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

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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.

Acetoacetate (AcAc) and β-hydroxybutyrate (βHB) are ketone bodies produced in hepatic mitochondria during conditions of reduced carbohydrate availability and serve as an alternative fuel source for peripheral tissues including skeletal muscle. Elevations in βHB can result from endogenous production i.e. ketogenesis, but also by ingestion of exogenous ketone supplements such as ketone salts or ketone esters. Ketogenesis from free fatty acids (FFA) involves sequential reactions of Ac-CoA acetyltransferase (ACAT), hydroxymethylglutaryl CoA synthase (HMGCS), and hydroxymethylglutary-CoA lyase (HMGCL). The end product of ketogenesis is AcAc, the majority of which is reduced to βHB by 3-hydroxybutyrate dehydrogenase (BDH) before entering the circulation. Upon uptake into peripheral tissues, βHB is oxidised to AcAc. Reactions of succinyl-CoA:3-oxoacid CoA transferase (OXCT) and ACAT ultimately produce acetyl CoA (Ac-CoA), which enters the TCA cycle for ATP synthesis. The metabolic actions of βHB include altered fuel selection during exercise through attenuating glycogen utilisation, lowering lactate production and increasing reliance on intramuscular triglyceride (IMTG). Additionally, βHB may regulate adaptive processes in skeletal muscle by acting as a signalling metabolite inhibiting histone deacetylases (HDAC), or through positive effects on muscle protein synthesis (MPS). Ketone ester supplements facilitate acute ingestion of βHB resulting in nutritional ketosis, which, through these mechanisms, may alter exercise metabolism, improve exercise performance, and influence recovery and the adaptive response to exercise.

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