INVESTIGATION OF THE EFFECTS OF CALORIC RESTRICTION ON OXIDATIVE STRESS, MITOCHONDRIAL FUNCTION AND LIPIDOMA DURING ISOPROTERENOL-INDUCED CARDIAC HYPERTROPHY IN MICE
Lipidome. Mitochondrion. Reactive Oxygen Species. Antioxidants. Calorie Restriction
Healthy cardiac tissue utilizes more fat than any other organ. Studies indicate that cardiac hypertrophy induces a metabolic shift leading to a preferential consumption of glucose over fatty acids. Calorie restriction is a dietary procedure that induces health benefits and lifespan extension in many organisms. In this work, we raise the hypothesis that part of the beneficial effects of calorie restriction, is due to changes in lipid content, maintenance mitochondrial and redox function. these effects combined lead to the prevention of hypertrophy. Indeed, calorie restriction reversed isoproterenol-induced cardiac hypertrophy. Isolated mitochondria from hypertrophic hearts produced significantly higher levels of H2O2 production (when succinate was used without the presence of rotenone). this effect was blocked by calorie restriction. Concomitantly, cardiac hypertrophy lowered mitochondrial respiratory control ratios, and decreased superoxide dismutase and glutathione peroxidase levels. These effects were also prevented by calorie restriction. Using metabolomics techniques, we also studied cardiac lipid profiles to gain insights into how calorie restriction could interfere with the metabolic changes induced by cardiac hypertrophy. Calorie restriction protected against changes in several triglycerides (TGs) linked to unsaturated fatty acids. Also, this dietary procedure protected against the accumulation of TGs containing saturated fatty acids observed in hypertrophic samples. Cardiac hypertrophy induced an increase in ceramides, phosphoethanolamines, and acylcarnitines (12:0, 14:0, 16:0, and 18:0). These were all reversed by calorie restriction. Altogether, our data demonstrate that hypertrophy changes the cardiac lipidome, causes mitochondrial disturbances, and oxidative stress. These changes are prevented (at least partially) by calorie restriction intervention in vivo. This study uncovers the potential for calorie restriction to become a new therapeutic intervention against cardiac hypertrophy, and mechanisms in which it acts.