Switching metabolic genes to build a better heart.

Abstract

The heart makes its living by liberating energy from a variety of oxidizable substrates, either simultaneously or vicariously.1 Because of built-in mechanisms that choose the most efficient substrate for a given physiological environment, the heart is a true metabolic omnivore.2 The link between metabolism and function of the heart was discovered by Langendorff3 when he demonstrated that the mammalian heart receives oxygen and nutrients through the coronary circulation and not through the endocardium, as it had been assumed until then. Early investigators also knew already that the heart oxidizes fatty acids and glucose,4 and myocardial fuel economy became a focus of biochemical investigation in the 1960s. Biochemists “discovered” the heart as a convenient bag of enzymes to study muscle metabolism and found that fatty acids suppress glucose oxidation, chiefly at the level of the pyruvate dehydrogenase complex.5 Conversely, we later found that glucose suppresses fatty acid oxidation,1 chiefly at the level of fatty acid entry into the mitochondria. In short, fuel metabolism in the heart is highly regulated, allowing the heart to respond to substrate availability, circulating hormones (such as insulin or catecholamines), coronary flow, and workload by choosing the “right” substrate at the right moment. Unless blood supply is curtailed, as it is the case in ischemia, the heart is never short of fuel to burn. See p 2125 What is, then, the principle that underlies substrate switching? As every nutritionist knows, fat has a higher caloric value than carbohydrates; at the same time, the oxidation of carbohydrates results in more efficient energy production than the oxidation of fat. The heart readily oxidizes both substances. Substrate switching in the heart is determined by an interaction of control and regulation of the metabolism of energy providing substrates. According to the metabolic control theory,6 …