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Age-dependent changes in diastolic Ca(2+) and Na(+) concentrations in dystrophic cardiomyopathy: Role of Ca(2+) entry and IP3.

Biochemical and biophysical research communications (2014-09-23)
Alfredo Mijares, Francisco Altamirano, Juan Kolster, José A Adams, José R López
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.

MATERIALS
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