Rapamycin, an inhibitor of mTOR signaling, has been shown to reverse diastolic dysfunction in old mice in 10 weeks, highlighting its therapeutic potential for a poorly treatable condition. However, the mechanisms and temporal regulation of its cardiac benefits remain unclear. We show that improved diastolic function in old mice begins at 2-4 weeks, progressing over the course of 10-week treatment.
We showed that rapamycin inhibits canonical TORC1 and TORC2 downstream targets in old hearts throughout the course of 10 week treatment. However, its effects on induction of autophagy and mitochondrial biogenesis are more transient and take place within 2 weeks of treatment.
This transient induction of autophagy and mitochondrial biogenesis suggests that damaged mitochondria are replaced by newly synthesized ones to rejuvenate mitochondrial homeostasis. This remodeling is shown to rapidly reverse the age-related reduction in fatty acid oxidation to restore a more youthful substrate utilization and energetic profile in old isolated perfused hearts, and modulates the myocardial metabolome in vivo.
This acute remodeling reverses the age-related reduction in FA utilization and is associated with improved cardiac energy metabolism. These benefits persist throughout the course of treatment, and seem likely to mediate the observed improvements in cardiac function. As there is no present treatment for age-related diastolic failure, the results of this study provide novel insight for the design and implementation of new effective therapies.
Citation & Full Text
Chiao, Y.A., Kolwicz, S.C., Basisty, N., Gagnidze, A., Zhang, J., Gu, H., Djukovic, D., Beyer, R.P., Raftery, D., MacCoss, M., Tian, R., Rabinovitch, P.S., Rapamycin Transiently Induces Mitochondrial Remodeling to Reprogram Energy Metabolism in Old Hearts, Aging, 8:314-27, 2016. PMCID: PMC4789585