Transgenic overexpression of human DMPK accumulates into hypertrophic cardiomyopathy, myotonic myophaty and hypotension traits of myotonic dystrophy

D. Fearghas O'Cochlain, Carmen M Terzic, Santiago Reyes, Garvan M Kane, Atta Behfar, Denice M. Hodgson, Jeffrey A. Strommen, Xiao Ke Liu, Walther van den Broek, Derick G. Wansink, Bé Wieringa, Andre Terzic

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Abstract

Abnormal expression of human myotonic dystrophy protein kinase (hDMPK) gene products has been implicated in myotonic dystrophy type 1 (DM1), yet the impact of distress accumulation produced by persistent overexpression of this poorly understood member of the Rho kinase-related protein kinase gene-family remains unknown. Here, in the aged transgenic murine line carrying approximately 25 extra copies of a complete hDMPK gene with all exons and an intact promoter region (Tg26-hDMPK), overexpression of mRNA and protein transgene products in cardiac, skeletal and smooth muscles resulted in deficient exercise endurance, an integrative index of muscle systems underperformance. In contrast to age-matched (11-15 months) wild-type controls, hearts from Tg26-hDMPK developed cardiomyopathic remodeling with myocardial hypertrophy, myocyte disarray and interstitial fibrosis. Hypertrophic cardiomyopathy was associated with a propensity for dysrhythmia and characterized by overt intracellular calcium overload promoting nuclear translocation of transcription factors responsible for maladaptive gene reprograming. Skeletal muscles in distal limbs of Tg26-hDMPK showed myopathy with myotonic discharges coupled with deficit in sarcolemmal chloride channels, required regulators of hyperexcitability. Fiber degeneration in Tg26-hDMPK resulted in sarcomeric disorganization, centralization of nuclei and tubular aggregation. Moreover, the reduced blood pressure in Tg26-hDMPK indicated deficient arterial smooth muscle tone. Thus, the cumulative stress induced by permanent overexpression of hDMPK gene products translates into an increased risk for workload intolerance, hypertrophic cardiomyopathy with dysrhythmia, myotonic myopathy and hypotension, all distinctive muscle traits of DM1. Proper expression of hDMPK is, therefore, mandatory in supporting the integral balance among cytoarchitectural infrastructure, ion-homeostasis and viability control in various muscle cell types.

Original languageEnglish (US)
Pages (from-to)2505-2518
Number of pages14
JournalHuman Molecular Genetics
Volume13
Issue number20
DOIs
StatePublished - Oct 15 2004

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Myotonic Dystrophy
Hypertrophic Cardiomyopathy
Hypotension
Myotonic Disorders
Genes
Muscle Cells
Smooth Muscle
Skeletal Muscle
Muscles
rho-Associated Kinases
Chloride Channels
Workload
Transgenes
Genetic Promoter Regions
Protein Kinases
Hypertrophy
Exons
Myocardium
Homeostasis
Fibrosis

ASJC Scopus subject areas

  • Genetics

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Transgenic overexpression of human DMPK accumulates into hypertrophic cardiomyopathy, myotonic myophaty and hypotension traits of myotonic dystrophy. / O'Cochlain, D. Fearghas; Terzic, Carmen M; Reyes, Santiago; Kane, Garvan M; Behfar, Atta; Hodgson, Denice M.; Strommen, Jeffrey A.; Liu, Xiao Ke; van den Broek, Walther; Wansink, Derick G.; Wieringa, Bé; Terzic, Andre.

In: Human Molecular Genetics, Vol. 13, No. 20, 15.10.2004, p. 2505-2518.

Research output: Contribution to journalArticle

O'Cochlain, D. Fearghas ; Terzic, Carmen M ; Reyes, Santiago ; Kane, Garvan M ; Behfar, Atta ; Hodgson, Denice M. ; Strommen, Jeffrey A. ; Liu, Xiao Ke ; van den Broek, Walther ; Wansink, Derick G. ; Wieringa, Bé ; Terzic, Andre. / Transgenic overexpression of human DMPK accumulates into hypertrophic cardiomyopathy, myotonic myophaty and hypotension traits of myotonic dystrophy. In: Human Molecular Genetics. 2004 ; Vol. 13, No. 20. pp. 2505-2518.
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AU - O'Cochlain, D. Fearghas

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AU - Reyes, Santiago

AU - Kane, Garvan M

AU - Behfar, Atta

AU - Hodgson, Denice M.

AU - Strommen, Jeffrey A.

AU - Liu, Xiao Ke

AU - van den Broek, Walther

AU - Wansink, Derick G.

AU - Wieringa, Bé

AU - Terzic, Andre

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