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. Ló pez |
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Affiliation: | 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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