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Mechanisms of [Ca²⁺]_i Transient Decrease in Cardiomyopathy of db/db Type 2 Diabetic Mice

¹ Institut National de la Santé et de la Recherche Médicale, U 637, University of Montpellier 1, Montpellier, France
² Department of Pharmacology and Center of Molecular Medicine, University of Cologne, Cologne, Germany
³ School of Medicine, University of Montpellier 1, EA 2992, Nîmes, France
⁴ Department of Physiology, University of Wisconsin Medical School, Madison, Wisconsin

Address correspondence and reprint requests to Ana María Gómez, Institut National de la Santé et de la Recherche Médicale U-637, CHU A. de Villeneuve, 34295 Montpellier, France. E-mail: agomez{at}montp.inserm.fr

Abbreviations: [Ca²⁺]_i, intracellular calcium concentration; NCX, Na⁺/Ca²⁺ exchanger; RyR, ryanodine receptor Ca²⁺ channel; SERCA, sarcoplasmic reticulum Ca²⁺ ATPase

Cardiovascular disease is the leading cause of death in the diabetic population. However, molecular mechanisms underlying diabetic cardiomyopathy remain unclear. We analyzed Ca²⁺-induced Ca²⁺ release and excitation-contraction coupling in db/db obese type 2 diabetic mice and their control littermates. Echocardiography showed a systolic dysfunction in db/db mice. Two-photon microscopy identified intracellular calcium concentration ([Ca²⁺]_i) transient decrease in cardiomyocytes within the whole heart, which was also found in isolated myocytes by confocal microscopy. Global [Ca²⁺]_i transients are constituted of individual Ca²⁺ sparks. Ca²⁺ sparks in db/db cardiomyocytes were less frequent than in +/+ myocytes, partly because of a depression in sarcoplasmic reticulum Ca²⁺ load but also because of a reduced expression of ryanodine receptor Ca²⁺ channels (RyRs), revealed by [³H]ryanodine binding assay. Ca²⁺ efflux through Na⁺/Ca²⁺ exchanger was increased in db/db myocytes. Calcium current, I_Ca, triggers sarcoplasmic reticulum Ca²⁺ release and is also involved in sarcoplasmic reticulum Ca²⁺ refilling. Macroscopic I_Ca was reduced in db/db cells, but single Ca²⁺ channel activity was similar, suggesting that diabetic myocytes express fewer functional Ca²⁺ channels, which was confirmed by Western blots. These results demonstrate that db/db mice show depressed cardiac function, at least in part, because of a general reduction in the membrane permeability to Ca²⁺. As less Ca²⁺ enters the cell through I_Ca, less Ca²⁺ is released through RyRs.

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