Mitochondria and Metabolism Journal Club – Presented by Lauren Abell – October 2016
Nutritional ketosis alters fuel preference and thereby endurance performance in athletes. By Cox et al. Cell Metabolism, Aug 2016

Ketone Supplementation: Does it promote physical activity?
This study by Cox et al. demonstrates the metabolic benefit of ketone metabolism through the supplementation of a ketone ester-based drink to athletes during exercise. Through the use of five exercise studies, they characterize the metabolic alterations achieved through acute nutritional ketosis. This paper concludes that high levels of ketone bodies can improve human physical performance through altering substrate preference in skeletal muscle during exercise.

Metabolic shifts caused by substrate availability
Exercise metabolism: The Crossover Concept describes the metabolic response to high intensity or endurance exercise. As exercise intensity/duration increases, mitochondrial oxidation of fatty acids reaches an energetic ceiling and muscle substrate preference shifts over to carbohydrate oxidation.

Starvation metabolism: During early periods of prolonged fasting the brain will continue to use glucose generated from glycogen stores while other tissues will primarily burn fatty acids as their metabolic fuel. As glucose levels fall over time, the body will begin producing ketone bodies from fatty acid oxidation in order to fuel the brain.

Ketone metabolism: Ketone metabolism is a shift in substrate preference from glucose to ketone bodies stimulated by prolonged starvation, fasting, or in diabetes, when the brain is unable to receive enough glucose to function. Decreased glucose availability decreases downstream TCA cycle intermediates, impeding entry of acetyl-CoA into the TCA cycle and promoting formation of the three ketone bodies – acetone, acetoacetate and β-hydroxybutyrate – which can be utilized by the brain for fuel.

Does supplementation promote metabolic efficiency?
Cox et al. found that high levels of circulating ketone bodies in high-performance athletes promote substrate competition for respiration during exercise. Throughout the five exercise studies the authors found reduced pyruvate utilization and glycolysis with conservation of glycogen stores paired with increased fat oxidation and promotion of triglyceride consumption. The authors conclude that high levels of ketone bodies prevented the metabolic crossover that occurs during exercise, increasing physical capacity in elite-athletes by removing glycogen exhaustion as a limiting factor for endurance exercise and promoting fatty acid oxidation as a fuel source.

Ketone supplementation: The next big fad?
The final study performed by Cox et al. tested the effect of nutritional ketosis on peak exercise performance by having athletes perform 60 minutes of high intensity cycling exercise followed by a 30 minute timed trial where total cycling distance was recorded. Criticisms of this trial arose due to its deviations from normal exercise capacity tests. One consideration is that a decreased reliance on glycolysis in the skeletal muscle can be detrimental to performance in high intensity sprinting exercise. This, paired with the author’s affiliation with a company specializing in the development and commercialization of ketone-based exercise supplements, raises skepticism that these promising results may not be reproducible in humans with average physical activity across a range of exercise trials.