, Volume 101, Issue 4, pp 281-291
Date: 08 Apr 2006

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.

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.