Dogs; Animals; Humans; RNA Interference; Biology (General); Muscle, Skeletal; 3' Untranslated Regions

The amount and distribution of dystrophin protein in myofibers muscle is highly variable Becker muscular dystrophy exon-skipping trials for Duchenne dystrophy. Here, we investigate a molecular basis this variability. In from patients sharing the same exon 45–47 in-frame deletion, levels negatively correlate with microRNAs predicted to target dystrophin. Seven inhibit expression vitro, three are validated vivo (miR-146b/miR-374a/miR-31). expressed dystrophic increase age disease severity. exon-skipping-treated mdx mice, significantly higher muscles low rescue. TNF-α increases microRNA vitro whereas NFκB inhibition blocks vivo. Collectively, these data show that contribute Our findings suggest model where chronic inflammation distinct microenvironments induces pathological microRNAs, initiating self-sustaining feedback loop exacerbates progression.