Rapamycin Relieves ER Stress and Improves Function in Hearts Subjected to High Workload

Abstract

Background When subjected to hemodynamic stress (HS), hearts increase their reliance upon glucose and activate pathways of cardiac growth such as the mTOR signaling pathway. Dysregulated mTOR activation is also known to causes endoplasmic reticulum (ER) stress. We have previously shown that with HS, glucose 6-phosphate (G6P) activates mTOR. We now explore whether G6P modulates ER stress and cardiac function with HS. Methods Hearts from 12-week-old male Sprague Dawley rats were perfused in the working mode with glucose (5mM) and subjected to an increase in workload after 7 day treatment with mTOR inhibitor rapamycin (4 mg/kg/day) or vehicle control. Cardiac power, rates of glucose uptake and oxidation, G6P levels, mTOR activation, and ER stress were assessed. Results Hearts from vehicle treated rats exhibited a 2-fold increase in glucose uptake and 1.5-fold increase in glucose oxidation, leading to G6P accumulation, mTOR activation, and ER stress. Rapamycin pretreatment blunted glucose uptake, depleted intracardiac G6P, inhibited mTOR, alleviated ER stress and improved cardiac function. Conclusion G6P accumulation correlates with mTOR activation and ER stress in hearts subjected to HS. By modulating the mismatch between glucose uptake and oxidation, rapamycin relieves ER stress and improves cardiac function in hearts subjected to high workload. This work was funded by the NIH.