Metabolism of ketone bodies during exercise and training: physiological basis for exogenous supplementation

Abstract

Optimising training and performance through nutrition strategies is central to supporting elite sportspeople, much of which has focused on manipulating the relative intake of carbohydrate and fat and their contributions as fuels for energy provision. The ketone bodies, namely acetoacetate, acetone and β-hydroxybutyrate (βHB), are produced in the liver during conditions of reduced carbohydrate availability and serve as an alternative fuel source for peripheral tissues including brain, heart and skeletal muscle. Ketone bodies are oxidised as a fuel source during exercise, are markedly elevated during the post-exercise recovery period, and the ability to utilise ketone bodies is higher in exercise-trained skeletal muscle. The metabolic actions of ketone bodies can alter fuel selection through attenuating glucose utilisation in peripheral tissues, anti-lipolytic effects on adipose tissue, and attenuation of proteolysis in skeletal muscle. Moreover, ketone bodies can act as signalling metabolites, with βHB acting as an inhibitor of histone deacetylases, an important regulator of the adaptive response to exercise in skeletal muscle. Recent development of ketone esters facilitates acute ingestion of βHB that results in nutritional ketosis without necessitating restrictive dietary practices. Initial reports suggest this strategy alters the metabolic response to exercise and improves exercise performance, while other lines of evidence suggest roles in recovery from exercise. The present review focuses on the physiology of ketone bodies during and after exercise and in response to training, with specific interest in exploring the physiological basis for exogenous ketone supplementation and potential benefits for performance and recovery in athletes.

Keywords: acetoacetate; ketosis; performance; substrate; β-hydroxybutyrate.

© 2016 The Authors. The Journal of Physiology © 2016 The Physiological Society.

Figures

Figure 1. Changes in [βHB] under various physiological states

Plasma [KB] is m in the postprandial state when consuming high CHO or high protein meals, and rises upward after an overnight fast and with ketogenic dieting, prolonged fasting, starvation, and pathological states of ketoacidosis. After prolonged aerobic exercise, post‐exercise ketosis (0.3 to 2.0 mm) may ensue depending on intensity and duration of exercise, aerobic fitness and nutrition status. The circulating KB ratio of βHB:AcAc is generally ∼1:1 to 3:1, but during the aforementioned nutritional states can rise six‐ to tenfold, such that [KB] primarily reflects changes in [βHB]. An optimal concentration range for βHB to improve performance after exogenous ketone ingestion is proposed as ∼1 to 3 mm, with concentrations ranging from ∼1 to 5 mm reported after ketone ester (KE) ingestion. See text for further details.

Figure 2. Metabolic pathways of ketone body metabolism in liver and skeletal muscle

Ketogenesis: FFAs are converted to fatty acyl CoA (FA‐CoA), enter hepatic mitochondria via CPT1‐mediated transport and undergo β‐oxidation to acetyl CoA. Sequential reactions of condensation of Ac‐CoA molecules to acetoacetyl CoA (AcAc‐CoA) by mitochondrial thiolase activity of Ac‐CoA acetyltransferase (ACAT), generation of hydroxymethylglutaryl‐CoA (HMG‐CoA) by hydroxymethylglutaryl CoA synthase (HMGCS), and decomposition of HMG‐CoA, liberating AcAc and Ac‐CoA, in a reaction catalysed by HMG‐CoA lyase (HMGCL). AcAc is the central KB, and some will be exported to the circulation but the majority is reduced to βHB in an NAD+–NADH‐coupled near equilibrium reaction catalysed by BDH, in which the equilibrium constant favours βHB formation. Ketolysis: The only metabolic fate of βHB is inter‐conversion with AcAc, and upon entry into peripheral tissues it is re‐oxidised to AcAc. Covalent activation of AcAc by CoA is catalysed by succinyl‐CoA:3‐oxoacid CoA transferase (OXCT) resulting in generation of AcAc‐CoA. This near equilibrium reaction exchanges CoA between succinate and AcAc, with succinyl‐CoA acting as a CoA donor. Because the free energy released by hydrolysis of AcAc‐CoA is greater than that of succinyl‐CoA, the equilibrium of this reaction thermodynamically favours the formation of AcAc. Two molecules of Ac‐CoA are liberated by thiolytic cleavage of AcAc‐CoA by ACAT, after which Ac‐CoA is incorporated into the TCA cycle. Protein content and enzyme activity that are higher in exercise‐trained skeletal muscle are indicated by the green cross (+).

Figure 3. βHB as a metabolic regulator and signalling metabolite

Effects of elevating βHB through acute nutritional ketosis may be mediated by acute regulation of substrate utilisation that may enhance performance, and/or possibly through regulation of recovery and adaptive processes related to inflammation, oxidative stress and changes in gene expression. See text for further discussion. AT, adipose tissue; HDAC, histone deacetylase; IMTG, intramuscular triglyceride; MPS, muscle protein synthesis.