title: Resveratrol enhances splicing of insulin receptor exon 11 in myotonic dystrophy type 1 fibroblasts.
abstract: BACKGROUND
  Myotonic dystrophy type 1 (DM1) is characterized by splicing abnormalities caused by CUG expansion of the DMPK gene transcript. Splicing of exon 11 of the insulin receptor (IR) gene is deregulated to suppress exon 11 inclusion into mRNA in DM1. Consequently, the exon 11-deleted IR isoform that is less sensitive to insulin is predominantly produced, leading to glucose intolerance in DM1. Upregulation of exon 11 retaining full-length IR mRNA is a potential way to recover insulin sensitivity in DM1.
  
  
  METHODS
  We examined candidate chemicals for their ability to enhance inclusion of exon 11 of the IR gene in cultured cells by reverse transcription-PCR amplification of a fragment extending from exons 10 to 12 of IR mRNA.
  
  
  RESULTS
  We revealed that resveratrol (RES) enhanced the percentage of exon 11-containing IR mRNA among the total IR mRNA in HeLa cells. The RES-mediated enhancement of exon 11 inclusion was cell-specific and highest in fibroblasts. We tested RES on four fibroblast samples from three generations of one DM1 family. In each sample, RES treatment significantly upregulated the percentage of exon 11-containing IR mRNA to levels higher than that of the control, irrespective of the length of the sample's CTG repeat expansion.
  
  
  CONCLUSIONS
  A natural compound, RES, was shown for the first time to upregulate the full-length IR mRNA in fibroblasts from DM1 cases. Our results provide the justification of RES as a leading compound to improve glucose tolerance in DM1.
authors.affiliation: Department of Medical Rehabilitation, Faculty of Rehabilitation, Kobegakuin University, Nishi, Kobe 6512180, Japan; Kobe Pharmaceutical University, Higashinada, Kobe 6588558, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Takarada
authors.affiliation: Department of Medical Rehabilitation, Faculty of Rehabilitation, Kobegakuin University, Nishi, Kobe 6512180, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Nishida
authors.affiliation: Kobe Pharmaceutical University, Higashinada, Kobe 6588558, Japan.
authors.forename: Atsuko
authors.initials: A
authors.lastname: Takeuchi
authors.affiliation: Department of Pediatrics, Hyogo College of Medicine, Nishinomiya 6638131, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Lee
authors.affiliation: Department of Pediatrics, Hyogo College of Medicine, Nishinomiya 6638131, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Takeshima
authors.affiliation: Department of Medical Rehabilitation, Faculty of Rehabilitation, Kobegakuin University, Nishi, Kobe 6512180, Japan. Electronic address: mmatsuo@reha.kobegakuin.ac.jp.
authors.forename: Masafumi
authors.initials: M
authors.lastname: Matsuo
mesh_terms: D005091:Exons / Q000187:drug effects*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D009223:Myotonic Dystrophy / Q000235:genetics*; D019154:Protein Splicing / Q000187:drug effects* / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D011972:Receptor, Insulin / Q000235:genetics*; D000077185:Resveratrol; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013267:Stilbenes / Q000494:pharmacology*; D015854:Up-Regulation
chemical_list: D012333:RNA, Messenger; D013267:Stilbenes; D011972:Receptor, Insulin; D000077185:Resveratrol
keywords: Insulin receptor; Myotonic dystrophy 1; Resveratrol; Splicing