Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

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Stypmann, J. et al.

Stypmann, Janssen, Prestle, Engelen, Kögler, Lüllmann-Rauch, Eckardt, von Figura, Landgrebe, Mleczko, Saftig,

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

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/mm(2), 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 beta-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.[1]

References

LAMP-2 deficient mice show depressed cardiac contractile function without significant changes in calcium handling. Stypmann, J., Janssen, P.M., Prestle, J., Engelen, M.A., Kögler, H., Lüllmann-Rauch, R., Eckardt, L., von Figura, K., Landgrebe, J., Mleczko, A., Saftig, P. Basic Res. Cardiol. (2006) [Pubmed]

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