Pathogenesis of Myopathy in Models of Myotonic Dystrophy

Summary

Principal Investigator: Charles A Thornton
Abstract: DESCRIPTION (provided by applicant): Myotonic dystrophy type 1 [DM1] leads to maldevelopment, myotonia, and wasting of skeletal muscle. DM1 is caused by an unstable CTG repeat expansion in the 3'untranslated region of DMPK. Our central hypothesis is that skeletal muscle findings in DM1 result from a toxic effect of repeat expansion transcripts. Support for this hypothesis comes from studies of HSALR transgenic mice that express CUG expansion RNA in muscle. (CUG)n transcripts accumulate in nuclear foci, leading to a myotonic myopathy that is similar to DM1. Our working model postulates the following sequence of events: expression of CUG expansion RNA ->accumulation of (CUG)n RNA in nuclear foci ->sequestration of muscleblind [Mbnl] proteins in nuclear foci ->abnormal regulation of alternative splicing ->expression of inappropriate splice isoforms ->symptoms of DM. We now have evidence that this model can explain certain aspects of DM1, such as, chloride channelopathy and myotonia. We plan to extend this model and define its limits. First, we will compare patterns of alternative splicing in HSALR, Mbnll knockout, and wild-type mice and test the hypothesis that CUG expansion RNA compromises a specific developmental program of alternative splicing that depends on Mbnl1, the predominant Mbnl protein expressed in muscle. A striking example of aberrant splicing involves Serca1, the calcium re-uptake pump in sarcoplasmic reticulum. The physiologic significance of mis-splicing Serca1 will be determined by calcium imaging. Second, there is little information about metabolism of (CUG)n transcripts. We have derived transgenic mice for inducible expression of CUG expansion transcripts. These mice will be used to compare the accumulation and degradation of transcripts with or without an expanded CUG repeat. We also will test the hypothesis that overexpression of nuclear mRNA-degradases can accelerate clearance of poly-CUG RNA. Third, we will assess myonuclear morphology and bromodeoxyuridine incorporation in HSA(LR) mice to test the hypothesis that accumulation of CUG expansion RNA leads to nuclear demise. In related experiments we will investigate the mechanism of cell death that occurs in HSA(LR) myoblasts when growth factors are withdrawn. Fourth, we have derived transgenic mice with cre-activation alleles to develop models for DM1-related maldevelopment and wasting and test the hypothesis that CUG expansion RNA interferes with muscle differentiation.
Funding Period: 2009-09-18 - 2010-09-17
more information: NIH RePORT

Top Publications

  1. pmc Mexiletine is an effective antimyotonia treatment in myotonic dystrophy type 1
    E L Logigian
    Department of Neurology, University of Rochester, Rochester, NY, USA
    Neurology 74:1441-8. 2010
  2. pmc Epigenetic changes and non-coding expanded repeats
    Masayuki Nakamori
    Department of Neurology, University of Rochester Medical Center, Rochester, New York 14642, USA
    Neurobiol Dis 39:21-7. 2010
  3. pmc Scaled-down genetic analysis of myotonic dystrophy type 1 and type 2
    Masayuki Nakamori
    Department of Neurology, Box 673, University of Rochester Medical Center, Rochester, NY 14642, USA
    Neuromuscul Disord 19:759-62. 2009
  4. pmc Aberrant alternative splicing and extracellular matrix gene expression in mouse models of myotonic dystrophy
    Hongqing Du
    RNA Center, Department of Molecular, Cell and Developmental Biology, Sinsheimer Labs, University of California, Santa Cruz, California, USA
    Nat Struct Mol Biol 17:187-93. 2010
  5. pmc Pentamidine reverses the splicing defects associated with myotonic dystrophy
    M Bryan Warf
    Department of Chemistry and Institute of Molecular Biology, University of Oregon, Eugene, OR 97403, USA
    Proc Natl Acad Sci U S A 106:18551-6. 2009
  6. pmc Triplet-repeat oligonucleotide-mediated reversal of RNA toxicity in myotonic dystrophy
    Susan A M Mulders
    Department of Cell Biology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
    Proc Natl Acad Sci U S A 106:13915-20. 2009
  7. pmc Reversal of RNA dominance by displacement of protein sequestered on triplet repeat RNA
    Thurman M Wheeler
    Departments of Neurology, Pharmacology and Physiology, University of Rochester, Rochester, NY 14642, USA
    Science 325:336-9. 2009
  8. pmc Rational design of ligands targeting triplet repeating transcripts that cause RNA dominant disease: application to myotonic muscular dystrophy type 1 and spinocerebellar ataxia type 3
    Alexei Pushechnikov
    Department of Chemistry and The Center of Excellence in Bioinformatics and Life Sciences, The State University of New York, 657 Natural Sciences Complex, Buffalo, New York 14260, USA
    J Am Chem Soc 131:9767-79. 2009
  9. pmc Transcriptional and post-transcriptional impact of toxic RNA in myotonic dystrophy
    Robert J Osborne
    Department of Neurology, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA
    Hum Mol Genet 18:1471-81. 2009
  10. pmc Cell-free cloning of highly expanded CTG repeats by amplification of dimerized expanded repeats
    Robert J Osborne
    Department of Neurology, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Rochester, NY 14642, USA
    Nucleic Acids Res 36:e24. 2008

Scientific Experts

  • Eric L Logigian
  • Robert J Osborne
  • Charles A Thornton
  • Thurman M Wheeler
  • John D Lueck
  • Masayuki Nakamori
  • Robert T Dirksen
  • Maurice S Swanson
  • Krzysztof Sobczak
  • Xiaoyan Lin
  • Ami Mankodi
  • Hongqing Du
  • Alexei Pushechnikov
  • Susan A M Mulders
  • M Bryan Warf
  • Richard T Moxley
  • T M Wheeler
  • Manuel Ares
  • Tyson A Clark
  • Megan P Hall
  • Melissa S Cline
  • Lily Shiue
  • Daniel L Tuttle
  • Charles Thornton
  • John Paul Donohue
  • J Andrew Berglund
  • Catherine M Matthys
  • Gerard J Platenburg
  • Huib J E Croes
  • Denis Furling
  • Genevieve Gourdon
  • Sjef J De Kimpe
  • Melissa M Lee
  • Petra van Kuik-Romeijn
  • Matthew D Disney
  • Jessica L Childs-Disney
  • Walther J A A van den Broek
  • Derick G Wansink
  • Jonathan M French
  • Be Wieringa
  • C A Thornton
  • Stephen L Welle
  • Codrin Lungu
  • M C Krym
  • Jill W Miller
  • Yuan Yuan
  • Rahul N Kanadia

Detail Information

Publications17

  1. pmc Mexiletine is an effective antimyotonia treatment in myotonic dystrophy type 1
    E L Logigian
    Department of Neurology, University of Rochester, Rochester, NY, USA
    Neurology 74:1441-8. 2010
    ..To determine if mexiletine is safe and effective in reducing myotonia in myotonic dystrophy type 1 (DM1)...
  2. pmc Epigenetic changes and non-coding expanded repeats
    Masayuki Nakamori
    Department of Neurology, University of Rochester Medical Center, Rochester, New York 14642, USA
    Neurobiol Dis 39:21-7. 2010
    ..Here we review the mechanisms of gene dysregulation induced by non-coding repeat expansions, and early indications that some of these disorders may prove to be responsive to therapeutic intervention...
  3. pmc Scaled-down genetic analysis of myotonic dystrophy type 1 and type 2
    Masayuki Nakamori
    Department of Neurology, Box 673, University of Rochester Medical Center, Rochester, NY 14642, USA
    Neuromuscul Disord 19:759-62. 2009
    ..These methods can facilitate genetic analysis in cells and tissues obtained from individuals with myotonic dystrophy...
  4. pmc Aberrant alternative splicing and extracellular matrix gene expression in mouse models of myotonic dystrophy
    Hongqing Du
    RNA Center, Department of Molecular, Cell and Developmental Biology, Sinsheimer Labs, University of California, Santa Cruz, California, USA
    Nat Struct Mol Biol 17:187-93. 2010
    ..These findings reveal unanticipated similarities between DM1 and other muscular dystrophies...
  5. pmc Pentamidine reverses the splicing defects associated with myotonic dystrophy
    M Bryan Warf
    Department of Chemistry and Institute of Molecular Biology, University of Oregon, Eugene, OR 97403, USA
    Proc Natl Acad Sci U S A 106:18551-6. 2009
    ..Furthermore, pentamidine partially rescued splicing defects of 2 pre-mRNAs in mice expressing expanded CUG repeats...
  6. pmc Triplet-repeat oligonucleotide-mediated reversal of RNA toxicity in myotonic dystrophy
    Susan A M Mulders
    Department of Cell Biology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
    Proc Natl Acad Sci U S A 106:13915-20. 2009
    ..Our data demonstrate proof of principle for therapeutic use of simple sequence AONs in DM1 and potentially other unstable microsatellite diseases...
  7. pmc Reversal of RNA dominance by displacement of protein sequestered on triplet repeat RNA
    Thurman M Wheeler
    Departments of Neurology, Pharmacology and Physiology, University of Rochester, Rochester, NY 14642, USA
    Science 325:336-9. 2009
    ..These findings suggest an alternative use of antisense methods, to inhibit deleterious interactions of proteins with pathogenic RNAs...
  8. pmc Rational design of ligands targeting triplet repeating transcripts that cause RNA dominant disease: application to myotonic muscular dystrophy type 1 and spinocerebellar ataxia type 3
    Alexei Pushechnikov
    Department of Chemistry and The Center of Excellence in Bioinformatics and Life Sciences, The State University of New York, 657 Natural Sciences Complex, Buffalo, New York 14260, USA
    J Am Chem Soc 131:9767-79. 2009
    ..These studies suggest a general approach to targeting RNA, including those that cause RNA dominant disease...
  9. pmc Transcriptional and post-transcriptional impact of toxic RNA in myotonic dystrophy
    Robert J Osborne
    Department of Neurology, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA
    Hum Mol Genet 18:1471-81. 2009
    ....
  10. pmc Cell-free cloning of highly expanded CTG repeats by amplification of dimerized expanded repeats
    Robert J Osborne
    Department of Neurology, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Rochester, NY 14642, USA
    Nucleic Acids Res 36:e24. 2008
    ..Amplification of dimerized expanded repeats (ADER) opens new possibilities for studies of repeat instability and pathogenesis in myotonic dystrophy, a neurological disorder caused by an expanded CTG repeat...
  11. pmc Correction of ClC-1 splicing eliminates chloride channelopathy and myotonia in mouse models of myotonic dystrophy
    Thurman M Wheeler
    Department of Neurology, University of Rochester, Rochester, New York 14618, USA
    J Clin Invest 117:3952-7. 2007
    ....
  12. ncbi Myotonic dystrophy: RNA-mediated muscle disease
    Thurman M Wheeler
    Department of Neurology, University of Rochester, Rochester, New York, USA
    Curr Opin Neurol 20:572-6. 2007
    ..The aim of this review is to highlight recent progress in elucidating the disease mechanism in myotonic dystrophy type 1 and type 2...
  13. pmc Ribonuclear foci at the neuromuscular junction in myotonic dystrophy type 1
    T M Wheeler
    Department of Neurology, University of Rochester, 601 Elmwood Avenue, Box 673, Rochester, NY 14642, USA
    Neuromuscul Disord 17:242-7. 2007
    ..Our findings indicate that subsynaptic nuclei and motor neurons are at risk for DM1-induced spliceopathy, which may affect function or stability of the neuromuscular junction...
  14. pmc Muscle chloride channel dysfunction in two mouse models of myotonic dystrophy
    John D Lueck
    Department of Physiology and Pharmacology, University of Rochester, Rochester, NY 14642, USA
    J Gen Physiol 129:79-94. 2007
    ....
  15. ncbi Chloride channelopathy in myotonic dystrophy resulting from loss of posttranscriptional regulation for CLCN1
    John D Lueck
    Department of Pharmacology and Physiology, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA
    Am J Physiol Cell Physiol 292:C1291-7. 2007
    ....
  16. ncbi RNA-dominant diseases
    Robert J Osborne
    Department of Neurology, University of Rochester Medical Center, Rochester, NY 14642, USA
    Hum Mol Genet 15:R162-9. 2006
    ..This review describes some of the recent advances in understanding the pathophysiology of RNA-dominant diseases...
  17. ncbi Failure of MBNL1-dependent post-natal splicing transitions in myotonic dystrophy
    Xiaoyan Lin
    Department of Neuroscience, University of Rochester Medical Center, Rochester, NY 14642, USA
    Hum Mol Genet 15:2087-97. 2006
    ..Sequestration of MBNL1, and failure to maintain these splicing transitions, has a pivotal role in the pathogenesis of muscle disease in DM...