In “The science!”, I discuss the scientific evidence available around a hot topic and present some recent exciting new studies in the field of sports nutrition and metabolism.
These discussions reflect my own understanding of a scientific topic and are not peer-reviewed scientific articles. If you think my views are wrong, I would be very grateful if you could yell at me in the comment section below or via the contact form. Because that’s what science is all about: discussing, making mistakes and constantly improving (and a bit of yelling at each other sometimes).
Sports physiology textbooks are very clear: during endurance exercise, the relevant fuels are carbohydrate (mostly from your muscle glycogen) and fat (mostly from your intramuscular triglycerides and plasma free fatty acids).
That was it… and for a long time…
And then, sports scientists started to talk about ketone bodies: a good old fuel that is produced during starvation and hence, seemed to be irrelevant for the field of sports energetics…
In this post, I’ll take you through the journey that brought ketone bodies from the status of useless sports fuel to the most trendy sports drink ever. This journey includes starvation, athletes running to the toilets and a touch of biochemistry. Still in? GREAT!
1. Ketone bo… what?
!!Biochemistry alert!!! (jump to the next paragraph if you have been traumatized at school by your biochemistry professor)
In a normal situation, glycolysis (via pyruvate) or the beta-oxidation of fatty acids lead to the production of acetyl-coA: the latter feeds the TCA aka Krebs cycle, which produces everything you need for the mitochondria to finish the work (produce ATP through the respiratory chain).
During starvation though (ie when carbohydrate availability is limited, insulin is low, glucagon is high, glycogen is exhausted), the liver converts some of its acetyl-coA into ketone bodies. These molecules are then released into the bloodstream and bear the great names of acetoacetate (AcAc), beta-hydroxybutyrate (we’ll say BHB), plus their breakdown products acetone.
Interestingly, the muscles, the brain and the heart are pretty good at taking up circulating ketone bodies and convert them back to acetyl-coA to oxidize them (which the liver can’t do because it lacks the converting enzyme).
Overall, ketone body metabolism is an organ crosstalk that, in the conditions of stringent energy deficit, provides an alternative, readily oxidizable substrate to the brain and peripheral organs. This has the double advantage to satisfy the energy requirements of these organs and to spare glucose reserves, two effects that will eventually prolong life.
!!!Biochemistry alert over!!! (traumatized people may read again)
2. Ketosis and the (difficult) relationship with exercise
So what does ketosis (high levels of ketone bodies in the plasma) have to do with exercise performance?
A/ Prolonged intense exercise stimulates ketone body production and post-exercise ketosis has been repetitively documented.
The exercise-induced ketosis, in some ways, resembles the starvation-induced ketosis: the progressive exhaustion of glycogen stores induces ketone body production, which in turn provides readily oxidizable substrates to the muscle and spares whatever is left from the glycogen. In other words, it can be seen as an evolutionary-relevant mechanism to prolong physical exercise. There is, however, ample evidence to suggest that an adequate nutrition strategy (CHO intake during exercise) positively impact endurance performance and endurance capacity while preventing or postponing exercise-induced ketosis.
B/ Dietary interventions, in the form of low carb high fat “ketogenic” diets, and their impact on performance, are debatable (that would be a whole other article).
In a nutshell, it is rather clear that low carbohydrate availability will negatively impact high intensity endurance performance. However, strategies that combine training in low carb conditions while competing with repleted glycogen seem to enhance submaximal exercise performance, via the upregulation of muscle fatty acid oxidation. Whether this is the result of the ketosis itself, or an adaptation to the high-fat content of the diet, remains unclear. The potential downside would be that a low carb diet reduces the capacity to oxidize carbohydrate, thereby limiting performance in a high glycolytic contexts (final sprinting, pace changes, hill running…). To summarize, a well-planned nutritional ketosis during training may positively impact submaximal exercise performance but it’s clearly not the magic bullet to improve endurance performance.
At this point, it’s clear that ketone bodies may be great oxidizable substrates for the muscles. But their main problem is that they are endogenously produced in a starvation-like context, which is not favorable to endurance performance. So, what about an exogenous source of ketone bodies? This should combine the best of both worlds (ketosis with high glucose stores)?
3. Drinking ketone bodies… not as easy as it sounds
To provide ketone bodies as an exogenous substrate for the muscles, you just need to drink it…
Yeah… no… not that easy…
First, there is an issue with the dose. We’re not talking about a bioactive compound in the microgram range here, but about an oxidizable substrate for the muscle. So, realistically, doses in the range of several hundreds of milligrams per kg are needed. For a 70 kg man, 500 mg/kg would mean that 35g should be given, for example, in a 500 mL drink. To compare with carbohydrates, you will find the same concentration of glucose in a typical sports drink (60-70 g/L).
In relation to that, there seems to be a problem with the taste of ketone bodies-based drinks. Although I haven’t tried myself, I keep reading blogs of self-experimenters describing the taste as “categorically horrible”, and close to what they “imagine jet fuel would taste” (these were BHB-monoesters and AcAc-diesters).
Moreover, gastrointestinal (GI) tolerance may be problematic when delivering ketone bodies at higher doses. Recent studies, however, report the production of ketone body esters that seem to partially resolve the taste and GI tolerance issues. (I say “seem” because the scientific article did not directly comment on palatability and still showed a great number of GI-related adverse events at higher doses – Clarke et al., 2012)
4. The impact of ketone esters on exercise metabolism and performance (new study!)
Recently, a study published in the prestigious journal Cell Metabolism (August 2016) provided the first solid evidence that ketone esters can indeed improve endurance performance.
At first, I saw that some of the authors actually are members of “UK sport” or orbiting around the Sky pro cycling team. Giving the time it takes to conduct a scientific study and to publish it in a high impact journal, team Sky and others probably had their first sips of ketone drinks 3-5 years ago.
And well … do you remember … rumors of drinks with ketone bodies on the TdF 2015, with Froome denying using ketones…
“I had to google it to find out what it was”, C. Froome
I find it hard to believe now. Maybe he didn’t use it but there were definitely Sky-related individuals involved in that scientific study in 2015. Anyway… back to science…
In the article, Cox and colleagues first studied the effect of ketone esters (provided as a drink) on plasma and muscle metabolites during a single short bout of cycling (45-60 minutes). The participants were given a ketone ester drink which, compared to an isocaloric carbohydrate drink, increased the plasma levels of ketone bodies and led to an increased oxidation of ketone bodies by the muscles during exercise. The authors estimated the contribution of ketone esters to 16-18% of O2 consumption during exercise at 40 to 70% Wmax.
Interestingly, in the muscle of the athletes that drank the ketone esters, glucose was spared during exercise via the reduction of glycolysis, which was also evidenced by a reduction in plasma lactate.
During a longer exercise bout (2h at 70% VO2max), the authors could also show that the two intramuscular forms of fuel storage were impacted by the ingestion of ketone esters. Indeed, after exercise, subjects that drank ketone esters had less intramuscular triglycerides and more glycogen left in their muscles.
Logically, the authors sought to test the effects of their new drinks on performance. They set up a protocol that included a 1 h steady state at 75% Wmax followed by a 30 min time trial (TT) on the bike. Ingestion of the ketone ester + CHO drink resulted in a 2% average increase in performance (around 400 m further) compared to CHO alone.
All of these impressive results were consistent with the ideas that:
a/ ketone esters can be oxidized at high levels by the muscles. The results presented here suggest that the oxidation of ketone bodies is prioritized over that of carbohydrates or fat, even at an exercise intensity that should be highly glycolytic. That is very interesting, because in a starvation state (with low glycogen), ketone oxidation by the muscle was consistently reported to be extremely low. So, the difference is that here, a high energy demand in the glycogen-repleted muscles coexists with high ketone body levels, leading to a high level of ketone bodies oxidation.
b/ beyond their own oxidation, ketone esters alter fuel selection, reducing glycolysis and (maybe) increasing fatty acid oxidation.
Because ketone bodies can be rapidly converted back to acetyl-coA, I would speculate that the changes in acetylcoA/coA ratio induced by ketone conversion probably is the molecular mechanism that inhibits glycolysis. In addition, because the acetyl-coA flux is provided rapidly by ketone bodies, this eases the reliance on pyruvate and restores fatty acid oxidation.
c/ these changes in muscle metabolism can enhance performance in a time trial cycling exercise bout. And that’s probably where the paper lacks a lot of speculations about the mechanisms. Here is what I think; after 1h of steady state at 75% Wmax, the muscle glycogen concentrations in the control group start to slightly drop sometimes in the middle of the 30 min time trial, whereas the ketone drinkers had a permanent supply of ketones to oxidize and therefore, relied less on their glycogen stores. Unfortunately, we don’t have the gas exchange during the time trial, but I would bet that, towards the end of it, the controls slowly started to switch to fatty acid oxidation, thus reducing their power output. In other words, I’m not sure that the effects on performance would still hold up if the time trial wasn’t preceeded by a glycogen-depleting steady state.
Conclusions and some thoughts
There are now several studies that shows it is possible to deliver ketone bodies at high doses using a ketone ester, and one study that shows the effect on muscle metabolism and performance. As good as the science is in these papers, there is still no large-scale evidence to recommend drinking ketone bodies while riding a bike. There is just not enough studies around to pinpoint with precision where the benefits might be, for which exercise modality and for which athlete populations (these were highly trained -pro?- cyclists). In addition, studies on the metabolic adaptations to a chronic exposure to ketone esters drinks would also need to be conducted.
The practical issues of taste or GI tolerance that are reported here and there will probably slow down the development of ketone drinks (at least by serious nutrition brands). But the drink used in the Cell metabolism study is supposed to be commercially available within the year, via an Oxford-university spinoff. I can’t wait to try… and report to you!
Finally, these drinks start to spread within the sports community; so the question whether it is doping or not doping will arise pretty fast. Indeed, like a lot of performance-enhancing drugs, ketone bodies are endogenous molecules, whose exogenous administration may increase performance (think about EPO or testosterone). It will be interesting to watch how antidoping agencies handle the issue. Stay tuned… The ketone debate is still on!