Designed By Nature

A recent paper was published in which Timothy Noakes PhD reviewed current evidence on what sustains endurance and came to the conclusion it is not based on muscle fatigue but rather on something unknown that does involve the brain.

“What Is the Evidence That Dietary Macronutrient Composition Influences Exercise Performance? A Narrative Review” https://www.mdpi.com/2072-6643/14/4/862/htm

When you are exercising and in case of endurance for several hours, where is that movement coming from? These muscle twitches that sustain the activity are generated by electrical impulses coming from the brain, transferred through the nerves.

These electrical impulses require energy, more energy than when you are sedentary. This means that if the higher energy demand cannot be sustained, these electrical impulses will not be sustainable and result in a reduced capacity to twitch, thus lower power and therefor also reduced movement.

This blog is focusing on the brain but also keep in mind that in the muscle itself there are elements to induce fatigue so do not think fatigue is only about the brain.

Instead of repeating much of what is covered in the following article, I suggest you read it directly as it covered exactly the point of fatigue and brain glycogen levels.

“Endurance and Brain Glycogen: A Clue Toward Understanding Central Fatigue” https://link.springer.com/chapter/10.1007/978-3-030-27480-1_11

Brain glycogen is used as a source of lactate production in the brain to support the endurance activity.

Isoglycemic brain fatigue

I would like to add onto that paper because it suggests that blood glucose levels result in this ‘central’ fatigue while there is also evidence of this fatigue despite maintaining glucose levels which Noakes showed in his review.

In order for the brain to suffer in its capacity despite sufficient plasma glucose, the energy consumption must be higher than what the brain can get from circulation.

During endurance exercise, the brain increases its uptake of lactate from circulation depending on availability.

Looking at glucose, there is only a small difference in uptake.

But we have to be careful with interpretation. A better indication of what is going on is via the metabolic rate. Is the brain metabolizing more glucose? The following graph shows that there is no difference, no trend with changing arterial supply of glucose.

Looking at lactate, the increase from rest to exercise shows a 0.55 mmol difference.

And for lactate we do see a nice correlation between uptake and metabolism based upon supply.

“Cerebral glucose and lactate consumption during cerebral activation by physical activity in humans” https://faseb.onlinelibrary.wiley.com/doi/full/10.1096/fj.11-183822

What this shows us is that the additional energy requirement for endurance capacity is driven by lactate in the brain, not by glucose. That does not mean that glucose doesn’t contribute in the brain to lactate. It is possible that a proportion of it is converted to lactate through glycolysis but that proportion seems constant across resting and exercising conditions.

The effect of utilizing lactate is that it spares glucose.

“Lactate and glucose interactions during rest and exercise in men: effect of exogenous lactate infusion” https://physoc.onlinelibrary.wiley.com/doi/10.1113/jphysiol.2002.027128

This puts everything in a very different picture. The brain is happy with glucose but doesn’t consume more than needed and instead makes use of the available lactate. Happy or is it protecting itself from too much glucose? (see GLP-1)

Yet in order to have lactate available in circulation, the skeletal muscle are the source.

GLP-1

Glucagon-like-peptide 1 is a hormone that is secreted from the intestines. The effect of GLP-1 shows that it reduces glucose uptake in the brain. When we eat carbohydrates, the resulting excess glucose in the blood could potentially increase the supply to the brain but GLP-1 is preventing this. Again it seems that the brain requires a certain supply but will not make use of more than what is required.

“Glucagon-Like Peptide-1 Inhibits Blood-Brain Glucose Transfer in Humans” https://diabetesjournals.org/diabetes/article/57/2/325/13136/Glucagon-Like-Peptide-1-Inhibits-Blood-Brain

Back to our question on fatigue despite sufficient glucose in the blood… If lactate fuels endurance capacity in the brain then it is not surprising that adding carbs via ingestion to raise plasma glucose do not support the brain. However, the quantity ingested may even work detrimental as GLP-1 may reduce brain glucose uptake gradually leading to a brain energy shortage as the athlete continues to ingest glucose.

A plausible reason is that increased uptake of glucose and resulting metabolism is detrimental to heat production. This is likely also the reason why fatty acid metabolism is minimal in the brain. Heat itself works detrimental to performance, understandable given that the brain is protected by the skull which makes it more difficult to dissipate heat.

On the other hand, not ingesting glucose will reduce blood levels of glucose which also result in reduced glucose delivery to the brain. It is clear from our long and extensive sports research history that glucose ingestion is the more sustainable approach.

Yet make no mistake, trying to dissect the contribution of hypoglycemia from exercise-induced fatigue they found that although low systemic glucose lowers brain glycogen, levels are lowered more due to exercise in the cortex, hippocampus, and brainstem.

“Exhaustive endurance exercise activates brain glycogen breakdown and lactate production more than insulin-induced hypoglycemia” https://journals.physiology.org/doi/abs/10.1152/ajpregu.00119.2020?journalCode=ajpregu

Strategies

Keep in mind the above pieces of information. Not only does the brain generate and consume lactate from its own glycogen stores, on top it also consumes lactate from the circulation.

This is in balance with the movement force generated. Higher efforts generate more lactate, that lactate is used by the brain to support stimulation of higher efforts. But note that the brain is first so it always consumes more energy before it obtains more energy resulting in lowering glycogen levels over time.

This indicates that even if the circulation provides lactate, it will not be sufficient to sustain the activity for ever.

Glucose is constant and total brain lactate availability(from circulation and endogenous production) drops over time leading to energy shortage for electrical impulses. What can we do to delay this onset in shortage?

Perhaps first we need to understand why lactate is used. It is already evident from the above information but testing on brain slices and particularly the hippocampus where we see the most glycogen depletion, provisioning lactate can induce activity for hours. Again proving that lactate is used for ATP to induce the electrical signals towards the muscle.

“Brain lactate metabolism: the discoveries and the controversies” https://journals.sagepub.com/doi/10.1038/jcbfm.2011.175 – “Lactate-supported synaptic function in the rat hippocampal slice preparation” https://www.science.org/doi/10.1126/science.3375817

Ketones

There isn’t much choice for the brain for alternative energy sources. Let’s have a look at one known alternative to glucose. Could β-hydroxybutyrate (BHB) also replace lactate while not increasing heat production?

The evidence is very thin so allow me to use research on animals and conditions which we would normally ignore.

Causing ischemia in rats followed immediately with BHB infusion was able to keep ATP production at level together with low lactate production.

“Effect of beta-hydroxybutyrate, a cerebral function improving agent, on cerebral hypoxia, anoxia and ischemia in mice and rats” https://www.sciencedirect.com/science/article/pii/S0021519819302872?via%3Dihub

In fetal sheep, arterial infusion of BHB caused a reduction in glucose usage and an increase in lactate. This test however showed that there was no significant uptake of BHB while at the same time they noted a reduction in glucose uptake. So BHB signaled to reduce glucose utilization yet did not seem to be utilized. This must have meant a reduction in ATP production capability and as expected it resulted in higher lactate production. It is possible that a fetal brain may not yet have the necessary expression for ketolysis.

“Effect of lactate and beta-hydroxybutyrate infusions on brain metabolism in the fetal sheep” https://pubmed.ncbi.nlm.nih.gov/2100739/

In humans fasting for several days, we see an interesting observation where the authors speculate that the rise in brain BHB helps save lactate (replacing lactate oxidation) in order to explain the paralleled rise in lactate they observed.

“Human Brain β-Hydroxybutyrate and Lactate Increase in Fasting-Induced Ketosis” https://journals.sagepub.com/doi/10.1097/00004647-200010000-00012

What about the heat? Extra heat is created by electron loss from the electron transport chain (ETC). The following paper indicates that BHB works protective.

Conversely, a beneficial influence over the electron transport chain’s redox potential is a mechanism commonly linked to d-βOHB. While all three ketone bodies (d/l-βOHB and AcAc) reduced neuronal cell death and ROS accumulation triggered by chemical inhibition of glycolysis, only d-βOHB and AcAc prevented neuronal ATP decline. Conversely, in a hypoglycemic in vivo model, (d or l)-βOHB, but not AcAc prevented hippocampal lipid peroxidation (Haces et al., 2008; Maalouf et al., 2007; Marosi et al., 2016; Murphy, 2009; Tieu et al., 2003). In vivo studies of mice fed a ketogenic diet (87% kcal fat and 13% protein) exhibited neuroanatomical variation of antioxidant capacity (Ziegler et al., 2003), where the most profound changes were observed in hippocampus, with increase glutathione peroxidase and total antioxidant capacities.

source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(16)30655-6

Note the distinction in d and l form of BHB. Some exogenous ketone products contain a racemic, which means both d and l forms of BHB. If you ever consider exogenous ketones then keep in mind that the l form does not help the brain cell to produce ATP.

Finally

It looks like BHB will be supportive of the goal. Serving as a source of energy that replaces both glucose and lactate consumption in the brain without deleterious effects from heat production.

Theory versus practice

But does it work? The theory supports it but trials don’t. Unless those trials lack a proper setup. We have seen a few elements that are important and I’ll add a few more:

• Does the brain have sufficient ketolysis capacity?
• Is the exogenous ketone a mix of d and l or just d or just l?
• How strong is the inhibitory effect of BHB on glucose usage?
• Is the pressure on pH detrimental?

The following trial used athletes habitually on a high-carb diet. Through a ketone ester they got the BHB up to 3.5mmol (KE) and 4.5mmol (KE+bicarbonate). Urinary analysis showed a 0.03g excretion. This would equal 0.29mmol. Given the 3~4mmol/L this is neglectable.

They did note both a glucose and lactate lowering effect. The following overview summarizes the result.

Although they stated impaired performance due to the on average lower power output, it is important to look at the individual results. There is not a general decrement in performance but very much dependent on the individuals.

As indicated, the pH may be an important factor. We see that the time to exhaustion is improved when the KE is combined with bicarbonate and the response at individual level is much more in agreement. In the picture below you see the KE in the dotted lines, solid circles is with bicarbonate.

“Exogenous Ketosis Impairs 30-min Time-Trial Performance Independent of Bicarbonate Supplementation” https://journals.lww.com/acsm-msse/Fulltext/2021/05000/Exogenous_Ketosis_Impairs_30_min_Time_Trial.21.aspx

What the trial didn’t look at is insulin and circulating fatty acids. The ingestion of the KE could also elicit a sufficiently high insulin response so that the control group would be favored by being able to release more glucose and fatty acids.

MCT oil

Whether there is an advantage or not will depend on optimal conditions.

Again not ideal circumstances but just to show that a difference can be made, the following trial compared MCT versus LCT ingestion on performance. MCT can easily get into the mitochondria to fuel performance and in the liver that means it can be converted to BHB easily so we end up with a more ideal approach rather than an KE ingestion.

Also here we see a reduction in lactate but now the time to exhaustion is stretched to 10 minutes more compared to the LCT group for an intensity at 80% VO2Max. Sadly the comparison is not against carbohydrate ingestion so is the LCT detrimental or MCT beneficial?

“Effect of Ingestion of Medium-Chain Triacylglycerols on Moderate- and High-Intensity Exercise in Recreational Athletes” https://www.jstage.jst.go.jp/article/jnsv/55/2/55_2_120/_article

One last study, in rats, that I want to bring is where they used MCT oil and tested performance in high temperature. An impressive >2-fold increase in endurance. My bet is that the resulting BHB supported this effort but unfortunately they did not measure BHB.

“Medium Chain Triglycerides enhances exercise endurance through the increased mitochondrial biogenesis and metabolism” https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0191182

To naturally raise BHB levels in the blood during exercise, MCT oil ingestion during the activity will be essential. I do not recommend ketone ingestion unless you are a professional well funded athlete because these supplements are expensive.

Although one needs to be careful with acidosis, it could be worthwhile to see where the optimal balance is for the best mix of glucose, BHB and lactate in the blood. Glucose metabolism results in CO2 production so you end up with several acidic components in the body. The answer doesn’t seem to be in exogenous ketones.

A small amount of glucose could help either glucose breakdown resulting in lactate and/or glucose metabolism in the mitochondria to increase the TCA and therefor fatty acid metabolism but it may not even be necessary.

Go out and give it a try and let me know if it works for you!

Pro-tip: The action potential that is required to create the electric impulse towards the muscle depends on a hydrated state of the brain. Reading up on Angela Stanton’s book Fighting migraine epidemic it shows the importance of of hydration to maintain ATP production. In my own experience, having a bowl of soup with sufficient salt before my tougher bicycle rides seems to have good influence. Try it out for yourself!

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