Abstract 776: Increased Myocardial Glucose Oxidation in Fatty Acid Translocase (FAT/CD36) Deficient Mice Attenuates Age-dependent Decreases in Cardiac Performance
Fatty acids (FA) provide the majority of energy in the heart, and it is thought that a decrease in myocardial FA oxidation (FAO) contributes to cardiac dysfunction associated with aging. Paradoxically, however, switching energy substrate use from FAO to glucose oxidation (GOX) improves mechanical function in a number of pathological instances suggesting that this approach may be useful for the treatment of age-related decline in mechanical function. To address this we used young (10 –12 week old) and aged (52–54 week old) wild type (WT) and fatty acid translocase (FAT)/CD36 knockout (KO) mice. FAT/CD36 is a FA transport protein and young KO mice have a 50% reduction (p<0.01) in cardiac FAO whereas GOX is increased 2-fold (p<0.05) compared to young WT mice. While cardiac performance was not different in young WT and KO mice, Doppler and two-dimensional/ M-mode echocardiography and treadmill exercise suggested that aged WT mice had impaired cardiac performance compared to aged KO mice. To confirm this and to determine if alterations in cardiac energy metabolism were responsible for the direct effects of the age-dependent decline in function in the WT hearts, hearts from WT and KO young and aged mice were studied using the ex vivo perfused working heart model. As expected, cardiac power was significantly depressed in the aged WT hearts compared to young WT hearts (young WT vs. aged WT; 1.0 ± 0.2 vs. 1.9 ± 0.2, mWatts p<0.01). Surprisingly, however, cardiac power was maintained in aged KO hearts compared to their young counterparts and was significantly higher compared to aged WT hearts (aged KO vs. aged WT 1.8 ± 0.1 vs. 1.0 ± 0.1, mWatts, p<0.005). Although FAO was decreased 2.5-fold (p<0.005) in aged WT hearts compared to young WT hearts, FAO was not different compared to aged KO hearts, yet GOX was significantly elevated in aged KO hearts compared to aged WT hearts (aged KO vs. aged WT 1744 ± 550 vs. 228 ± 58 nmol/g dry weight/min, p<0.001). Therefore, increased GOX in the aged KO heart compared to the aged WT heart improves cardiac ATP supply and attenuates the age-dependent decrease in cardiac performance. This supports the concept that inhibiting FA uptake and oxidation and promoting GOX may be beneficial for the treatment of age-related decline in cardiac performance.