Abstract 17088: Pharmacological SERCA Activation Shifts Cardiac Fuel Preference Without Impairing Function in Obese Mice

Abstract

Introduction: Prior studies suggest that restoring Ca 2+ homeostasis by activating SERCA improves liver health and metabolism in a mouse model of metabolic syndrome. We were interested to know if these benefits extended to the heart. Here, we test the impact of pharmacological SERCA activation by CDN1163 on heart metabolism. We modeled data from in vivo 13 C tracer experiments to determine cardiac metabolic fluxes in obese mice at the end of an 8-week CDN1163 treatment period. Flux measurements were combined with echocardiography data to assess the effects of SERCA activation on heart function and metabolism. Methods: All mice in the study were hyperphagic Mc4r -/- mice. We studied three groups of Mc4r -/- mice at 16 weeks of age (n≥6 per group): mice fed a chow diet (Chow) or those switched to a western diet at 8 weeks of age (WD) ± CDN1163 (3 injections per week). Stable and radio-labeled isotopes were infused and blood was sampled from unrestrained, conscious mice through jugular vein and carotid artery catheters, respectively. Fluxes were estimated by fitting a mathematical model of liver and cardiac metabolism to 13 C enrichment measurements of plasma and tissue metabolites taken at the end of the infusion. A separate cohort of mice was used for echocardiography and gene expression analysis. Results: We found that WD increased absolute cardiac glycolytic, anaplerotic, and citric acid cycle (CAC) fluxes (~2-fold; p<0.05). In contrast, CDN1163 treatment decreased these fluxes compared to both Chow and WD (~2-3-fold; p<0.05). Additionally, the pyruvate partitioning between pyruvate carboxylase (PC) and pyruvate dehydrogenase (PDH) favored PDH with WD feeding (~2-fold), concurring with increased glycolysis. However, in WD+CDN1163 mice, pyruvate partitioning was restored to the Chow phenotype, favoring PC (p<0.05 WD vs. WD+CDN11163), suggesting decreased reliance on glucose for the generation of acetyl CoA for the CAC. These metabolic shifts occurred without changes in cardiac function or compensatory structural remodeling of the left ventricle. Conclusions: CDN1163 treatment changes metabolic fluxes in the hearts of obese mice. These metabolic changes do not impact heart function.