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Dysfunction of dysferlin-deficient hearts

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Abstract

Mutations in the gene encoding dysferlin cause limb-girdle muscular dystrophy 2B (LGMD2B), a disorder that is believed to spare the heart. We observed dilated cardiomyopathy in two out of seven LGMD2B patients and cardiac abnormalities in three others. Cardiac biopsies showed that dysferlin was completely absent from the sarcolemma and appeared to be trapped within the cardiomyocytes. SJL/J mice (33-week-old) had diminished end-systolic pressure and reduced dP/dt; however, the hearts were histologically normal. Gene expression profiles of cardiac tissue were obtained and later confirmed by quantitative RT-PCR. Dysferlin-deficient and control mice had different gene expression patterns in terms of cardiomyocyte Z-disc and signal transduction proteins. CapZ, LIM-domain-binding protein 3 (LDB3, MLP), cypher (ZASP), desmin, and the cardiac ankyrin-repeated protein (CARP) were differentially expressed, compared to controls. Mechanical stress induced by the nonselective beta-adrenergic agonist isoproterenol (5 mg/kg body weight) given daily for 10 days resulted in reduced fractional shortening and increased cardiac fibrosis in SJL/J mice as compared to controls. Isoproterenol also caused metalloproteinase-2 upregulation in SJL/J mice. In A/J mice, the effect of isoproterenol injection was even more dramatic and lead to premature death as well as marked sarcolemmal injury as demonstrated by Evans blue dye penetration. Our data suggest that disturbances in dysferlin as well as Z-line proteins and transcription factors particularly under mechanical stress cause cardiomyopathy.

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Acknowledgment

We thank Mathilde Schmidt, May-Britt Köhler, Astrid Schiche, and Jutta Meisel for excellent technical assistance. We thank Friedrich C. Luft, M.D., for critical discussion of the manuscript. The work was supported by the German Research Foundation (DFG; KFO 192/1, Simone Spuler) and research grants of the Humboldt University to Simone Spuler, Karl Josef Osterziel, and Cemil Özcelik.

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Authors and Affiliations

  1. Department of Cardiology, Franz Volhard Clinic, Helios Clinic and Campus Virchow Clinic, Charité, Berlin, Germany

    Katrin Wenzel, Christian Geier, Fatimunnisa Qadri, Ralf Dechend, Rainer Dietz, Karl Josef Osterziel & Cemil Özcelik

  2. Max Delbrück Center for Molecular Medicine, Berlin, Germany

    Norbert Hubner, Herbert Schulz, Bettina Erdmann & Volkmar Gross

  3. Schering AG, Berlin, Germany

    David Bauer

  4. Muscle Research Unit, Experimental and Clinical Research Center at the Charité and the Max-Delbrück Center, Berlin, Germany

    Simone Spuler

  5. ECRC at the Charité and the Max-Delbrück Center, Lindenberger Weg 80, Berlin, 13125, Germany

    Simone Spuler

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  1. Katrin Wenzel
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  3. Fatimunnisa Qadri
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Correspondence to Simone Spuler.

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Simone Spuler and Cemil Özcelik contributed equally to this paper.

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Wenzel, K., Geier, C., Qadri, F. et al. Dysfunction of dysferlin-deficient hearts. J Mol Med 85, 1203–1214 (2007). https://doi.org/10.1007/s00109-007-0253-7

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  • DOI: https://doi.org/10.1007/s00109-007-0253-7

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