Age-dependent changes in diastolic Ca and Na concentrations in dystrophic cardiomyopathy: Role of Ca entry and IP3 |
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Authors: | Alfredo Mijares Francisco Altamirano Juan Kolster José A Adams José R López |
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Institution: | 1. Instituto Venezolano de Investigaciones Científicas, Centro de Biofísica y Bioquímica, Caracas, Venezuela;2. Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, CA 95616, USA;3. Centro de Investigaciones Biomédicas, México D.F., Mexico;4. Division of Neonatology, Mount Sinai Medical Center, Miami, FL 33140, USA |
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Abstract: | Duchenne muscular dystrophy (DMD) is a lethal X-inherited disease caused by dystrophin deficiency. Besides the relatively well characterized skeletal muscle degenerative processes, DMD is also associated with a dilated cardiomyopathy that leads to progressive heart failure at the end of the second decade. The aim of the present study was to characterize the diastolic Ca2+ concentration (Ca2+]d) and diastolic Na+ concentration (Na+]d) abnormalities in cardiomyocytes isolated from 3-, 6-, 9-, and 12-month old mdx mice using ion-selective microelectrodes. In addition, the contributions of gadolinium (Gd3+)-sensitive Ca2+ entry and inositol triphosphate (IP3) signaling pathways in abnormal Ca2+]d and Na+]d were investigated. Our results showed an age-dependent increase in both Ca2+]d and Na+]d in dystrophic cardiomyocytes compared to those isolated from age-matched wt mice. Gd3+ treatment significantly reduced both Ca2+]d and Na+]d at all ages. In addition, blockade of the IP3-pathway with either U-73122 or xestospongin C significantly reduced ion concentrations in dystrophic cardiomyocytes. Co-treatment with U-73122 and Gd3+ normalized both Ca2+]d and Na+]d at all ages in dystrophic cardiomyocytes. These data showed that loss of dystrophin in mdx cardiomyocytes produced an age-dependent intracellular Ca2+ and Na+ overload mediated at least in part by enhanced Ca2+ entry through Gd3+ sensitive transient receptor potential channels (TRPC), and by IP3 receptors. |
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Keywords: | DMD Duchenne muscular dystrophy [Ca2+]d diastolic Ca2+ concentration [Na+]d diastolic Na+ concentration IP3 inositol 1 4 5-trisphosphate Gd3+ gadolinium TRPC transient receptor potential channels PLC phospholipase C DAG diacylglycerol RyR2 type-2 ryanodine receptor XeC xestospongin C IP3R IP3 receptor |
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