β-Hydroxybutyrate Increases Exercise Capacity Associated with Changes in Mitochondrial Function in Skeletal Muscle.

Matías Monsalves-Alvarez,Mauricio Castro-Sepulveda,Sergio Lavandero,Mario Chiong,Verónica Eisner,Juan Manuel Rodriguez,Pablo Esteban Morales,Rodrigo Troncoso,Carlos Sepulveda

doi:10.3390/nu12071930

Abstract

β-hydroxybutyrate is the main ketone body generated by the liver under starvation. Under these conditions, it can sustain ATP levels by its oxidation in mitochondria. As mitochondria can modify its shape and function under different nutritional challenges, we study the chronic effects of β-hydroxybutyrate supplementation on mitochondrial morphology and function, and its relation to exercise capacity. Male C57BL/6 mice were supplemented with β-hydroxybutyrate mineral salt (3.2%) or control (CT, NaCl/KCl) for six weeks and submitted to a weekly exercise performance test. We found an increase in distance, maximal speed, and time to exhaustion at two weeks of supplementation. Fatty acid metabolism and OXPHOS subunit proteins declined at two weeks in soleus but not in tibialis anterior muscles. Oxygen consumption rate on permeabilized fibers indicated a decrease in the presence of pyruvate in the short-term treatment. Both the tibialis anterior and soleus showed decreased levels of Mitofusin 2, while electron microscopy assessment revealed a significant reduction in mitochondrial cristae shape in the tibialis anterior, while a reduction in the mitochondrial number was observed only in soleus. These results suggest that short, but not long-term, β-hydroxybutyrate supplementation increases exercise capacity, associated with modifications in mitochondrial morphology and function in mouse skeletal muscle.

Highlights

Ketone bodies (KB) are lipid-derived molecules produced by the liver under starvation as an alternative energy substrate for the brain, heart, and skeletal muscle (SkM) [1]
We showed that β-HB supplementation can induce an improvement in exercise capacity and grip strength and that these enhancements are associated with changes in mitochondrial morphology and function
Our results showed that β-HB supplementation had no impact on body weight or caloric intake during the whole experimental protocol, despite transiently reducing food intake in week two, which was corrected by the calorie intake of the supplement

Summary

Introduction

Ketone bodies (KB) are lipid-derived molecules produced by the liver under starvation as an alternative energy substrate for the brain, heart, and skeletal muscle (SkM) [1]. Β-HB has been shown to reduce oxidative stress [5,6,7], inflammation [8,9,10], and protein degradation [11], while improving cardiac efficiency by increasing myocardial blood flow and heart rate in humans [12,13,14]. Cox et al, showed that the acute ingestion of a ketone ester (d-β-hydroxybutyrate-r, 1, 3-butanediol monoester) improved endurance capacity by 2% in highly trained cyclists [23]. Athletes receiving the supplementation showed glycogen preservation and an increase in intramyocellular lipid utilization after an endurance time trial test, suggesting the role of acute nutritional ketosis in metabolism preference during exercise [24]. Acute β-HB supplementation impairs high-intensity performance despite an increase in fatty acid oxidation [25], suggesting that the type of exercise must be considered when the supplementation is considered

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