Carbohydrate stored as glycogen in the myofiber is the main energetic substrate for muscle work during intense endurance exercise. Considering this fact, depletion of muscle glycogen stores accelerates fatigue onset during strenuous tasks.
Traditionally, carbohydrate loading has been viewed as
the best nutritional strategy before and during endurance exercise, in order to preserve muscle glycogen deposits and thus to prevent premature fatigue [1].
In recent years, ketone supplementation has been propagated as an alternative (or complementary) strategy that may potentially also boost endurance sports performance, yet through different metabolic pathways [2].
The professed ergogenic effect of ketone supplementation is attracting scientific [3] as well as mass media attention, with these supplements allegedly used by numerous elite endurance athletes.
Ketone bodies can be produced within your body or come from a synthetic, exogenous source outside your body.
Ketones found in supplements are exogenous ketones and only contain the beta-hydroxybutyrate ketone because the other primary ketone body, acetoacetate, is not chemically stable as a supplement.
There are two main forms of ketone supplements:
Biologically speaking, there is justification to support a potential ergogenic effect of ketone supplementation (see figure below).
Figure: Ketosis and ketones: effects on mitochondrial metabolism. D-βHB, D-β-hydroxybutyrate; TCA cycle, tricarboxylic acid cycle [7].
Ketone bodies (acetoacetate, acetone), as well as β-hydroxybutyrate (βHB) synthesized from acetoacetate (all 3 herein considered as ketone bodies for the sake of simplicity), are produced from fatty acids by the liver mitochondria during periods of energy deficiency [prolonged fasting, ketogenic (low-carbohydrate) diets, long-duration exercise] to replace glucose as the primary energy substrate for extra-hepatic tissues like the brain, heart, or
skeletal muscle [5].
Ketone bodies seem to inhibit glycolytic flux.
Therefore, the idea is that oral acute ketone supplementation before or during exercise (resulting in increased concentrations of ketone bodies in plasma) might represent an extra energy supply for muscle work, potentially sparing muscle glycogen stores [5].
Furthermore, ketone bodies would represent a more efficient energy substrate than glucose or fatty acids because the activation of ketone bodies into an oxidizable form does not require ATP [6], thereby enabling generation of more muscle work for a given energy cost.
Despite the alleged benefits of ketone supplements on sports performance the actual evidence is controversial.
A recent systematic review concluded that the results provided across studies are mixed and equivocal [8].
In addition, a recent meta-analysis concluded that acute (i.e., before or during an exercise bout) ketone supplementation seems to exert no consistent effects on exercise performance [9] although no information was provided regarding the effects on other important outcomes for sports such as cognitive performance or
post-exercise recovery.
Also, the effects of chronic ketone supplementation were not assessed.
Below I will summarize and discuss the evidence currently available on the physiological and exercise performance effects of both acute and chronic oral ketone supplementation on exercise performance in humans (as typically assessed in healthy, usually well-trained individuals). The potential
effects on cognitive performance during or after fatiguing exercise and on post-exercise muscle recovery will also be assessed.
A seminal study published in 2016 reported an improvement in simulated endurance bicycling performance with acute administration of ketone esters along with carbohydrates (dextrose) in trained athletes, as reflected by a slight (∼2%), albeit significant, increase in the total distance covered during a fixed time (i.e., 30 min) on a cycle ergometer compared with the administration of carbohydrates alone.
There is no doubt that this study contributed to the growing popularity of ketone supplements.
However, subsequent studies have failed to replicate performance benefits with acute ketone supplementation and some research reported decrements in performance. (see table below)
Studies using both ketone esters and salts at different dosages (e.g., 330 vs. 750 mg/kg of body weight) have failed to demonstrate beneficial effects on performance.
Moreover, some studies have reported no benefits on sports performance despite acute supplementation resulting in similar [∼3 mmol/L; range: 2.6 to 5.2 mmol/L] if not higher [3.7 mmol/L] plasma ketone concentration than that observed by that 2016 seminal study (∼2–3.5 mmol/L).
It's important to recognize that most studies have assessed performance using tests with a duration <60 min.
Although the glucose-sparing effect of ketone supplementation could be potentially beneficial for performance, ketones could also impair carbohydrate metabolism and consequently reduce performance during intense endurance exercise, which relies mostly on muscle glycolytic flux for rapid provision of energy.
Indeed, muscle glycogen–derived ATP plays an important role in cellular functions whose failure might accelerate onset of fatigue, notably calcium handling by the sarcoplasmic reticulum [10].
In support of this, other strategies with the intent of reducing reliance on muscle glycogen during exercise (e.g.,
low-carbohydrate, high-fat diets) have failed to provide clear benefits on competitive performance, and might reduce the capacity to sustain high-intensity exercise.
A mechanistic insight on the importance of muscle glycogen for intense endurance exercise performance can be demonstrated through McArdle's disease (glycogenosis type V).
This condition is a myopathy caused by an inherited deficiency of the skeletal‐muscle isoform of glycogen phosphorylase, “myophosphorylase.”
Because this enzyme catalyzes the breakdown of glycogen into glucose 1‐phosphate in muscle fibers, patients are unable to obtain energy from their muscle glycogen stores and show very poor aerobic capacity [11] and extremely low muscle efficiency during endurance exercise [12].
Cognitive performance is critical in some sports, particularly in those where the ability to make fast decisions can influence performance (e.g., team, combat, or racquet sports). Glucose is the preferred energy source for the brain, but
strenuous exercise can reduce bloodborne glucose, thereby contributing to the development of “central fatigue” [13].
During periods of prolonged starvation, ketones can substitute glucose as the main energy source for the brain, thereby preventing cognitive impairment [14].
Ketone bodies can cross the blood–brain barrier, stimulate acetylation of histones at the brain-derived neurotrophic factor (Bdnf) gene promoters, and stimulate the production of hippocampal BDNF, a neurotrophin that is crucial for brain plasticity and regulation of cognitive function [15].
Under this context, it has been proposed that ketone supplements might reduce brain reliance on glucose, increase BDNF production, and thus improve cognitive performance (or
attenuate cognitive impairment) during and after strenuous exercise.
Evidence on the effects of ketone supplements on cognitive function is, however, scarce, and mixed. Therefore, there is currently insufficient evidence indicating any positive effect of ketone supplements to improve cognitive performance in sports.
Ketone supplementation has been proposed to expedite recovery after exercise, which is paramount in multistage events (e.g., Tour de France). The administration of ketones together with carbohydrates after exercise can increase the conversion rate of glucose to glycogen, thus promoting muscle glycogen replenishment.
In addition, ketone bodies could potentially attenuate protein oxidation and thus favor muscle repair [5].
Despite these purported claims, the research data is very mixed.
Therefore, the evidence for the effectiveness of ketone supplements for the enhancement of post-exercise recovery is, therefore, still scarce, and inconclusive.
Despite a biological rationale for supporting a potential ergogenic effect of oral ketone supplementation, the current evidence to date shows no clear physiological or performance effects with acute supplementation, and the evidence for a potential benefit on cognition or post-exercise recovery is scarce and mixed (see figure below).
There is also very little evidence available on the effects of chronic supplementation, and more importantly, evidence is needed regarding the safety of the long-term use of ketone supplements.
Currently, there is insufficient evidence to support the effectiveness of ketone supplementation for performance enhancement in athletes.
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References:
1. Mata, F., et al., Carbohydrate Availability and Physical Performance: Physiological Overview and Practical Recommendations. Nutrients, 2019. 11(5).
2. Cox, P.J., et al., Nutritional Ketosis Alters Fuel Preference and Thereby Endurance Performance in Athletes. Cell Metab, 2016. 24(2): p. 256-68.
3. Pinckaers PJM , C.-V.T., Bailey D, van Loon LJC., Ketone bodies and exercise performance: the next magic bullet or merely hype? Sport Med., 2017. 47: p. 383-91.
4. Scott, J.M. and P.A. Deuster, Ketones and Human Performance. J Spec Oper Med. 17(2): p. 112-116.
5. Evans, M., K.E. Cogan, and B. Egan, Metabolism of ketone bodies during exercise and training: physiological basis for exogenous supplementation. J Physiol, 2017. 595(9): p. 2857-2871.
6. Puchalska, P. and P.A. Crawford, Multi-dimensional Roles of Ketone Bodies in Fuel Metabolism, Signaling, and Therapeutics. Cell Metab, 2017. 25(2): p. 262-284.
7. Valenzuela, P.L., et al., Perspective: Ketone Supplementation in Sports-Does It Work? Adv Nutr, 2021. 12(2): p. 305-315.
8. Margolis LM , O.F.K., Utility of ketone supplementation to enhance physical performance: a systematic review. . Adv Nutr, 2019. 11: p. 412–9.
9. Valenzuela PL , M.J., Castillo-García A, Lucia A. , Acute ketone supplementation and exercise performance: a systematic review and meta-analysis of randomized controlled trials. Int J Sport Physiol Perform., In press.
10. Ortenblad, N., H. Westerblad, and J. Nielsen, Muscle glycogen stores and fatigue. J Physiol, 2013. 591(18): p. 4405-13.
11. Santalla, A., et al., Genotypic and phenotypic features of all Spanish patients with McArdle disease: a 2016 update. BMC Genomics, 2017. 18(Suppl 8): p. 819.
12. Mate-Munoz, J.L., et al., Favorable responses to acute and chronic exercise in McArdle patients. Clin J Sport Med, 2007. 17(4): p. 297-303.
13. Meeusen, R. and B. Roelands, Fatigue: Is it all neurochemistry? Eur J Sport Sci, 2018. 18(1): p. 37-46.
14. Owen, O.E., et al., Brain metabolism during fasting. J Clin Invest, 1967. 46(10): p. 1589-95.
15. Sleiman, S.F., et al., Exercise promotes the expression of brain derived neurotrophic factor (BDNF) through the action of the ketone body beta-hydroxybutyrate. Elife, 2016. 5.
