Ketones To The Rescue

In desperate times, ketones come to the rescue. When carbohydrates are limited, glycogen stores deplete and the bodies levels of glucose begin to drop severely, there needs to be another source of energy at the ready. That rescue source of energy are ketones. When the body reaches an energy crisis, fatty acid mobilisation increases, combines with its good old friend Acetyl-CoA and boom, ketone bodies arise which can be utilised by the body for its energy needs. Although ketones are mostly seen as an emergency source of energy, there is now an emerging interest in the role of ketones in enhancing exercise performance. Now that seems like pretty interesting stuff!

Exercise Performance

During exercise, your bodies energy requirements increase massively. Your body is working overtime and so it’s going to need a lot more fuel to keep itself powered. Ok, so that was pretty obvious! But, what might not be so obvious is that your body requires different types of fuel, depending on the intensity of the exercise. As the intensity of exercise increases the body shifts its fuel preference from blood-borne fatty acids (and glucose) towards those of intramuscular triglycerides (IMTG) and glycogen. At moderate-to-high exercise intensities (<75% of maximal oxygen uptake, V02max), muscle glycogen is the main source of energy provision (Egan and Agostino, 2016). As a result of this shift in energy substrate preference by skeletal muscle during exercise, there have been many nutritional strategies applied in terms of trying to optimise carbohydrate provision before and during exercise in order to increase performance (Egan and Agostino, 2016)

In times of starvation, ketone bodies are produced in order to spare the last of the glucose reserves needed to fuel the brain. These ketone bodies can then be used to fuel the heart and skeletal muscle in times of low carbohydrate availability. It is this glucose sparing role of ketones that make it an extremely interesting player in enhancing exercise performance. Really, if you think about it, prolonged exercise is similar to starvation (just on a more rapid time scale). In both situations, carbohydrates become used up and the body starts to drive up its production of ketones in order to keep the body powering on and preserve remaining glucose reserves (Cox and Clarke, 2014). As observed in studies, carbohydrate content falls during exhaustive exercise and muscle fatty acid oxidation increases with a concomitant increase in blood ketone concentrations (Cox and Clarke, 2014).

What is interesting is that if the presence of ketones during prolonged exercise can shift energy preferences away from blood glucose and glycogen stores to ketone utilisation by skeletal muscle, this could spare vital intramuscular glucose to be used later on. Allowing athletes to perform longer. 

Ketosis For Enhanced Exercise Performance? (The Non-Over Sciencey Version!)

Exogenous ketone (KE) ingestion might play a role in increased exercise performance through metabolic alterations. These metabolic alterations are likely to include changes in substrate hierarchical preferences, reduction in glycolysis activity, an increase in intramuscular fat oxidation and changes in metabolic flexibility. As a result of all these changes, it’s likely that preferential use of ketones (during exogenous application), an increase in muscle glycogen sparing and, increased utilisation of intramuscular fats for fuel, would all contribute to significant physical activity performance improvements.

This has a significant advantage over simply trying to improve exercise through dietary-induced (low carbohydrate) ketosis. This is because in this method, glycogen stores and glucose must be severely depleted before ketosis fully kicks in. This depletion would likely negatively impact exercise performance, outweighing any potential benefits through ketosis itself. So if you think low-carbohydrate diets are great for exercise due to ketosis, then think again! There is actually no point trying to seize the benefits of ketosis for increased exercise performance if your glycogen stores are already depleted. That kind of defeats the point! 

Interestingly, KE ingestion might not be advantageous for anaerobic activities. Basically these are activities which require a fast, immediate energy source and so can tap into ATP production systems that don’t require oxygen. Here we are talking about anaerobic glycolysis (glucose in the absence of oxygen to produce ATP). Activities such as weight lifting will generally utilise anaerobic glycolysis due to the fact that your muscles become exhausted within a very short period of time, it therefore needs a quick source of energy. Since ketosis has been shown to restrict glycolysis, this might not  actually be optimal during anaerobic activities in which ATP needs to be produced in a short period of time through rapid anaerobic glycolytic activity. In this case, ketosis might actually cause a reduction in your performance! 

It would seem that ketosis is best suited in which incremental improvements in energy transaction and CHO preservation translate into increases in muscular endurance. For weight lifting, you might want to hold off on this now until further research is out! 

Still interested in knowing the science that backs this up? Keep reading below!

A Pioneer Study By Cox et al. (2016)

In this study, Cox et al looked at the effects of exogenous ketone administration in 39 high performance athletes on metabolic state. By metabolic state, I simply mean changes in how the body utilises different forms of energy during exercise and the resulting physiological changes that take place. This study is highly interesting as changes in metabolic states as a result of exogenous ketones, is likely to hold many clues into greater human potential with respect to exercise performance. 

•Experiment 1 (The Metabolic Effects Of Nutritional Substrate Alteration During Exercise)•

Each of the 39 athletes completed three experimental trials consisting of 1 hour of constant  load cycling (high-intensity at 75% Wmax) in a randomised, single-blind, cross-over design. Isocaloric drinks contained a minimum of 96% of their calories from the one substrate. Athletes were given a ketone ester (KE), carbohydrate (CHO) or fat (FAT) drink 15 minutes prior to the start of the exercise and 45 minutes into the 1 hour trial.


The athletes who ingested the KE drink, were found to display lower levels of lactate, plasma free fatty acids (FFA), glycerol and plasma glucose than those athletes that ingested the CHO or FAT drink, throughout the entire 1 hour exercise trial period.

In muscle biopsies to measure metabolites before and after exercise in skeletal muscle, intramuscular concentrations of KE and glucose were found to be higher in those athletes on KE after 1 hour of exercise in comparison to those that ingested CHO or FAT. 

Pre-exercise skeletal muscle concentrations of glycolytic intermediates (e.g. pyruvate) were significantly lower following KE consumption compared with CHO or FAT. Even following exercise the concentrations of these glycolytic intermediates were significantly lower in athletes following KE ingestion than those that ingested CHO or FAT. 

The sum of the glycolytic intermediates decreased proportionately as the concentration of intramuscular KE increased. 

During exercise, intramuscular leucine + isoleucine (amino acids) increased, but were 50% lower in athletes following ingestion of KE compared with CHO or FAT. 

Increasing intramuscular KE proportionately decreased intramuscular leucine + isoleucine and pyruvate. 

After 1 hour of high-intensity exercise on KE, free carnitine concentrations were lower and acetyl-carnitine and short-chain C3 carnitines were higher in comparison to athletes on CHO or FAT drinks. There was also a positive relationship between acetyl-carnitine/free carnitine ratio and KE concentration. Also, there was no change in TCA (The Citric Acid Cycle) intermediates following KE, CHO or FAT ingestion both at rest and following exercise.


The lower levels of plasma lactate, plasma glucose, glycolytic intermediates and higher levels of intramuscular glucose in athletes during the 1 hour exercise period following KE ingestion, suggests that KE might have some sort of sparing effect on intramuscular glucose stores. Probably through a suppressive effect on muscle glycolysis (conversion of glucose to pyruvate). The reduction in intramuscular branched chain amino acids following KE ingestion suggests that KE also limits skeletal muscle protein for gluconeogenesis (conversion of amino acids to glucose). 

The fact that glycolytic intermediates were reduced (e.g. pyruvate), acetyl-carnitine concentrations increased and TCA intermediates remained unchanged following KE ingestion, suggests that ketones were oxidised as an alternative to pyruvate, reducing the reliance on glycolysis to provide acetyl-CoA needed for the TCA cycle. 

The increase in acetyl-carnitine represents an increase in acetyl-CoA production from ketones. The increase in acetyl-CoA through ketosis could serve as an ‘inhibitory signal’ for glycolysis. This could account for the decrease in glycolytic intermediates (e.g. pyruvate) with KE ingestion. 

•Experiment 2 (The Effects Of Synergistic CHO And Ketone Delivery On Human Substrate Metabolism)•

Each of the 39 athletes completed three experimental trials consisting of 1 hour of constant load cycling at high-intensity (75% Wmax) in a randomised, single-blind, cross-over design. The metabolic effects of synergistic nutritional provision of KE and CHO combined during exercise were then measured. 


It was found following 1 hour of exercise at 75% Wmax, KE + CHO ingestion resulted in significantly higher intramuscular hexose concentrations compared with CHO alone. This increased intramuscular hexose reflected preserved intramuscular CHO stores. 

Free carnitine concentrations were significantly elevated after exercise for 60 minutes on CHO + KE in comparison with CHO alone. This is contrast to KE ingestion alone which resulted in lower free carnitine concentrations after exercise. 



The inhibition of glycolysis (and subsequently the reduction in glycolytic intermediates) in response to acetyl-CoA production through ketone oxidation could account for the increase in intramuscular CHO stores. 

The increase in free carnitine in the presence of CHO (with ketosis) could be due to the increase in oxidative ATP production efficiency through improvement in matching the TCA flux with acetyl-CoA supply. 

•Experiment 3 (The Effect Of Nutritional Ketosis On Intramuscular Fat And Glycogen Stores In Prolonged Exercise)•

This experiment was conducted to investigate changes of ketosis on intramuscular stores of FAT and glycogen during prolonged 2 hour exercise at 70% of VO2 max (maximal oxygen uptake). 


Plasma glucose concentrations were generally higher throughout the exercise period following ingestion of CHO alone in comparison with ingestion of CHO + KE together. 

Plasma FFA concentrations were significantly higher following ingestion of CHO alone after 2 hours of exercise in comparison with ingestion of CHO + KE together. 

The respiratory exchange ratios (ratio of carbon dioxide produced/oxygen used) were consistently lower for much of the 2 hour exercise period on CHO + KE versus CHO alone. 

Intramuscular triacylglycerol (IMTG) content (extent of red staining) fell by 24% after 2 hours of exercise at 70% of VO2 max following ingestion of CHO + KE in comparison with a 1% drop following ingestion of only CHO. 

Intramuscular glycogen content (as measured by the extent of dark staining) was significantly reduced following 2 hours of exercise on CHO in comparison to CHO + KE ingestion. 


The significant increase in oxidation of IMTGs occurs when KE is ingested in the presence of CHO. This occurred during highly glycolytic workloads and with increased concentrations of glucose and insulin (due to the CHO given with the KE). The increased oxidation of IMTGs by KE in the presence of CHO could power improvements in exercise capacity reducing the negative performance effects which could happen when glycogen reserves become depleted. 

•Experiment 4 (The Effect Of Nutritional Ketosis On Endurance Exercise Performance)•

This experiment was set up to investigate whether exercise performance could be altered by metabolic changes through CHO + KE provision. Athletes following an overnight fast, performed two blinded bicycle exercises trials consisting of 1 hour steady-state workload at 75% Wmax, followed by a 30 minute time trial for maximum distance. 


There were significant improvements in the CHO + KE group in time trial performance following 1 hour of high intensity exercise in comparison to CHO alone. Athletes cycled on average ~ 411m further over 30 minutes on CHO + KE versus CHO alone. 



The metabolic adaptations caused by KE ingestion with CHO (as seen in the previous studies above) seemed to cause an increase in physical capacity in these trained athletes as demonstrated by their ability to cycle further over 30 minutes during the time trial test.