Do Exogenous Ketones Fuel Exercising Skeletal Muscle?

The contents of one’s diet undoubtedly affect one’s capacity to exercise. Appreciation of this has led to huge volumes of research investigating the amounts and timings of carbohydrates, fat, and protein that should be consumed to optimize exercise performance across a variety of intensities. Until relatively recently, the effect of consuming ketone bodies, as opposed to inducing an endogenous ketosis through the adoption of a ketogenic diet, had not been considered.

Previously, our group reported that acutely supplementing athletes with a ketone drink (exogenous ketones) may enhance endurance exercise capacity. The proposed mechanisms were twofold. First, ketones may provide a novel substrate for exercising skeletal muscle that, unlike fat, might support oxidative phosphorylation at high exercise intensities (>70% maximal oxygen uptake). Using calculations based on measured respiratory gases, we estimated that exogenous ketones contribute approximately 15% to overall energy expenditure. However, further work was required to provide more accurate predictions. Second, through an array of metabolic signaling actions, ketones may spare intramuscular glycogen catabolism (a finite fuel) and increase intramuscular lipid catabolism (an abundant fuel).

In this study, published in the March 2021 issue of Medicine & Science in Sports & Exercise®, we aimed to provide better estimates for the contribution of ketones to overall energy expenditure during exercise. Furthermore, we sought to understand whether this contribution changed depending on the intensity of exercise or the concentration of ketones in the blood (i.e., their availability to exercising muscles). To this end, we asked highly trained athletes to undertake cycle-ergometer exercises at light (25% maximal watts), moderate (50% maximal watts), and high (75% maximal watts) intensities on three occasions. Before exercise, the athletes consumed either a high-dose ketone drink, a low-dose ketone drink, or a control drink (a 3×3 factorial, randomized-order design). The ketone drink was enriched with 13C. By collecting respiratory gas samples, we could estimate exogenous ketone oxidation rates by measuring the appearance of the 13C label in the breath.

Our main finding was that ketones contributed minimally (approximately 2.5% to 4.5%) to overall energy production, regardless of the intensity of exercise. Furthermore, doubling blood ketone concentrations from 2 mM to 4.4 mM had no effect on ketone oxidation rates. Others have recently reported similar findings in isolated mitochondria.

It seems implausible that such a small contribution to overall energy expenditure might confer an increase in exercise capacity. As such, we posit that any ergogenic effects of acute ketone supplementation, which have not been confirmed, are most likely derived from alterations in carbohydrate and fat metabolism as described above or as a yet unidentified mechanism. This implies that ketone supplementation should be preserved for athletic events lasting over 60 minutes, where intramuscular glycogen availability is performance-limiting. Indeed, the ketone-mediated inhibition of glycolysis may, in fact, be detrimental to exercise performance during short, very high-intensity exercise. Work to determine whether a performance versus exercise duration threshold exists is underway.

About the author:
David Dearlove, DPhil, is a postdoctoral researcher at the University of Oxford, where he also earned his DPhil. Using exercise as a metabolic stressor, his work seeks to understand the effects of exogenously induced ketosis on human metabolism. Connect with Dr. Dearlove at 

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