Setmelanotide Administration Improves Cardiac Systolic Function in Sirtuin-3 Deficient Mice

Abstract

We previously showed that activation of the brain leptin-melanocortin system, particularly melanocortin-4 receptors (MC4R), markedly improves cardiac function in experimental models of heart failure (HF) via mechanisms that are still poorly understood. Sirtuin 3 (Sirt3) is an important regulator of mitochondrial oxidative phosphorylation and deficiency of Sirt3 has been implicated in cardiovascular diseases. We recently found increased Sirt3 expression as well as increased levels of NAD+, the main Sirt3 activator, in cardiomyocytes of rats treated with chronic intracerebroventricular infusion of leptin at a dose that does not spill over into the systemic circulation. Therefore, we hypothesized that stimulation of Sirt3 activity is required for the improvement of cardiac function during activation of the brain leptin-MC4R axis. To test this hypothesis, we first examined if chronic MC4R activation, using an MC4R agonist, setmelanotide, improves cardiac function in naïve Sirt3-deficient (Sirt3-KO) mice. Baseline cardiac function was assessed by echocardiography (VisualSonics-VEVO3100®) in male and female Sirt3-KO and wild-type (WT) control mice (n=5/group) at 20 weeks of age, and then weekly during setmelanotide treatment (2 mg/kg/day — i.p. via osmotic minipump model 1002) for 3 weeks. Chronic MC4R activation with setmelanotide transiently reduced food intake in both groups and promoted weight loss in Sirt3-KO mice. Setmelanotide treatment improved systolic function in WT mice as evidenced by increases in ejection fraction and fractional shortening (EF: 52.8±4.4 vs. 72.4±4.4%; FS: 26.9±2.7 vs. 42.8±6.4%, for baseline vs. week 3, respectively) and other measures of systolic function including circumferential and longitudinal strains. Despite showing a tendency for reduced systolic function compared to WT controls at baseline, Sirt3-KO mice also exhibited improvement in systolic function with setmelanotide administration (EF: 44.1±1.8 vs. 65.3±2.9% and FS: 21.4±1.0 vs. 35.1±2.1%). No major changes were observed in measures of diastolic function. These results suggest that in a non-HF model, MC4R activation does not require stimulation of Sirt3 to improve indices of systolic function. (1R01HL163076, 1R01DK121411, P20GM104357, P30GM149404, U54GM115428, and AHA-835218). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.