Cunha, P. L. O. | bioRxiv Science

bioRxiv2022

Effects of calorie restriction on reactive oxygen species production by mitochondrial reverse electron transport, mitochondrial permeability transition pore, and beta-adrenergic stimulation during cardiac hypertrophy

Calorie restriction is a nutritional intervention that reproducibly protects against the maladaptive consequences of cardiovascular diseases. Pathological cardiac hypertrophy leads to cellular growth, dysfunction (with mitochondrial dysregulation), and oxidative stress. The mechanisms behind the cardiovascular protective effects of calorie restriction are still under investigation. In this study, we addressed the impact of calorie restriction on mitochondria, oxidative stress markers, and {beta}-adrenergic signaling during cardiac hypertrophy. This dietetic intervention prevented cardiac protein elevation, decreased atrial natriuretic peptide levels, and blocked the increase in heart weight per tibia length index seen in isoproterenol-induced cardiac hypertrophy. Our data suggest that inhibition of cardiac pathological growth by calorie restriction is accompanied by a lower mitochondrial reactive oxygen species formation and improved mitochondrial content. We also found that superoxide dismutase and glutathione peroxidase activities negatively correlate with cardiac hypertrophy. Calorie restriction also attenuated the opening of the Ca2+-induced mitochondrial permeability transition pore in mitochondria isolated from isoproterenol-treated mice. Isoproterenol (a {beta}-agonist) increases cardiac rate (chronotropic response) and force of contraction (inotropic response). Given the nature of cardiac hypertrophy induction by isoproterenol, we tested whether calorie restriction could change the cardiac {beta}-adrenergic sensitivity. Using isolated rat hearts in a langendorff system, we found that calorie restriction mice (similar to controls) have preserved {beta}-adrenergic signaling. On the flipside, hypertrophic hearts (treated for seven days with isoproterenol) were insensitive to {beta}-adrenergic activation using isoproterenol (50 nM). Despite protecting against cardiac hypertrophy, calorie restriction did not alter the lack of responsiveness to isoproterenol of isolated hearts harvested from isoproterenol-treated rats. These results suggest (through a series of mitochondrial, oxidative stress, and cardiac hemodynamic studies) that calorie restriction possesses beneficial effects against hypertrophic cardiomyopathy. However, it may lack effects on some of the hypertrophic consequences, such as {beta}-adrenergic signaling repression.

biochemistry↗

bioRxiv2021

Calorie Restriction Maintains Mitochondrial Function and Redox Balance Avoiding Lipidomic Reprogramming during Isoproterenol-Induced Cardiac Hypertrophy

Cardiac hypertrophy induces a metabolic shift, leading to a preferential consumption of glucose (over fatty acids) to support the high energetic demand. Typically, health cardiac tissue utilizes more fat than any other organ. Calorie restriction is a dietary procedure that induces health benefits and lifespan extension in many organisms. Given the beneficial effects of calorie restriction and the metabolic dysregulation seen during cardiac hypertrophy, we hypothesized that calorie restriction prevents cardiac hypertrophy, lipid, mitochondrial, and redox dysregulations. Strikingly, calorie restriction reversed isoproterenol-induced cardiac hypertrophy, lowered succinate driven mitochondrial H2O2 production, improved mitochondrial function (indicated as a higher Respiratory Control Ratio - RCR) and avoided mitochondrial superoxide dismutase (MnSOD) and glutathione peroxidase (GPX) repression. To gain insight into how calorie restriction could interfere with the metabolic changes induced by cardiac hypertrophy, we performed lipidomic profiling. Calorie restriction protected against the consumption of several triglycerides (TG) linked to unsaturated fatty acids, and 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) that were also reversed by calorie restriction. Altogether, our data demonstrate that hypertrophy changes the cardiac lipidome, causes mitochondrial disturbances and oxidative stress. All these changes are prevented by calorie restriction intervention in vivo. This study uncovers calorie restriction as a resource protect cardiac tissue and prevent cardiac hypertrophy-induced lipidomic remodeling.

biochemistry↗