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INVESTIGATION OF PATHOMECHANISM AND TREATMENT OF MYOTONIC DYSTROPHY

Research Project

Project/Area Number 16590825
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Neurology
Research InstitutionOSAKA UNIVERSITY

Principal Investigator

TAKAHASHI Masanori  OSAKA UNIVERSITY, GRADUATE SCHOOL OF MEDICINE, ASSISTANT, 医学系研究科, 助手 (20359847)

Co-Investigator(Kenkyū-buntansha) SAKODA Saburo  OSAKA UNIVERSITY, GRADUATE SCHOOL OF MEDICINE, PROFESSOR, 医学系研究科, 教授 (00178625)
小仲 邦  大阪大学, 医学部附属病院, 医員(臨床研究)
Project Period (FY) 2004 – 2005
Project Status Completed (Fiscal Year 2005)
Budget Amount *help
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2005: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 2004: ¥2,500,000 (Direct Cost: ¥2,500,000)
KeywordsNEUROMUSCULAR DISORDER / RYANODINE RECEPTOR / mRNA / SPLICING / NA CHANNEL / ANTIARRHYTHMIC / CALCIUM / SKELETAL MUSCLE / 筋強直性ジストロフィー
Research Abstract

RNA gain of function model has recently been implicated for the pathomechanism of myotonic dystrophy (DM). The RNA with abnormally expanded repeats is suggested to cause altered splicing of several mRNAs, which might relate to clinical features of DM. Viewing the pattern of missplicing reported so far, we hypothesized that the alternative splicing of mRNAs, which are regulated during normal muscle differentiation, might be affected in DM, and we have examined splicing of several candidate mRNAs. In addition to ryanodine receptor, misregulated splicing of sarcoplasmic/endoplasmic reticulum Ca^<2+> -ATPase (Ca^<2+>-pump) has been newly identified in muscles from DM patients and model mice. Since both proteins play major role in regulation of intracellular Ca^<2+> in skeletal muscle, the missplicing might cause impaired Ca^<2+> in DM muscle. Functional studies of the aberrantly spliced ryanodine receptor isoform have consistently showed reduction in channel activity.
In parallel, the effect of a class Ic antiarrhythmic (flecainide) to heterologously expressed Na channels has been investigated in order to develop a new remedy against myotonia. When stimulated comparable to myotonic discharges, flecainide significantly reduced Na current at therapeutic concentration. The data provide basis of simulating the drug effect for myotonia and suggest possible clinical efficacy of flecainide against myotonia.

Report

(3 results)
  • 2005 Annual Research Report   Final Research Report Summary
  • 2004 Annual Research Report
  • Research Products

    (5 results)

All 2005 2004

All Journal Article (4 results) Book (1 results)

  • [Journal Article] Altered mRNA splicing of the skeletal muscle ryanodine receptor and sarcoplasmic/endoplasmic reticulum Ca^<2+>-ATPase in myotonic dystrophy type 1.2005

    • Author(s)
      Kimura T, Nakamori M, Lueck JD, Pouliquin P, Aoike F, Fujimura H, Dirksen RT, Takahashi MP, Dulhunty AF, Sakoda S.
    • Journal Title

      Human Molecular Genetics 14.15

      Pages: 2189-2200

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Class Ic antiarrhythmics block human skeletal muscle Na channel during myotonia-like stimulation.2005

    • Author(s)
      Aoike F, Takahashi MP, Sakoda S
    • Journal Title

      European Journal of Pharmacology 532.1-2

      Pages: 24-31

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Altered mRNA splicing of the skeletal muscle ryanodine receptor and sarcoplasmic/endoplasmic reticulum Ca^<2+>-ATPase in myotonic dystrophy type 1.2005

    • Author(s)
      Kimura T, Nakamori M, Lueck JD, Pouliquin P, Aoike F, Fujimura H, Dirksen RT, Takahashi MP, Dulhunty AF, Sakoda S
    • Journal Title

      Human Molecular Genetics 14・15

      Pages: 2189-2200

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Annual Research Report 2005 Final Research Report Summary
  • [Journal Article] Class Ic antiarrhythmics block human skeletal muscle Na channel during myotonia-like stimulation.2005

    • Author(s)
      Aoike F, Takahashi MP, Sakoda S
    • Journal Title

      European Journal of Pharmacology 532・1-2

      Pages: 24-31

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Annual Research Report 2005 Final Research Report Summary
  • [Book] 神経内科の最新医療 第8章3項 筋強直性ジストロフィーの病態と治療(金澤一郎ほか 編集主幹)2004

    • Author(s)
      高橋正紀, 松村剛
    • Publisher
      先端医療技術研究所
    • Related Report
      2004 Annual Research Report

URL: 

Published: 2004-04-01   Modified: 2016-04-21  

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