title: Age-dependent changes in diastolic Ca(2+) and Na(+) concentrations in dystrophic cardiomyopathy: Role of Ca(2+) entry and IP3.
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 Ca(2+) concentration ([Ca(2+)]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 (Gd(3+))-sensitive Ca(2+) entry and inositol triphosphate (IP3) signaling pathways in abnormal [Ca(2+)]d and [Na(+)]d were investigated. Our results showed an age-dependent increase in both [Ca(2+)]d and [Na(+)]d in dystrophic cardiomyocytes compared to those isolated from age-matched wt mice. Gd(3+) treatment significantly reduced both [Ca(2+)]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 Gd(3+) normalized both [Ca(2+)]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 Ca(2+) and Na(+) overload mediated at least in part by enhanced Ca(2+) entry through Gd(3+) sensitive transient receptor potential channels (TRPC), and by IP3 receptors.
authors.affiliation: Instituto Venezolano de Investigaciones Científicas, Centro de Biofísica y Bioquímica, Caracas, Venezuela.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Mijares
authors.affiliation: Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, CA 95616, USA.
authors.forename: Francisco
authors.initials: F
authors.lastname: Altamirano
authors.affiliation: Centro de Investigaciones Biomédicas, México D.F., Mexico.
authors.forename: Juan
authors.initials: J
authors.lastname: Kolster
authors.affiliation: Division of Neonatology, Mount Sinai Medical Center, Miami, FL 33140, USA.
authors.forename: José A
authors.initials: JA
authors.lastname: Adams
authors.affiliation: Instituto Venezolano de Investigaciones Científicas, Centro de Biofísica y Bioquímica, Caracas, Venezuela; Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, CA 95616, USA. Electronic address: jrlopez@ucdavis.edu.
authors.forename: José R
authors.initials: JR
authors.lastname: López
mesh_terms: D000375:Aging / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D009202:Cardiomyopathies / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D003971:Diastole; D016189:Dystrophin / Q000378:metabolism; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000378:metabolism*; D051379:Mice; D018101:Mice, Inbred mdx; D020388:Muscular Dystrophy, Duchenne / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism*; D012964:Sodium / Q000378:metabolism*
chemical_list: D016189:Dystrophin; D053496:Inositol 1,4,5-Trisphosphate Receptors; D012964:Sodium; D002118:Calcium
keywords: Aging; Calcium; Duchenne cardiomyopathy; Inositol triphosphate receptors; Sodium; Transient receptor potential channels