Abstract 17128: Subacute Treatment With Rapamycin Reverses Cardiac Aging by Proteome Remodeling and Improved Mitochondrial Energy Metabolism
Caloric restriction of mice is known to attenuate age-related impairment in diastolic function. Rapamycin, a caloric restriction mimetic, is protective in models of cardiac hypertrophy and heart failure, but the effect of rapamycin on cardiac aging has not been previously established. The objective of this study is to determine the effects of subacute rapamycin treatment on cardiac aging.
We monitored cardiac function in 25 month old C57BL6/CR mice fed for 10 weeks with control diet or diet containing 14ppm encapsulated rapamycin, the dose previously shown to extend murine lifespan. By tissue doppler imaging, Ea/Aa increased from 1.00 to 1.26 in mice fed with rapamycin, indicating improvement in diastolic function. This improvement began as early as 4 weeks. Also, mice fed with rapamycin showed a trend of reduced MPI, while fractional shortening did not change with rapamycin treatment. We observed lower normalized heart weights in mice treated with rapamycin compared to old control mice, suggesting that 10 week rapamycin treatment can regress age-related cardiac hypertrophy. These results indicate that relatively short-term rapamycin treatment can reverse cardiac aging phenotypes in old mice.
LC-MS/MS proteomic analysis showed that the age-related reduction of mitochondrial proteins in control hearts, including multiple subunits of electron transport chain complexes and fatty acid oxidation enzymes, was restored to higher levels in old rapamycin-treated hearts. Deuterated-leucine labeled proteomic analysis of protein turnover revealed a 12% increase in half-lives of cardiac global proteome (823 proteins) in rapamycin-treated old mice compared to old controls. Surprisingly, this slower protein turnover was accompanied by attenuated protein oxidative damage. In addition, LC-MS/MS targeted metabolic analysis detected increased TCA cycle intermediates and reduced glycolytic intermediates in old rapamycin-treated hearts, concordant with proteomics. These changes suggest that proteomic and metabolic remodeling after subacute rapamycin treatment modulates protein homeostasis and improves mitochondrial energy metabolism, contributing to the improved cardiac aging phenotypes observed in 10 week rapamycin-treated old mice.
- © 2013 by American Heart Association, Inc.