Journal Article

Transgenic overexpression of human <i>DMPK</i> accumulates into hypertrophic cardiomyopathy, myotonic myopathy and hypotension traits of myotonic dystrophy

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

in Human Molecular Genetics

Volume 13, issue 20, pages 2505-2518
Published in print October 2004 | ISSN: 0964-6906
Published online August 2004 | e-ISSN: 1460-2083 | DOI:
Transgenic overexpression of human DMPK accumulates into hypertrophic cardiomyopathy, myotonic myopathy and hypotension traits of myotonic dystrophy

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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.

Journal Article.  7433 words.  Illustrated.

Subjects: Genetics and Genomics

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