Abstract 647: Uncoupling Protein 3 Does Not Regulate Myocardial Fatty Acid Oxidation Rates But Regulates ROS Production and Cardiac Efficiency

Abstract

The biological functions of uncoupling protein 3 (UCP3) in cardiac muscle are incompletely understood. These studies were designed to investigate the role of UCP3 in cardiac muscle energy metabolism under normal and high fat diet (HFD) conditions. Mice lacking UCP 3 (UCP3KO) and wildtype (WT) littermate controls were fed normal chow (NC) or HFD for 10 weeks. Palmitate oxidation rates (POX), myocardial oxygen consumption (MVO2), cardiac efficiency (CE) and cardiac power were determined in isolated working hearts perfused with 5mM glucose and 0.4mM palmitate. Mitochondrial respiration and ATP synthesis were determined in saponin-permeabilized cardiac fibers. ROS levels were determined using the dye dichlofluorescein (DCF). HFD increased UCP3 protein levels by 2-fold in WT (p<0.005). On NC, POX rates were similar between UCP3KO and WT and increased similarly with HFD to 726.5 ± 41.8 and 731.7 ± 7.1 nmol/min/mg DHW, respectively. MVO2 increased by 21% in WT on HF (P < 0.05) but did not increase in HFD UCP3KO. On the HFD, cardiac efficiency (16.3±1.9 vs. 20.4±1.2) and cardiac power (38.1±1.5 vs.45.8±2.6, mW/g) were lower in WT vs. UCP3KO (p<0.05). Mitochondrial state 3 respirations were similar in WT and UCP3KO under NC or HFD conditions. However, ATP synthesis rates were 28% higher in HF UCP3KO vs. HF WT. HFD increased ROS generation by 49% (P < 0.005) in WT hearts. However, ROS generation increased to a greater extent in UCP3KO on HF when compared to WT on HF (212.1 ± 16.2 versus 177.8 ± 9.1, P < 0.05). Thus the efficiency of ATP production was increased in UCP3KO hearts despite higher levels of ROS. In conclusion, UCP3 mediates the increase in MVO2 that accompanies HF feeding without influencing the increase in FA Oxidation. UCP3 limits FA-induced ROS accumulation, by reducing membrane potential and mitochondrial ATP generation and regulates the efficiency of ATP generation in the heart.