Metabolic profiling indicates impaired pyruvate dehydrogenase function in myalgic encephalopathy/CFS (Fluge et al., 2016)

[Hip]

All this is so way, way over my head that I'd love to find someone to supervise me but I just don't know who to trust to do that in the UK.

From my reading, perhaps the most important thing on a ketogenic diet is to drink more water and take the supplemental electrolytes of sodium, potassium and magnesium. This forum article gives info on doses.

 

[Hip]

but lactate supposedly diffuses into the blood if not oxidized ... but wouldn't it require an equal amount of energy to turn it back into glucose making the entire exercise pointless unless the cell desperately needed energy at a certain time ?

It's worse than that: it takes 3 times more energy to convert lactate back to glucose (a conversion which takes place in the liver), than the energy that was gained when originally converting glucose to lactate (which takes place in anaerobic glycolysis within every cell).

Myhill, Booth and McLaren-Howard suggest that this creation and build-up of lactic acid during exercise (from anaerobic glycolysis), and the extra energy that is required to convert the lactic acid back to glucose in the liver, is an exacerbating factor in PEM, because of the energy that the liver drains from the body when performing this conversion (the Cori cycle in the liver converts lactic acid back to glucose).

Although thinking about it, I am not too clear how the extra energy the liver requires to run the Cori cycle could make PEM worse, because the extra energy used up by the liver occurs locally in the liver, and does not affect the energy metabolism of the other cells of the body.



Anaerobic glycolysis is thus a short-term gain of energy in the cells, but in the long term, you pay a high price for this energy, because the lactic acid created in anaerobic glycolysis has to be dealt with by the liver, which costs 3 times more energy than was originally gained. Anaerobic glycolysis is a bit like a loan shark, who gives you some money right now, when you need it; but in the long term you end up paying him back three times the amount. Though the advantage of anaerobic glycolysis is that it can work completely independently to the mitochondria, and can work when there is no oxygen.

Aerobic glycolysis however is more efficient than anaerobic glycolysis, because aerobic glycolysis works in conjunction with the mitochondria. In aerobic glycolysis, the pyruvate created as the end product of glycolysis is not converted into lactic acid (as happens in anaerobic glycolysis), but instead this pyruvate is passed onto the mitochondria, where even more energy is extracted from it, inside the mitochondria. That makes aerobic glycolysis very efficient.

But if there is a problem in the mitochondria such that the mitochondria cannot accept the pyruvate that is output from glycolysis, you cannot achieve aerobic glycolysis. So you then fall back to the less efficient anaerobic glycolysis, and its problem of lactic acid build-up.

 

[SherDa]

So taking say 5 grams (1 heaped teaspoon) of leucine each day, along with some coconut oil or MCT oil, may make it easier to kickstart and maintain ketogenesis, and get your ketogenic diet going without too many transitioning hiccups.

I haven't tried leucine yet. I cannot make it more than a week or two without supplementing lysine though. I frequently run low on it, which manifests as EBV/mono flare (since lysine suppresses the virus). Bloodshot eyes and hair loss are my early warning signs that I am running out of lysine.

It always perks me up when I begin taking it again. It maybe the biggest reason I feel almost normal most of the time. I'm just well aware of the fact that taking a particular amino acid in isolation can cause deficiencies in other aminos, so I'm trying to increase my overall protein intake.

I'm not sure I should be too concerned about it though- it's not my supplementation that is creating deficiencies, it's my wonky biochemistry that is creating imbalances by using aminos for fuel.

 

[leokitten]

That is precisely what I was suggesting in this earlier post, when I pointed out that: "the failure to efficiently process glucose via the pyruvate pathway into the mitochondria should not lead to an energy shortage, because mitochondria can also process dietary fats and protein as alternative energy sources. "

In other words, the pyruvate blockage cannot be the only blockage in energy metabolism.

Nevertheless, if fat metabolism in the mitochondria were also compromised, but working more efficiently than glucose metabolism, then you would expect a ketogenic diet to bring benefits, as it clearly has for several people who tried it.

Unfortunately I'm fairly sure if the glucose metabolic pathway is dysfunctional there will always be serious health consequences that cannot be made up for by upregulating amino and fatty acid metabolism.

Each organ and tissue in the body has a unique metabolic profile. The brain and muscle cells, for example, rely very heavily on glucose metabolism to function effectively. While the brain can utilize ketone bodies for metabolism during extreme situations, it prefers to use ketones in those situations for lipid synthesis since fatty acids cannot pass the blood brain barrier. The brain requires a constant supply of glucose and a working glucose metabolic pathway to function. Skeletal muscle can use glucose, fatty acids, and ketone bodies, but it requires glucose for bursts of activity and maintains the largest glycogen stores of any organ for this purpose. If muscle cells cannot metabolize that glucose properly then we all know what happens because we live with the symptoms every day.

People who are healthy and eat a ketogenic diet have a properly functioning glucose metabolism, so even if they aren't eating more than 20-30g carbs per day the body performs extensive gluconeogenesis in the liver from all the non-carb substrates they are eating. They are still effectively utilizing glucose in all their tissues and maintain full metabolic flexibility, but I agree I think there is some shift toward more fatty acid metabolism and less glucose when compared to people on a regular diet.

But @Hip I do agree with you I think there is likely more to this metabolic dysfunction story.

What excites me so much about all metabolic research coming since 2015 and the concurrence of findings is that, at least to me, they explain my symptoms and most laboratory result much better than any previous hypotheses.

Our brain, muscles, and blood vessels are some of the most severely effected by this disease and many, if not most, of the symptoms seem to come from dysfunction in these organs.

 

[SherDa]

I'd really like to thank those who brought up primary biliary cirrhosis as a possibility. My symptoms match pretty well (especially my itchy skin!) I spent the evening reading about it and am going to test the theory that it's an extension of celiac disease/gluten enteropathy.

I wanted to try the keto diet, but I think that's going to have wait. I've switched to a higher protein paleo diet (grain and dairy free with low sugar). I also intend to use resistant starch and soluble fiber to improve gut health. The resistant starch has already helped lessen my Raynaud, so I'm hoping it will help with this possible PBC too. But the lack of bile flow in a PBC situation makes bacterial overgrowth much more likely, so this could be tricky.

I'm anxious to get to the point where I can tolerate vitamin A. I think it's extremely important for autoimmune conditions, but it taxes my already low protein reserves. (I already have ankylosing spondylitis, Raynaud and suspicion of Hashimoto, so the autoimmune etiology seems likely in my case.)

 

[hixxy]

I'm too fogged lately to research this myself, but I take it PDH inhibition can explain low NADPH availability?

 

[Hip]

People who are healthy and eat a ketogenic diet have a properly functioning glucose metabolism, so even if they aren't eating more than 20-30g carbs per day the body performs extensive gluconeogenesis in the liver from all the non-carb substrates they are eating. They are still effectively utilizing glucose in all their tissues and maintain full metabolic flexibility, but I agree I think there is some shift toward more fatty acid metabolism and less glucose when compared to people on a regular diet.

That's a really pertinent point, and I see what you are saying: in terms of the food energy consumed, someone on a ketogenic diet may be eating 75% fat and just 5% carbohydrates; but due to interconversion processes like gluconeogenesis, in the actual blood, you will still find that glucose levels and blood lipid levels maintained within certain ranges, and do not vary that much, in spite of the extreme dietary input.

Thanks for pointing this out, as it is very important.



But such high fat ketogenic diets presumably must create some kind of shortage of blood glucose — a shortage that even gluconeogenesis cannot fully rectify — because otherwise why would the liver produce ketone bodies in order to fuel the brain (and heart) when dietary carbohydrates are in short supply?

I read that in ketogenic diets, 70% of the brain's energy will come from ketone bodies. The brain can use glucose and ketone bodies for energy, but cannot really use fatty acids.

So if the brain is running on 70% ketone bodies and 30% glucose during a ketogenic diet, rather than the usual 100% glucose, there must be some shortage of blood glucose when you are following such a diet.

And if we assume that brain fog is due to low energy supply to the brain cells, as a result of the brain cells not being able to process glucose properly (due to the mitochondrial pyruvate defect found by Fluge and Mella), then once the brain starts fueling itself primarily on ketone bodies, which will bypass this pyruvate defect, one might expect large improvements in brain fog.

That is, unless there are also other blockages in the energy metabolism, such as those Myhill, Booth and McLaren-Howard found.



(Note: my understanding is that the brain has only low levels of the beta-oxidation enzyme (which converts blood fatty acids to acetyl CoA, which enters the mitochondrial Krebs cycle), so for this reason the brain cannot make use of blood fatty acids for energy; but the brain can make good use of ketone bodies, which can be converted to acetyl CoA without the need of the beta-oxidation enzyme).

 

[ash0787]

seems like they need to do some sort of quantitative test to find out exactly what is going on in these culture grown muscle cells, is the pyruvate usage really obstructed ? how are the cells actually producing energy, it cant always be out of control glycolysis, no idea how they can do this, sounds very difficult, maybe there are some world experts on this specific topic they can bring on board ?

 

[alex3619]

I think we really really really need the science to evolve on all this, specifically for ME and CFS.

One problem I have with the idea we can bypass our energy deficits with fats is that, aside from brain energy issues, during aerobic exercise, after the initial period, the body mostly uses fat as fuel, and requires a higher oxygen utilization than normal because of this. We would expect to see that ME patients would have trouble starting aerobic exercise, but once underway we would be fine. We would just need to get past the initial issue. This is not what happens. Too many of the ideas we might come up with are likely to be contrary to the broader evidence.

Let me remind people that all these pathways we are discussing, from glycolysis to the electron transport chain, and beta oxidation, probably have a high reliance on adequate metabolic intermediates. If the metabolomics research is right, though this will required detailed and probably personalized analysis, then we simply might not have enough of those metabolites.

Let me use an inadequate metaphor that is probably easier to understand. We are concerned about fuel in a car engine. Normal vehicles use petroleum products. They can however use natural gas or even alcohol as fuel. However we have failed to take into account the missing spark plugs, failing battery, bad wiring, and the hole dripping oil onto the ground below the engine. Without all these secondary factors we cannot expect the engine to work well, regardless of what fuel we use.

I have an expectation that many will improve on a higher protein diet. However we still do not know so very much about what is going on. The research will provide some of that ... this coming year is going to be very interesting.

In medicine there is a focus on acute failure, and a problem converting pyruvate to acetyl-CoA might qualify as that. However I have always asked the question, how would a failure of 60-80% in one system, an acute failure, compare to a systemic failure of 10-20% at many stages of the deeply complex processes in human biochemistry? Systemic failure is not the same as acute failure, but the end outcome might look similar at first glance.

I am sure many are going to experiment on themselves. I probably will. That will give us empirical evidence, though potentially flawed, and maybe some clues. However I expect this story will evolve dramatically in the next few years. Big things are ahead.

 

[lansbergen]

Let me use an inadequate metaphor that is probably easier to understand. We are concerned about fuel in a car engine. Normal vehicles use petroleum products. They can however use natural gas or even alcohol as fuel. However we have failed to take into account the missing spark plugs, failing battery, bad wiring, and the hole dripping oil onto the ground below the engine. Without all these secondary factors we cannot expect the engine to work well, regardless of what fuel we use.

Good one

 

[roller]

everything goes wrong.
what does not?
we cant breath, walk, stand, sit, talk, pee, poo, shower, eat ... oh boy..

whatever pathway you look at, there will be things that go very wrong.
and none of the findings, will explain even 50% of your symptoms. and neither fix them.
its futile.

we dont have a special or new disease.
we are victims of their stupidity and ignorance.

 

[Undisclosed]

everything goes wrong.
what does not?
we cant breath, walk, stand, sit, talk, pee, poo, shower, eat ... oh boy..

whatever pathway you look at, there will be things that go very wrong.
and none of the findings, will explain even 50% of your symptoms. and neither fix them.
its futile.

we dont have a special or new disease.
we are victims of their stupidity and ignorance.

I am not sure why you feel the need to derail a research thread with comments like this. If researchers like Fluge and Mella felt it was futile we wouldn't have the research moving forward to either try to get to a cause or treatment or rule out certain things. The only people we are victims of are those that claim we can be treated with CBT/GET.

 

[eljefe19]

I am not sure why you feel the need to derail a research thread with comments like this. If researchers like Fluge and Mella felt it was futile we wouldn't have the research moving forward to either try to get to a cause or treatment or rule out certain things. The only people we are victims of are those that claim we can be treated with CBT/GET.

Just ignore him. Every post I've seen by him is some pessimistic derailment of healthy conversation.

 

[ash0787]

maybe english is not his best language, what he says in the 3rd paragraph contradicts the 2nd paragraph though

I sort of get what he means though sometimes I feel like it is futile but I think you have to be patient and have faith that the scientists are doing the best they can to try and apply logic and deduction even though it seems like its impossible to solve and it defies conventional explanation.

Also what alex said yes theres probably lots of little mechanisms involved that we don't even know exist,
for the layman its obviously easier to go for the most simple and understandable explanations that we can relate to.

 

[eljefe19]

@ash0787 i know you're trying to be nice to him but really, what's the point in coming on here and sharing despair with the whole community, when we actually have some dedicated researchers working their asses off on our behalf. Could things be better? Sure, but I trust the scientists over the Monday morning quarterbacks online.

 

[alicec]

I'm too fogged lately to research this myself, but I take it PDH inhibition can explain low NADPH availability?

Not really, or only indirectly and partially.

NAD+/NADH is mainly used in catabolic processes, NADP+/NADPH in anabolic processes. The distinct redox cofactors enable these processes to be regulated independently.

The energy pathways being discussed here ultimately produce NADH, via the citric acid cycle, which in turn is used in the linked electron transport chain to produce ATP.

The PDH defect discussed in the study affects the conversion of pyruvate to acetylCoA, which is the route used for carbohydrate catabolism to feed into the citric acid cycle.

The body may try to bypass the defect by increasing breakdown of amino acids and/or fatty acids which feed into the cycle at acCoA, or other amino acids which feed into several other points in the cycle.

In the study, women particularly showed increased use of such amino acids.

There has been a little discussion in this thread of fatty acid oxidation as an alternative energy source. The study did not look at this but mentions it in discussion.

The PDH inhibition in ME/CFS suggested in the present study, with compensatory use of amino acids as substrates for TCA oxidation, would also be expected to affect mitochondrial fatty acid β-oxidation in attempts to rescue energy homeostasis. A recent study assessed 612 metabolites in 45 ME/CFS patients and 39 healthy controls and reported multiple abnormalities in several pathways involved in lipid metabolism and mitochondrial energy metabolism (32). The most prominent changes in ME/CFS patients were widespread decreases in sphingolipids, glycosphingolipids, and phospholipids. These findings were consistent with a lower ATP and GTP turnover and with decreased amounts of branched amino acid metabolic intermediates. However, there were also indications of reduced mitochondrial fatty acid oxidation only in female ME/CFS patients (32). Adding to PDH inhibition, reduced mitochondrial fatty acid oxidation would expectedly compromise the supply of acetyl-CoA further and thereby increase the dependency of category II amino acids for alternative fueling of the TCA cycle, as shown in our study

.

In other words theoretically this might work but the Naviaux study which they refer to showed many defects in lipid metabolism with women showing particular defects in beta oxidation. This would preclude the increased use of lipids for energy and force women into reliance on amino acids, as this study found.

This is of course a generalisation among women. Any individual woman might not have all these defects.

Getting back to NADPH. It is generated predominantly by the pentose phosphate pathway, but also by several NADH -dependant enzymes. Furthermore, NADPH acts as a monitor of cellular fuel status, including NADH levels, and adjusts NADPH-dependant reactions accordingly (as discussed by Naviaux).

So indirectly there could be a link between the PDH defect and NADPH if compensatory mechanisms were unable to generate sufficient NADH and this in turn affected NADPH levels. This would be only one factor in the many possible contributors to the defective NADPH metabolism revealed and discussed in the Naviaux study.

 

[roller]

I am not sure why you feel the need to derail a research thread with comments like this. If researchers like Fluge and Mella felt it was futile we wouldn't have the research moving forward to either try to get to a cause or treatment or rule out certain things. The only people we are victims of are those that claim we can be treated with CBT/GET.

I am not sure why you write they are looking to get to a cause or treatment or rule out certain things.

this was my criticism - there is no info that they did that.
at least i can find it nor did lipkin reply with that info to my email.

if you know, what parasites/pathogens the study participants of
- the naviaux study have been tested based on the findings or if you have that info from
- the fluge/mella study or if you have that info from
- the lipkin study, please post that.

i'm most interested in this info.
and i believe - others, are looking for progress are too.

 

[Snow Leopard]

One problem I have with the idea we can bypass our energy deficits with fats is that, aside from brain energy issues, during aerobic exercise, after the initial period, the body mostly uses fat as fuel, and requires a higher oxygen utilization than normal because of this. We would expect to see that ME patients would have trouble starting aerobic exercise, but once underway we would be fine. We would just need to get past the initial issue. This is not what happens. Too many of the ideas we might come up with are likely to be contrary to the broader evidence.

One hypothesis is there is a block in processing the fatty acids into the mitochondria and the gene expression. This blockage leads to a build up of fatty acids, which stimulates PPAR-delta, as an attempt to increase fatty acid metabolism (to clear out the backlog). (with further feedback loops of SIRT4)

Let me remind people that all these pathways we are discussing, from glycolysis to the electron transport chain, and beta oxidation, probably have a high reliance on adequate metabolic intermediates. If the metabolomics research is right, though this will required detailed and probably personalized analysis, then we simply might not have enough of those metabolites.

The problem with the "we simply might not have enough of those metabolites" is that it has to be an incredible coincidence that we all seem to have ended up with the same problem. There has to be a deeper reason for this coincidence.

 

[alex3619]

The problem with the "we simply might not have enough of those metabolites" is that it has to be an incredible coincidence that we all seem to have ended up with the same problem. There has to be a deeper reason for this coincidence.

That also fits with the metabolite findings. It is in no way coincidence. Something or things are driving it.

 

[nandixon]

This blockage leads to a build up of fatty acids, which stimulates PPAR-delta, SIRT4 etc as an attempt to increase fatty acid metabolism (to clear out the backlog).

SIRT4 inhibits fatty acid oxidation, which you had actually mentioned in a previous post citing a 2010 reference. [There's also a newer 2013 reference that demonstrates a mechanism for the inhibition, namely by SIRT4 repressing PPAR-alpha. (PPAR-alpha is an inducer of CPT-1A.)]