The Effect of Ketone Monoesters on Skeletal Muscle Protein Synthesis and Whole-body Protein Metabolism.

Overview

The ketone β-hydroxybutyrate (BHB) is endogenously produced during periods of low glucose availability, serving as an alternative metabolic fuel. Beyond its role as an energy substrate, BHB acts as a pleiotropic signalling molecule, modulating various physiological processes across multiple tissues. BHB can also be ingested orally as a ketone monoester, transiently elevating plasma concentrations of BHB to a level similar to those seen following several days of fasting, thereby obviating the need for dietary manipulation. The influence of BHB on human skeletal muscle protein metabolism remains poorly understood, although emerging evidence suggests that BHB may play a role in regulating muscle protein turnover. As such, BHB supplementation may support skeletal muscle remodelling and offer therapeutic benefits, and investigating this is of considerable interest. This study will investigate the ability of oral BHB ingestion - co-ingested with protein - to stimulate skeletal muscle anabolism in young healthy adults. A dual amino acid stable isotope tracer approach will be utilised to determine postprandial (i.e., fed state) muscle protein synthesis (MPS) rates and whole-body amino acid kinetics, given BHBs systemic effects. This research will advance our understanding of the fundamental biology of exogenous ketosis and provide insight into the potential of BHB supplementation as a novel nutritional strategy to optimise muscle mass and quality.

The ketone body β-hydroxybutyrate (BHB) is produced endogenously during periods of low glucose availability (e.g., fasting or starvation) and provides an alternative metabolic fuel. BHB also acts as a metabolic signalling molecule, modulating physiological processes across multiple tissues, including skeletal muscle. However, the impact of exogenous ketosis on muscle protein turnover, which regulates muscle mass and modulates physical function, remains largely unexplored. As such, understanding how BHB affects skeletal muscle protein turnover is fundamentally important. The ingestion of 0.5g/kg body mass BHB appreciably increases plasma BHB concentrations for several hours, to \~3-5 mM; equivalent to several days of fasting. This offers a model to exogenously elevate plasma BHB concentrations and investigate how BHB interacts with feeding to affect postprandial protein metabolism, the period primarily responsible for driving changes in muscle quality and quantity. An early study demonstrated that the infusion of BHB stimulates muscle protein synthesis rates (MPS), whilst only a single recent study has investigated the effect of oral BHB ingestion (exogenous ketosis) on MPS. Prior work demonstrated that the ingestion of an oral ketone monoester stimulated MPS, and it did so to a similar extent as 10 g whey protein or co-ingestion of the two, in healthy young males. While this study provides useful insights, several unanswered questions/objectives that justify the need for further investigation remain: * To determine how BHB ingestion influences myofibrillar protein synthesis, plasma amino acid concentrations, and amino acid kinetics following the co-ingestion of a physiologically relevant meal-like protein dose. * To examine how BHB ingestion affects plasma amino acid concentrations and kinetics following protein co-ingestion, addressing prior research limitations where differences in carbohydrate intake and postprandial insulin levels confounded the independent effects of ketones. * To assess the impact of BHB ingestion on whole-body protein metabolism following protein co-ingestion, as previous studies have not examined its potential influence on protein breakdown, amino acid kinetics, and net protein balance. * To investigate whether BHB ingestion influences mitochondrial muscle protein synthesis following protein co-ingestion, given its established effects on mitochondrial metabolism, yet unexamined role in mitochondrial protein turnover. The aim, therefore, is to establish the effect of BHB and protein co-ingestion on myofibrillar protein synthesis rates, mitochondrial protein synthesis rates, and whole-body protein turnover. We will address this question by utilising a meal-like bolus of protein (0.3 g/kg whey protein), with and without 0.5g/kg body mass BHB (matching the test drinks caloric content via the addition of fat to minimally stimulate insulin secretion), whilst applying a dual-stable isotope tracer approach.