Regulation of Energy Metabolism of the Heart during Acute Increase in Heart Work

Abstract

We determined the contribution of all major energy substrates (glucose, glycogen, lactate, oleate, and triglycerides) during an acute increase in heart work (1 microM epinephrine, afterload increased by 40%) and the involvement of key regulatory enzymes, using isolated working rat hearts exhibiting physiologic values for contractile performance and oxygen consumption. We accounted for oxygen consumption quantitatively from the rates of substrate oxidation, measured on a minute-to-minute basis. Total beta-oxidation (but not exogenous oleate oxidation) was increased by the work jump, consistent with a decrease in the level of malonyl-CoA. Glycogen and lactate were important buffers for carbon substrate when heart work was acutely increased. Three mechanisms contributed to high respiration from glycogen: 1) carbohydrate oxidation was increased selectively; 2) stimulation of glucose oxidation was delayed at glucose uptake; and 3) glycogen-derived pyruvate behaved differently from pyruvate derived from extracellular glucose. Despite delayed activation of pyruvate dehydrogenase relative to phosphorylase, glycogen-derived pyruvate was more tightly coupled to oxidation. Also, glycogen-derived lactate plus pyruvate contributed to an increase in the relative efflux of lactate versus pyruvate, thereby regulating the redox. Glycogen synthesis resulted from activation of glycogen synthase late in the protocol but was timed to minimize futile cycling, since phosphorylase a became inhibited by high intracellular glucose.