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

Cherrie H.T. Kong, Simon M. Bryant, Judy J. Watson, Hanne C. Gadeberg, David M. Roth, Hemal H. Patel, Mark B. Cannell, Clive H. Orchard, Andrew F. James*

*Corresponding author for this work

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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.

Original languageEnglish
Article numberglx242
Pages (from-to)711-719
Number of pages9
JournalJournals of Gerontology, Series A
Volume73
Issue number6
Early online date9 Dec 2017
DOIs
Publication statusPublished - 9 May 2018

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Keywords

  • Ca signaling
  • Caveolin-3
  • Excitation-contraction coupling

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