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LAMP-2 deficient mice show depressed cardiac contractile function without significant changes in calcium handling

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Abstract

Objective

Mutations in the highly glycosylated lysosome associated membrane protein-2 (LAMP-2) cause, as recently shown, familial Danon disease with mental retardation, mild myopathy and fatal cardiomyopathy. Extent and basis of the contractile dysfunction is not completely understood.

Methods

In LAMP-2 deficient mice, we investigated cardiac function in vivo using Doppler-echocardiography and contractile function in vitro in isolated myocardial trabeculae.

Results

LAMP-2 deficient mice displayed reduced ejection fraction (EF) (58.9±3.4 vs. 80.7±5.1%, P<0.05) and reduced cardiac output (8.3±3.1 vs. 14.7±3.6 ml/min, P<0.05) as compared to wild-type controls. Isolated multicellular muscle preparations from LAMP-2 deficient mice confirmed depressed force development (3.2±0.6 vs. 8.4±0.9 mN/mm2, P<0.01). All groups showed similar force-frequency behaviour when normalised to baseline force. Post-rest potentiation was significantly depressed at intervals >15 s in LAMP-2 deficient mice (P<0.05). Although attenuated in absolute force development, the normalised inotropic response to increased calcium and β-adrenoreceptor stimulation was unaltered. Electron microscopic analysis revealed autophagic vacuoles in LAMP-2 deficient cardiomyocytes. Protein analysis showed unaltered levels of SERCA2a, calsequestrin and phospholamban.

Conclusions

Cardiac contractile function in LAMP-2 deficient mice as a model for Danon disease is significantly attenuated. The occurrence of autophagic vacuoles in LAMP-2 deficient myocytes is likely to be causal for the depressed contractile function resulting in an attenuated cardiac pump reserve.

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Acknowledgements

This work was supported by the Deutsche Forschungsgemeinschaft (DFG Sa 683/1-3) and the Fonds der Chemischen Industrie, the BMFT genomic network “Genetic susceptibility to heart failure and predictors of therapeutic response”, and the Interdisciplinary Centrum for Clinical Research (IZKF, ZPG 4a), University Hospital Münster, Germany. This work was partly supported by grants from the Deutsche Forschungsgemeinschaft (DFG), Sonderforschungsbereich 656 MoBil (project C3), Münster, Germany. We acknowledge technical assistance of Nicole Beikirch, Geerd Hensmann, Ellen Eckermann und Dagmar Niemeier.

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Authors and Affiliations

  1. Department of Cardiology and Angiology, University Hospital Münster, Münster, Germany

    Jörg Stypmann, Markus A. Engelen & Lars Eckardt

  2. Interdisciplinary Center for Clinical Research, Central Project Group (ZPG 4a), Westfälische Wilhelms Universität, Münster, Germany

    Jörg Stypmann & Lars Eckardt

  3. Department of Physiology and Cell Biology , The Ohio State University , Columbus, OH, 43210, USA

    Paul M.L. Janssen

  4. Department of Cardiology and Pneumology , University Göttingen, Göttingen, Germany

    Jürgen Prestle & Harald Kögler

  5. Department of Medical Physiology , University Medical Center Utrecht , Utrecht, The Netherlands

    Markus A. Engelen

  6. Anatomisches Institute, University of Kiel, Kiel, Germany

    Renate Lüllmann-Rauch

  7. Department of Biochemistry II, University of Göttingen, Göttingen, Germany

    Kurt von Figura, Jobst Landgrebe & Anna Mleczko

  8. Department of Biochemistry, University of Kiel, Kiel, Germany

    Paul Saftig

  9. Medizinische Klinik und Poliklinik C Kardiologie und Angiologie , Universitätsklinikum Münster, 48149, Münster, Germany

    Jörg Stypmann

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  1. Jörg Stypmann
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Corresponding author

Correspondence to Jörg Stypmann.

Additional information

Returned for 1. revision: 5 December 2003 1. Revision received: 18 November 2005 Returned for 2. revision: 12 December 2005

2. Revision received: 23 December 2005 Returned for 3. revision: 1 February 2006

3.Revision received: 8 February 2006

Drs. Stypmann and Janssen contributed equally.

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Stypmann, J., Janssen, P.M., Prestle, J. et al. LAMP-2 deficient mice show depressed cardiac contractile function without significant changes in calcium handling. Basic Res Cardiol 101, 281–291 (2006). https://doi.org/10.1007/s00395-006-0591-6

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  • DOI: https://doi.org/10.1007/s00395-006-0591-6

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