The Effects of Aging on the Regulation of T-Tubular i Ca by Caveolin in Mouse Ventricular Myocytes

Abstract

Aging is associated with diminished cardiac function in males. Cardiac excitation-contraction coupling in ventricular myocytes involves Ca influx via the Ca current (I Ca) and Ca release from the sarcoplasmic reticulum, which occur predominantly at t-tubules. Caveolin-3 regulates t-tubular I Ca, partly through protein kinase A (PKA), and both I Ca and caveolin-3 decrease with age. We therefore investigated I Ca and t-tubule structure and function in cardiomyocytes from male wild-type (WT) and caveolin-3-overexpressing (Cav-3OE) mice at 3 and 24 months of age. In WT cardiomyocytes, t-tubular I Ca -density was reduced by ∼50% with age while surface I Ca density was unchanged. Although regulation by PKA was unaffected by age, inhibition of caveolin-3-binding reduced t-tubular I Ca at 3 months, but not at 24 months. While Cav-3OE increased cardiac caveolin-3 protein expression ∼2.5-fold at both ages, the age-dependent reduction in caveolin-3 (WT ∼35%) was preserved in transgenic mice. Overexpression of caveolin-3 reduced t-tubular I Ca density at 3 months but prevented further I Ca loss with age. Measurement of Ca release at the t-tubules revealed that the triggering of local Ca release by t-tubular I Ca was unaffected by age. In conclusion, the data suggest that the reduction in I Ca density with age is associated with the loss of a caveolin-3-dependent mechanism that augments t-tubular I Ca density.