It doesn’t sound like a cheerful statement as we desire an abundance of energy to support our daily activities whatever they are.
But do not despair, it is part of our evolution so there are some benefits to it, and in my opinion there are some major benefits. I’ll also address what it means for sports performance.
First the technical scientific bits that support the idea of reduced mitochondrial ATP production. It should be supported by scientific studies so this first part gets into the biochemistry of cellular energy production.
Part of the fatty acid beta oxidation is the cutting up of the fatty acid into acetyl-coa. As part of this process, each acetyl-coa formation results in the production of a NADH molecule.
NADH is the crucial element here and I’ll explain why further down.
source: https://en.wikipedia.org/wiki/Beta_oxidation#/media/File:Metabolism4.jpg
These are all the same names for the following energy production steps within the mitochondria.
source: https://en.wikipedia.org/wiki/Citric_acid_cycle#/media/File:Citric_acid_cycle_with_aconitate_2.svg
If you pay attention to the NADH elements, you see that at several steps NADH is produced. The enzymes that catalyze the reaction are pyruvate dehydrogenase, isocitrate dehydrogenase, alpha-ketoglutarate dehydrogenase and malate dehydrogenase.
The conversion of glucose to acetyl-coa also generates NADH but in a lower ratio. Per molecule of glucose, 2 molecules of pyruvate are generated with 1 NADH molecule produced for each. Next pyruvate to acetyl-coa results in 1 additional molecule of NADH. So we get a total of 4 molecules NADH per molecule of glucose.
For fatty acids, each 2 carbons result in NADH so a saturated fatty acid of 16 carbons results in 8 NADH molecules. So you can see that the NADH yield is higher with fatty acids.
Why we are focussing on NADH is because its concentration is an inhibitor of the enzymes that produce it. In other words it forms a negative feedback on its own production.
“Regulation of Pyruvate Dehydrogenase by End Product Inhibition and by Phosphorylation”
https://link.springer.com/chapter/10.1007/978-3-642-66461-8_17
Pyruvate dehydrogenase is regulated by end product inhibition by acetyl CoA (competitive with CoA) , NADH 2 (competitive NAD) and acetoin (competitive pyruvate); and through inactivation by phosphorylation catalysed by an intrinsic kinase utilising ATPMg++ and reactivation by a phosphatase. Recent studies in this laboratory have been concerned with the site of action of phosphorylation on the overall reaction sequence of pyruvate dehydrogenase; the relationship between end-product inhibition and phosphorylation and the mechanism whereby oxidation of fatty acids and ketone bodies leads to phosphorylation and inactivation of pyruvate dehydrogenase; with the action of insulin on pyruvate dehydrogenase, and the role of calcium; and with the biochemical pharmacology of dichloroacetate.
“Structure and allosteric regulation of human NAD-dependent isocitrate dehydrogenase”
https://www.nature.com/articles/s41421-020-00220-7
Human NAD-dependent isocitrate dehydrogenase or HsIDH3 catalyzes the decarboxylation of isocitrate into α-ketoglutarate in the TCA cycle. HsIDH3 exists and functions as a heterooctamer composed of the αβ and αγ heterodimers, and is regulated allosterically and/or competitively by numerous metabolites including CIT, ADP, ATP, and NADH
“2-Oxo acid dehydrogenase complexes in redox regulation” (2-oxo acid is a different name for alpha-ketoglutarate)
https://febs.onlinelibrary.wiley.com/doi/full/10.1046/j.1432-1033.2003.03470.x
Sensitivity of the 2-oxo acid dehydrogenase complexes to NADH/NAD+ has long been recognized as a mechanism of feedback control [[18, 19]].
“Function, kinetic properties, crystallization, and regulation of microbial malate dehydrogenase” –> Note that this is in microbes. I’m still looking for a source more closely related to humans.
https://link.springer.com/article/10.1631/jzus.B1500219
MDH activity is regulated by feedback inhibition. Substrate inhibition studies have shown that MDH activity is strongly inhibited by excess of oxaloacetate and NADH. In some cases, high concentrations of malate can inhibit the reduction of oxaloacetate. The activation by L-malate has been reported in P. stutzeri (Labrou and Clonis, 1997) (Table 2).
Unfortunately I can’t tell much about how fast NADH is formed with glucose versus fatty acids. It could still mean the same level of ATP is generated per time unit but there is one critical difference to point out.
In order for pyruvate to enter the mitochondria and convert to acetyl-coa, it depends on the pyruvate dehydrogenase enzyme which is under influence of negative feedback as we’ve just seen. This would mean that for glucose there is a control in the NADH that is generated that directly influences the potential for ATP production.
Fatty acids, on the other hand, can cause a greater production of acetyl-coa because the beta oxidation is not influenced by negative feedback. This would make you think it has a greater potential to generate ATP. But that beta oxidation also means that more NADH is produced which slows down the reactions to generate ATP.
My guess is that this is also the reason why ketone production is possible in the liver cells. It causes a greater availability of acetyl-coa in the liver which, under the influence of glucagon, can go into the pathway of ketogenesis.
One other indication that ATP production is reduced could be supported by the fact that increasing reliance on fatty acid metabolism tends to increase mitochondrial mass. Low levels of ATP stimulate AMPK activation. This in turn will help your cells to produce more mitochondrial mass. As a result, balance is achieved so that the required minimum level of ATP production is maintained again but this time under a higher mitochondrial mass.
MCT oil is great for testing this because it diffuses easily into the mitochondria due to its short chain length. Most commercial products contain a mix of carbon lengths 8 and 10. So we can test and see what an increased fatty acid availability does.
We found that MCT up-regulates the expression and protein levels of genes involved in mitochondrial biogenesis and metabolism. Further investigation demonstrated that the increased mitochondrial biogenesis and metabolism is mediated through the activation of Akt and AMPK signaling pathways and inhibition of TGF-β signaling pathway.
“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
As a consequence of fatty acid metabolism, I’ve already indicated that it increases mitochondrial mass.
One of the symptoms that people can experience during the transition period, getting onto a ketogenic diet, is fatigue. It is possible that this comes from the reduced ATP production capacity which gets resolved as the body increases mitochondrial mass.
This could potentially also explain the effect that some people experience when, after this transition, they ingest carbs again and feel as if it works like ‘rocket fuel’, a boost. With that increase in mitochondrial mass, using carbs as a fuel, it should give the possibility to increase ATP production.
When NADH is building up and pyruvate dehydrogenase activity is reduced, pyruvate will increase its pathway towards lactate. As long as fatty acid metabolism is plentiful, glucose can go to glycogen storage or lactate production.
You may think of increased lactate as a negative thing but this is not necessarily the case. Lactate is a good alternative fuel to glucose for the brain. It is often mentioned that the lactate will go to the liver and get converted to glucose. That is true but that is an incomplete picture. Lactate can and will be taken up everywhere. Lactate can be converted to pyruvate via lactate dehydrogenase so that pyruvate then further follows the path to acetyl-coa.
It would be very inefficient if the body requires lactate to travel to the liver to get converted to glucose and then distributed again via the bloodstream to end up at all the right places.
Because NAD+ is hydrogenated into NADH, negative feedback on the enzymes that are responsible for this means that less NAD+ is consumed. So, as NADH is building up, so it is for NAD+.
This is actually a positive thing because NAD+ is supporting sirtuins in their action to maintain DNA integrity and health.
https://www.elysiumhealth.com/blogs/science101/the-science-of-sirtuins-guardians-of-the-genome
“Sirtuins and NAD+ in the Development and Treatment of Metabolic and Cardiovascular Diseases” https://www.ahajournals.org/doi/10.1161/CIRCRESAHA.118.312498
One should not extrapolate NAD+/NADH ratios in the brain to the rest of the body. In the brain, NADH is actually reduced because the brain doesn’t use fatty acids to a considerable degree but instead uses the resulting ketones.
BHB conversion to acetyl-coa reduces only 1 molecule of NAD+ to NADH versus 4 for glucose in the production of acetyl-coa. For the brain this is important because it is the most energy hungry organ in the body. Here we don’t want to slow down energy production.
Glucose will reduce 111 molecules of NAD+ per 1000 molecules of ATP made, while ketone bodies reduce only 41 to produce a comparable amount of ATP. Decreased use of NAD+ by ketone bodies in energy production pathways could increase the amount of free NAD+ available as substrate for enzymes and cellular signaling processes.
source: “Ketone-Based Metabolic Therapy: Is Increased NAD+ a Primary Mechanism?” https://www.frontiersin.org/articles/10.3389/fnmol.2017.00377/full
source: “Nutritional Ketosis Increases NAD+/NADH Ratio in Healthy Human Brain: An in Vivo Study by 31P-MRS” https://www.frontiersin.org/articles/10.3389/fnut.2018.00062/full
This shows again how energy is conserved in the rest of the body while still maintaining sufficiency in the brain while also in the brain we get an increase in NAD+ which helps integrity of DNA.
Because the TCA cycle is less inhibited thanks to a reduction in NADH when using BHB, it may in fact be faster at producing ATP than glucose, if it is abundantly available.
As I’ve experimented with different dosages of MCT oil, I started to look for ways to avoid the intestinal issues. Different emulsions created variable and inconsistent results.
Until I combined the intake with easily digestible carbs like a cookie. What I did was let the MCT oil soak up in a soft bread-like cookie. And the issues were completely gone.
I’m fully speculating here but given the information above and knowing that MCT oil can simply diffuse into mitochondria so it is absorbed at a fast rate, it is possible that the ATP production is brought down by the fast influx of MCT oil and causes the resulting cramping/diarrhea. The addition of carbs may help restore the ATP production so that these side effects are neutralized.
To evidence the speed at which they are absorbed, even without pancreatic lipase do the MCT get absorbed in the intestine which is not the case for long chain fatty acids.
This study demonstrated that medium chain triglycerides were absorbed in the absence of lipase whereas long chain triglyceride was not. There was no significant variation in the absorption of the five different medium chain triglycerides perfused. The molecular weight of the medium chain triglyceride did not affect its intact absorption by the small intestine.
“Absorption of triglycerides in the absence of lipase” https://cdnsciencepub.com/doi/10.1139/y90-074
Whether continuous daily ingestion makes matters worse or relieves the symptoms needs to be tested but good luck finding test subjects who are willing to handle a negative outcome for so long.
In the following rat study we do see that the body adapts to higher fat ingestion by increasing its lysis capacity via pancreatic lipase. Little is known if this enhances the transition through the endothelial cell layer, causing less irritation. The medium chain fatty acids leave the cells broken down from its glycerol backbone and attach to albumin entering directly into the bloodstream.
The amount of fat in the diet regulates PL and PLRP 1 expression (3, 14–16). When a high-fat diet is introduced to rats, PL protein synthesis and content and PLRP 1 mRNA levels increase within 24 h (36%, 20%, and 412%, respectively) (14). After 5 d, PL content and synthesis and PLRP 1 mRNA levels reach steady-state maximal levels (191%, 217%, and 650%, respectively) (14). The regulation of PLRP 1 by the amount of dietary fat is transcriptional, as demonstrated by increased nuclear transcript run-on assay (15). The parallel changes in PL mRNA levels (16) and synthetic rates (14) suggest that the regulation of PL is pretranslational and likely to be transcriptional. However, such transcriptional regulation has yet to be conclusively documented.
“Regulation of Pancreatic Lipase by Dietary Medium Chain Triglycerides in the Weanling Rat” https://www.nature.com/articles/pr2004143
As we’ve seen by now, fat seems to be slower at ATP production (given sufficient substrate availability when comparing glucose against fat). New equilibriums are achieved in the redox state with an altered ratio of NAD+/NADH and absolute values of both.
In the skeletal muscle however, ATP demand needs to be able to go up manyfold. The biochemistry and mechanics is complex but the same principle exists.
With the high energy potential of fatty acids, could there be a way to increase the ATP production rate? Not necessarily for daily activities and not even for lowish intensity exercise but how about for maximal performance? Be it strength or endurance competition.
I’m looking into making more glucose available concomitantly with MCT oil in the hope that this will lead to a faster NADH oxidation. The thinking goes that after the glucose is converted to pyruvate, more lactate can be produced which oxidizes NADH to NAD+ so that at least part of the ATP generated will be under a 1/1 ratio (2 NADH molecules produced, 2 NAD+ molecules produced). This in turn may help to get more acetyl-coa from the MCT oil through the TCA cycle also helping to generate more ATP.
We need a way to change the ratio so that more NAD+ becomes available versus less NADH buildup. If we can succeed in this then the acetyl-coa that comes available from fat oxidation can be processed quicker through the TCA cycle, leading to more ATP.
If the mechanism makes sense and is the reason why I don’t experience issues in the gut then it may also have its effect in the exercising skeletal muscle.
This could lead to an equal performance, saving more glycogen and perhaps a longer sustained high intensity performance.
But first of all, it looks like the gastric emptying seems to be faster when glucose is combined with MCT oil. I have no idea why that is but this is beneficial if it can be replicated during exercise. This test was done sedentary.
(% CHO-% MCT): Drink (Dr) 1: 70%-30%, Dr2: 80%-20%, Dr3: 90%-10%, Dr4: 100%-0%. GE was measured at rest for 90 min according to the modified double sampling technique. GE rate, expressed as t1/2 (SEM), was 23 (2.3), 24 (1.6), 27 (2.2) and 36 (2.9) min, respectively, from drink 1 to drink 4. Statistical analysis showed that all MCT containing drinks emptied faster than the 100% CHO drink.
“Gastric Emptying of Carbohydrate – Medium Chain Triglyceride Suspensions at Rest” https://www.thieme-connect.com/products/ejournals/abstract/10.1055/s-2007-1024569
Faster emptying? Is this already a sign of increased performance?
In a 100km cycling TT, they found no difference when comparing carbohydrate versus carbohydrate + MCT oil. Although they didn’t specify the order in which this was tested, it is possible that given the hard work it demands, the subjects were less keen on doing the consecutive tests after the first one.
There is no mention of a cross-over design so that each subject starts and ends with a different beverage. Also no mention of how much time is between the different TT tests so have they been able to recover sufficiently for the 2nd and 3rd test?
“Effect of carbohydrate or carbohydrate plus medium-chain triglyceride ingestion on cycling time trial performance” https://journals.physiology.org/doi/full/10.1152/jappl.2000.88.1.113
A similar study, randomized double-blind and cross over, shows no benefit and documented gastrointestinal issues. They supplemented MCT oil before the exercise. This is a confounder because such side effects influence your ability and desire to perform. I have personally experienced this during my own testing.
“The effects of medium-chain triacylglycerol and carbohydrate ingestion on ultra-endurance exercise performance” https://journals.humankinetics.com/view/journals/ijsnem/15/1/article-p15.xml
In the following research (female subjects), cross-over and 14 days wash out, we find a great enhancement in performance. A big difference with the previous studies is that here the athletes were put on an MCT supplemented diet to habituate. This may have already caused some adaptation in the mitochondrial mass.
MCT + CHO trial
CHO trial
That duration is 33.5% longer which is a massive result in sports. Of note, these were recreational athletes.
“Medium-chain Triglycerides with Maltodextrin Increase Fat Oxidation during Moderate-intensity Exercise and Extend the Duration of Subsequent High-intensity Exercise” https://www.jstage.jst.go.jp/article/jos/67/11/67_ess18112/_article
Yet another trial shows an increase in MCT oil oxidation with the addition of carbs although a similar plateau was reached. At least it supports the faster absorption and availability.
During the second hour (60- to 120-min period), the amount of MCT oxidized was 72% of the amount ingested during the CHO+MCT trial, whereas during the MCT trial only 33% was oxidized. The rate of MCT oxidation increased more rapidly during the HCHO+MCT and CHO+MCT trials compared with the MCT trial, yet in all three cases the oxidation rate stabilized at 0.12 g/min during 120–180 min of exercise. It is concluded that more MCTs are oxidized when ingested in combination with CHOs.
“Metabolic availability of medium-chain triglycerides co-ingested with carbohydrates during prolonged exercise” https://journals.physiology.org/doi/abs/10.1152/jappl.1995.79.3.756
So is the combination of carbs + MCT oil making the TCA run faster or is it because the increase in mitochondrial mass causes carbohydrates alone to be responsible for the enhancement effect?
These studies do not give me a conclusive answer although the last 2 are encouraging. Me being on a low carb high fat diet, I have experienced the boosting effect of carbohydrates but found it short lived. I will try out the carbohydrate + MCT oil for my next race and see if it results in improved wattage.
In the Electron Transport Chain, Complex I is a place where NADH is oxidized to NAD+. If a higher reliance on fatty acid metabolism means an increase in ETC then it would also mean a greater processing of NADH so that the TCA process is not inhibited as much. However, given the increase in mitochondrial mass, I doubt that fatty acid metabolism increases ETC units in the mitochondrial inner membrane but the possibility is there, perhaps in a way that doesn’t fully compensate.
source: “Mitochondrial NAD+/NADH Redox State and Diabetic Cardiomyopathy” https://www.liebertpub.com/doi/10.1089/ars.2017.7415
This step is significant. When looking at skeletal muscle in diabetics, we find that the ETC is deficient. This leads to further accumulation of NADH and results in too low ATP production which explains fatigue in T2D and obese people. It is not just the weight that is heavy to carry.
In the state of decreased contractile activity and excessive caloric intake, the suppressed ability of mitochondrial electron transport chain to oxidize NADH accompanied by excessive activity of CS in TCA cycle or HAD in β-oxidation pathway can lead to abnormally high steady-state concentration of intramitochondrial and cytoplasmic NADH. The increased concentration of NADH can impair substrate oxidation of 2 key enzymes that control oxidation of glucose and fatty acids, pyruvate dehydrogenase complex (PDC) and HAD, respectively. Thus the defect in mitochondrial electron transport chain can lead to general slowdown of basal metabolism in skeletal muscle, and perhaps it can result in decreased rate of ATP generation during contractile activity.
“Deficiency of electron transport chain in human skeletal muscle mitochondria in type 2 diabetes mellitus and obesity” https://journals.physiology.org/doi/full/10.1152/ajpendo.00317.2009
When NAD+ increases in availability, it increases the capability to metabolize fatty acids. This would create a self-enforcing loop. This cannot go on forever so how is equilibrium achieved? My guess would be with fatty acid substrate availability itself.
In summary, activation of hepatic OXPHOS increases NAD+ and interdicts NAFLD. The ratio of [NAD+]/[NADH] is dictated by cellular respiration and increases in NAD+ promote complete oxidation of fatty acids.
“OXPHOS-Mediated Induction of NAD+ Promotes Complete Oxidation of Fatty Acids and Interdicts Non-Alcoholic Fatty Liver Disease” https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0125617
It is also not clear to me if this increased oxidation is happening within the same mitochondria or if this NAD+ increase also drives an increase in mitochondrial mass. The following study does point into this direction.
Therefore, NAD+ levels influence a myriad of cellular processes including mitochondrial biogenesis, transcription, and organization of the extracellular matrix.
“A need for NAD+ in muscle development, homeostasis, and aging” https://skeletalmusclejournal.biomedcentral.com/articles/10.1186/s13395-018-0154-1
As an example, malate dehydrogenase can be inhibited by excess NADH but it is also regulated by citrate. In how far these other factors influence the result is not known from the scientific literature.
“Kinetic studies of the regulation of mitochondrial malate dehydrogenase by citrate” https://portlandpress.com/biochemj/article-abstract/283/1/289/27132/Kinetic-studies-of-the-regulation-of-mitochondrial?redirectedFrom=fulltext
It should be clear that the adaptation is complex to maintain homeostasis in energy production. Fat as a substrate for energy looks like it is signaling efficiency, conservative on the energy consumption, maintenance mode. Glucose on the other hand does not mean spilling or wasting energy but under sufficient nutrient availability (amino acids) it is a substrate that is beneficial for proliferation. As we see in cancer cells and immune cells, rapid multiplication requires glucose not just for energy but also as a carbon source for constructing the cells and its organelles.
This is something that was outlined in the book from David Sinclair “Lifespan: Why We Age – and Why We Don’t Have To” where he pointed out 2 states of cells.
One where they wait for replication and simply try to survive as long as possible, which requires DNA integrity, being conservative with energy, protecting protein from damage, recycling damaged protein, protection from environmental stressors.
The other state where all effort is directed to replication to create a viable offspring when it gets the environmental signals that the conditions are right. This state means that the parent cell doesn’t care about itself and diverts all efforts to the daughter cell in order to increase the success of the offspring.
These 2 states are still embedded in our cells although complexity has grown ever since because these cells have started to collaborate into a body with the purpose of passing on DNA successfully.
– – – T H E – E N D – – –
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