Lactate – the forgotten fuel!

A balance between energy supply and demand is essential for the viability of all cells but is particularly critical in the heart where energy demand is high and continuous. The maintenance of energy homeostasis is dependent on a continual supply of ADP, inorganic phosphate, oxygen and reducing equivalents in the form of NAD(P)H. The importance of sufficient oxygen delivery for maintenance of cardiac energy production is well established; however, the fact that this must be matched to NAD(P)H production is frequently overlooked. The principal source of NAD(P)H is from the metabolism of blood-borne carbon substrates. Some organs and tissues are able to use only a limited number of substrates for energy production; for example, the brain relies almost exclusively on glucose for oxidative ATP production. In contrast the heart is able to use a wide range of substrates for energy production, including glucose, fatty acids, ketone bodies, lactate and pyruvate. Despite this, the often stated view, which has changed little for many years, continues to be that the predominant fuels for cardiac energy production in vivo are long chain fatty acids and glucose (Neely & Morgan, 1974). In part this perception is sustained by the belief that glucose and fatty acids are the only substrates available in vivo. However, at rest circulating lactate concentrations are approximately 1 mm and during exercise can easily reach to 3–5 mm (Kemppainen et al. 2002). Even higher serum lactate concentrations may be seen after surgery. More than 20 years ago Drake et al. (1980) showed that the uptake of lactate by the heart in vivo is directly proportional to its serum concentration. We and others have shown in the isolated perfused heart, that lactate contributes significantly to acetyl-CoA formation often contributing more than glucose (Chatham et al. 1999). Despite the evidence that lactate may be an important fuel for myocardial energy metabolism, there is remarkably little information, either in vivo or in vitro, on the interactions between lactate and glucose utilization or lactate and fatty acid oxidation. This represents a significant gap in our knowledge of metabolic regulation in the heart, especially in light of recent interest in manipulation of cardiac metabolism as a potential therapeutic intervention. Evidence is accumulating to suggest that increasing myocardial carbohydrate utilization and decreasing fatty acid metabolism improve the outcome following myocardial ischaemia (Stanley et al. 1997). However, much of the experimental data used to support this mechanism are based on studies where glucose and fatty acids are the only substrates considered. Consequently, it is unclear whether the conclusions from such studies are relevant to in vivo conditions where lactate may be present in significant concentrations. In this issue of The Journal of Physiology Kemppainen et al. (2002) use positron emission tomography (PET) to quantify cardiac and skeletal muscle glucose uptake and phosphorylation in healthy human subjects at rest and at three different intensities of exercise. As expected they found that increasing exercise in skeletal muscle was associated with increased glucose metabolism. However, in the heart, although glucose uptake was slightly increased at low or moderate exercise levels, at the highest exercise level it was no different from rest. At rest and at the lowest exercise level there was a negative correlation between serum free fatty acid concentration and myocardial glucose uptake in accordance with the classic glucose-fatty acid cycle originally proposed by Randle et al. (1963). However, at moderate and high exercise levels this correlation disappeared; this was associated with a significant increase in serum lactate at these exercise intensities. They concluded that during high intensity exercise, substrates other than glucose, such as lactate, might contribute significantly to cardiac energy production. This conclusion was supported by a negative correlation between serum lactate levels and glucose uptake at moderate exercise intensity. An important issue that the work by Kemppainen et al. (2002) illustrates is that the regulation of substrate selection by the myocardium is a dynamic process. That is the contribution of different substrates to energy production will change depending on the physiological milieu. Whilst this may seem obvious, it should be put in the context that much of our knowledge of cardiac metabolism is based on the use of a limited range of substrate and hormone concentrations as well as limited mixtures of substrates. The use of only a single concentration of substrates may result in erroneous conclusions regarding the impact of a specific physiological or pathophysiological state on cardiac energy metabolism. For example, we found that cardiac fatty acid oxidation was markedly increased following diabetes, at low fatty acid concentrations compared with the non-diabetic group, but was significantly depressed at high concentrations (Chatham et al. 1999). The use of only a single fatty acid concentration would have resulted in an incomplete understanding on the effects of diabetes on cardiac fatty acid metabolism. This demonstrates the importance of using of a range of substrate concentrations to characterize the metabolic phenotype of the heart. There are some limitations with the study by Kemppainen et al. (2002) that should be noted. For example, the measurement of 2-[18 F]fluoro-2-deoxy-d-glucose uptake by PET reflects the uptake and phosphorylation of glucose by the heart, but not necessarily glucose oxidation. Furthermore there are no measurements of lactate metabolism by the heart. The use of 14 C- or 13 C-labelled lactate and glucose would provide a quantitative measure of substrate oxidation. Such methods are routinely used in isolated heart preparations and have also been performed in human subjects (Gertz et al. 1988). However, in humans this requires cardiac catheterization, which is clearly invasive and associated with substantially increased risk compared with PET. Despite these limitations, the study by Kemppainen et al. (2002) is an important reminder that lactate, primarily considered a metabolic waste product and typically ignored as a potential fuel, may be an important substrate for cardiac energy metabolism in vivo.