Basic Research in Cardiology

, Volume 101, Issue 4, pp 281–291

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

  • Jörg Stypmann
  • Paul M.L. Janssen
  • Jürgen Prestle
  • Markus A. Engelen
  • Harald Kögler
  • Renate Lüllmann-Rauch
  • Lars Eckardt
  • Kurt von Figura
  • Jobst Landgrebe
  • Anna Mleczko
  • Paul Saftig
ORIGINAL CONTRIBUTION

DOI: 10.1007/s00395-006-0591-6

Cite this article as:
Stypmann, J., Janssen, P.M., Prestle, J. et al. Basic Res Cardiol (2006) 101: 281. doi:10.1007/s00395-006-0591-6

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.

Keywords

contractile functioncalciummechanotransductiondanon diseaseLAMP-2

Copyright information

© Steinkopff Verlag Darmstadt 2006

Authors and Affiliations

  • Jörg Stypmann
    • 1
    • 2
    • 9
  • Paul M.L. Janssen
    • 3
  • Jürgen Prestle
    • 4
  • Markus A. Engelen
    • 1
    • 5
  • Harald Kögler
    • 4
  • Renate Lüllmann-Rauch
    • 6
  • Lars Eckardt
    • 1
    • 2
  • Kurt von Figura
    • 7
  • Jobst Landgrebe
    • 7
  • Anna Mleczko
    • 7
  • Paul Saftig
    • 8
  1. 1.Department of Cardiology and AngiologyUniversity Hospital MünsterMünsterGermany
  2. 2.Interdisciplinary Center for Clinical Research, Central Project Group (ZPG 4a)Westfälische Wilhelms UniversitätMünsterGermany
  3. 3.Department of Physiology and Cell Biology The Ohio State University ColumbusUSA
  4. 4.Department of Cardiology and Pneumology University GöttingenGöttingenGermany
  5. 5.Department of Medical Physiology University Medical Center Utrecht UtrechtThe Netherlands
  6. 6.Anatomisches InstituteUniversity of KielKielGermany
  7. 7.Department of Biochemistry IIUniversity of GöttingenGöttingenGermany
  8. 8.Department of BiochemistryUniversity of KielKielGermany
  9. 9.Medizinische Klinik und Poliklinik C Kardiologie und Angiologie Universitätsklinikum MünsterMünsterGermany