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Although pre-clinical evidence has suggested that partial inhibition of myocardial fatty acid oxidation (FAO) and subsequent switch to greater glucose oxidation for ATP production can prevent ischemia/reperfusion injury, controversy about this approach persists. For example, mice with germline deletion of the FA transporter CD36, exhibited either impaired or unchanged post-ischemic functional recovery despite a 40–60% reduction in FAO rates. Because there are limitations to cardiac studies utilizing whole body CD36 knockout (totalCD36KO) mice, we have now generated an inducible and cardiomyocyte-specific CD36 KO (icCD36KO) mouse to better address the role of cardiomyocyte CD36 and its regulation of FAO and post-ischemic functional recovery. Four to six weeks following CD36 ablation, hearts from icCD36KO mice had significantly decreased FA uptake compared to controls, which was paralleled by significant reductions in intramyocardial triacylglycerol content. Analysis of cardiac energy metabolism using ex vivo working heart perfusions showed that reduced FAO rates were compensated by enhanced glucose oxidation in the hearts from icCD36KO mice. In contrast to the totalCD36KO mice, hearts from icCD36KO mice exhibited significantly improved functional recovery following ischemia/reperfusion (18 min of global no-flow ischemia followed by 40 min of aerobic reperfusion). This improved recovery was associated with lower calculated proton production prior to and following ischemia compared to controls. Moreover, the amount of ATP generated relative to cardiac work was significantly lower in the hearts from icCD36KO mice compared to controls, indicating significantly increased cardiac efficiency in the hearts from icCD36KO mice. These data provide genetic evidence that reduced FAO as a result of diminished CD36-mediated FA uptake improves post-ischemic cardiac efficiency and functional recovery. As such, targeting cardiomyocyte FA uptake and FAO via inhibition of CD36 in the adult myocardium may provide therapeutic benefit during ischemia–reperfusion.

Myocardial triacylglycerol (TAG) constitutes a highly dynamic fatty acid (FA) storage pool that can be used for an energy reserve in the cardiomyocyte. However, derangements in myocardial TAG metabolism and accumulation are commonly associated with cardiac disease, suggesting an important role of intramyocardial TAG turnover in the regulation of cardiac function. In cardiomyocytes, TAG is synthesized by acyltransferases and phosphatases at the sarcoplasmic reticulum and mitochondrial membrane and then packaged into cytosolic lipid droplets for temporary storage or into lipoproteins for secretion. A complex interplay among lipases, lipase regulatory proteins, and lipid droplet scaffold proteins leads to the controlled release of FAs from the cardiac TAG pool for subsequent mitochondrial β-oxidation and energy production. With the identification and characterization of proteins involved in myocardial TAG metabolism as well as the identification of the importance of cardiac TAG turnover, it is now evident that adequate regulation of myocardial TAG metabolism is critical for both cardiac energy metabolism and function. In this article, we review the current understanding of myocardial TAG metabolism and discuss the potential role of myocardial TAG turnover in cardiac health and disease. This article is part of a Special Issue entitled "Focus on Cardiac Metabolism".