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Dystrophin deficiency markedly increases enterovirus-induced cardiomyopathy: A genetic predisposition to viral heart disease

Nature Medicine volume 8, pages 872–877 (2002)Cite this article

Abstract

Both enteroviral infection of the heart and mutations in the dystrophin gene can cause cardiomyopathy. Little is known, however, about the interaction between genetic and acquired forms of cardiomyopathy. We previously demonstrated that the enteroviral protease 2A cleaves dystrophin; therefore, we hypothesized that dystrophin deficiency would predispose to enterovirus-induced cardiomyopathy. We observed more severe cardiomyopathy, worsening over time, and greater viral replication in dystrophin-deficient mice infected with enterovirus than in infected wild-type mice. This difference appears to be a result of more efficient release of the virus from dystrophin-deficient myocytes. In addition, we found that expression of wild-type dystrophin in cultured cells decreased the cytopathic effect of enteroviral infection and the release of virus from the cell. We also found that expression of a cleavage-resistant mutant dystrophin further inhibited the virally mediated cytopathic effect and viral release. These results indicate that viral infection can influence the severity and penetrance of the cardiomyopathy that occurs in the hearts of dystrophin-deficient individuals.

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Figure 1: Dystrophin deficiency markedly increases enterovirus-mediated disruption of the sarcolemma.
Figure 2: Increased viral titers and localization of virus and Evans blue dye (EBD).
Figure 3: Mutation of dystrophin in hinge 3 (H3) region prevents cleavage of dystrophin by enteroviral protease 2A.
Figure 4: Dystrophin decreases the enterovirus-induced cytopathic effect and viral release in cultured cells.

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Acknowledgements

We thank R. Myers and D. Rappaport for providing equipment and advice for cryosections, immunostaining and imaging; J. Chen and S. Evans for helpful discussions; A. Henke for the anti-CVB3 antibody; and P.R. Clemens and C.C. Lee for providing the mouse dystrophin expression vector. This work was supported in part by a US National Institutes of Health grant (5 R01 HL57365-03) and an American Heart Association Established Investigator Award (to K.U.K.); by Our Lady of Mercy Hospital, Catholic University of Korea (to G.H.L.); and by a training grant from the Deutsche Forschungsgemeinschaft (Ba 1668/1-1) (to C.B.).

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Authors and Affiliations

  1. Department of Medicine, Institute of Molecular Medicine and The Cardiovascular Center, University of California, San Diego, California, USA

    Dingding Xiong, Gil-Hwan Lee, Cornel Badorff, Andrea Dorner & Kirk U. Knowlton

  2. Department of Surgery, University of California, San Diego, California, USA

    Sang Lee

  3. Department of Pathology, University of California, San Diego, California, USA

    Paul Wolf

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  1. Dingding Xiong
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Correspondence to Kirk U. Knowlton.

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Xiong, D., Lee, GH., Badorff, C. et al. Dystrophin deficiency markedly increases enterovirus-induced cardiomyopathy: A genetic predisposition to viral heart disease. Nat Med 8, 872–877 (2002). https://doi.org/10.1038/nm737

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