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/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 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.
Stypmann
Jörg
J
Department of Cardiology and Angiology, University Hospital Münster, Münster, Germany. Stypmann@mednet.uni-muenster.de
Janssen
Paul M L
PM
Prestle
Jürgen
J
Engelen
Markus A
MA
Kögler
Harald
H
Lüllmann-Rauch
Renate
R
Eckardt
Lars
L
von Figura
Kurt
K
Landgrebe
Jobst
J
Mleczko
Anna
A
Saftig
Paul
P
D000818:Animals; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D006321:Heart / Q000502:physiology*; D066298:In Vitro Techniques; D052119:Lysosomal-Associated Membrane Protein 2 / Q000502:physiology*; D008297:Male; D051379:Mice; D009200:Myocardial Contraction / Q000502:physiology*; D009206:Myocardium / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis
D052119:Lysosomal-Associated Membrane Protein 2; D002118:Calcium