title: Overexpression of CUG triplet repeat-binding protein, CUGBP1, in mice inhibits myogenesis.
abstract: Accumulation of RNA CUG repeats in myotonic dystrophy type 1 (DM1) patients leads to the induction of a CUG-binding protein, CUGBP1, which increases translation of several proteins that are required for myogenesis. In this paper, we examine the role of overexpression of CUGBP1 in DM1 muscle pathology using transgenic mice that overexpress CUGBP1 in skeletal muscle. Our data demonstrate that the elevation of CUGBP1 in skeletal muscle causes overexpression of MEF2A and p21 to levels that are significantly higher than those in skeletal muscle of wild type animals. A similar induction of these proteins is observed in skeletal muscle of DM1 patients with increased levels of CUGBP1. Immunohistological analysis showed that the skeletal muscle from mice overexpressing CUGBP1 is characterized by a developmental delay, muscular dystrophy, and myofiber-type switch: increase of slow/oxidative fibers and the reduction of fast fibers. Examination of molecular mechanisms by which CUGBP1 up-regulates MEF2A shows that CUGBP1 increases translation of MEF2A via direct interaction with GCN repeats located within MEF2A mRNA. Our data suggest that CUGBP1-mediated overexpression of MEF2A and p21 inhibits myogenesis and contributes to the development of muscle deficiency in DM1 patients.
authors.affiliation: Department of Pathology and Huffington Center on Aging, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
authors.forename: Nikolai A
authors.initials: NA
authors.lastname: Timchenko
authors.forename: Roma
authors.initials: R
authors.lastname: Patel
authors.forename: Polina
authors.initials: P
authors.lastname: Iakova
authors.forename: Zong-Jin
authors.initials: ZJ
authors.lastname: Cai
authors.forename: Ling
authors.initials: L
authors.lastname: Quan
authors.forename: Lubov T
authors.initials: LT
authors.lastname: Timchenko
mesh_terms: D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D001835:Body Weight; D000067879:CELF1 Protein; D002474:Cell-Free System / Q000378:metabolism; D002478:Cells, Cultured; D003432:Cross-Linking Reagents / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000737:chemistry; D005347:Fibroblasts / Q000378:metabolism; D005838:Genotype; D006801:Humans; D007150:Immunohistochemistry; D026161:MADS Domain Proteins; D064326:MEF2 Transcription Factors; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D018482:Muscle, Skeletal / Q000378:metabolism; D009132:Muscles / Q000166:cytology / Q000378:metabolism*; D018006:Myogenic Regulatory Factors; D009223:Myotonic Dystrophy / Q000378:metabolism; D010957:Plasmids / Q000378:metabolism; D011485:Protein Binding; D014176:Protein Biosynthesis; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D012313:RNA / Q000737:chemistry; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000096:biosynthesis* / Q000737:chemistry; D014157:Transcription Factors / Q000737:chemistry; D019076:Transgenes; D014466:Ultraviolet Rays; D015854:Up-Regulation
chemical_list: D000067879:CELF1 Protein; C102843:CELF1 protein, human; D003432:Cross-Linking Reagents; D004268:DNA-Binding Proteins; D026161:MADS Domain Proteins; D064326:MEF2 Transcription Factors; C578035:MEF2A protein, human; C578036:Mef2a protein, mouse; D018006:Myogenic Regulatory Factors; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D014157:Transcription Factors; D012313:RNA; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)