Muscle-Liver Substrate Fluxes in Exercising Humans and Potential Effects on Hepatic Metabolism

Abstract

Abstract Context The liver is crucial to maintain energy homeostasis during exercise. Skeletal muscle-derived metabolites can contribute to the regulation of hepatic metabolism. Objective We aim to elucidate which metabolites are released from the working muscles and taken up by the liver in exercising humans and their potential influence on hepatic function. Methods In two separate studies, young healthy men fasted overnight and then performed an acute bout of exercise. Arterial-to-venous differences of metabolites over the hepato-splanchnic bed and over the exercising and resting leg were investigated by capillary electrophoresis- and liquid chromatography-mass spectrometry metabolomics platforms. Liver transcriptome data of exercising mice were analyzed by pathway analysis to find a potential overlap between exercise-regulated metabolites and activators of hepatic transcription. Results During exercise, hepatic O2 uptake and CO2 delivery were increased two-fold. In contrast to all other free fatty acids (FFA), those FFA with 18 or more carbon atoms and a high degree of saturation showed a constant release in the liver vein and only minor changes by exercise. FFA 6:0 and 8:0 were released from the working leg and taken up by the hepato-splanchnic bed. Succinate and malate showed a pronounced hepatic uptake during exercise and were also released from the exercising leg. The transcriptional response in the liver of exercising mice indicates the activation of HIF-, NRF2-, and cAMP-dependent gene transcription. These pathways can also be activated by succinate. Conclusion Metabolites circulate between working muscles and the liver and may support the metabolic adaption to exercise by acting both as substrates and as signaling molecules.