title: TNF-α-Induced microRNAs Control Dystrophin Expression in Becker Muscular Dystrophy.
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.
authors: Center for Genetic Medicine Research, Children's National Medical Center, Washington, DC 20010, USA.
authors: Alyson A
authors: AA
authors: Fiorillo
authors: Center for Genetic Medicine Research, Children's National Medical Center, Washington, DC 20010, USA.
authors: Christopher R
authors: CR
authors: Heier
authors: Center for Genetic Medicine Research, Children's National Medical Center, Washington, DC 20010, USA.
authors: James S
authors: JS
authors: Novak
authors: Center for Genetic Medicine Research, Children's National Medical Center, Washington, DC 20010, USA.
authors: Christopher B
authors: CB
authors: Tully
authors: 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.
authors: Kristy J
authors: KJ
authors: Brown
authors: Center for Genetic Medicine Research, Children's National Medical Center, Washington, DC 20010, USA.
authors: Kitipong
authors: K
authors: Uaesoontrachoon
authors: Center for Genetic Medicine Research, Children's National Medical Center, Washington, DC 20010, USA.
authors: Maria C
authors: MC
authors: Vila
authors: Center for Genetic Medicine Research, Children's National Medical Center, Washington, DC 20010, USA.
authors: Peter P
authors: PP
authors: Ngheim
authors: Center for Genetic Medicine Research, Children's National Medical Center, Washington, DC 20010, USA; Fondazione Ospedale S. Camillo, IRCCS, Lido Venice 30126, Italy.
authors: Luca
authors: L
authors: Bello
authors: Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, TX 77845, USA.
authors: Joe N
authors: JN
authors: Kornegay
authors: Fondazione Ospedale S. Camillo, IRCCS, Lido Venice 30126, Italy.
authors: Corrado
authors: C
authors: Angelini
authors: 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.
authors: Terence A
authors: TA
authors: Partridge
authors: 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.
authors: Kanneboyina
authors: K
authors: Nagaraju
authors: 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.
authors: Eric P
authors: EP
authors: Hoffman
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D004285:Dogs; D016189:Dystrophin / Q000235:genetics* / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D034622:RNA Interference; D015533:Transcriptional Activation; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
chemical_list: D020413:3' Untranslated Regions; D016189:Dystrophin; D035683:MicroRNAs; C439524:TNF protein, human; D014409:Tumor Necrosis Factor-alpha