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

ash0787

Senior Member
Messages
308
I heard something recently that seems to be relevant to CFS, I think it was an assessment of military performance, the metabolism of women is different in such a way that they turn extra energy into fat whereas men keep more in the form of temporary energy reserves.

Not knowing much about these tests I wonder as to how accurate they are, I am afraid that we might see a contradictory result from a different source later on ... I have heard of upregulation before so I presume it is a standard procedure. Aside from that little doubt though it does actually feel like we are getting somewhere with this one.

So maybe if they can find the chain of command they can find that a single chemical in the blood is ultimately controlling this particular effect and inject something to counteract it and see what happens ?
 
this is no landmark study.
this was to be expected.
it can straight go to the rubbish bin.



could they at least reveal what pathogens and parasites the participants have been tested for (found with titres/not found)?

if we had at least this info from such rubbish-studies, we could be there already...

this is needed. and really, its just something that belongs to a scientific approach.
for data analysis anyway. big data studies.
:rofl::rofl::rofl:
 

Riley

Senior Member
Messages
178
Edit:I'm trying to quote what AndyPR quoted but can't figure it out on mobile :p.

"Poe's law is an Internet adage that states that, without a clear indicator of the author's intent, it is impossible to create a parody of extreme views so obviously exaggerated that it cannot be mistaken by some readers or viewers as a sincere expression of the parodied views."

I've never seen true trolling on these forums which leads me to believe that this person is sincere.
 

Snow Leopard

Hibernating
Messages
5,902
Location
South Australia
Wait, did someone mention PPAR-delta and PDK4?

*dusts off my old hypothesis involving CD36 and fatty acid metabolism dysregulation*

"The pivotal role of pyruvate dehydrogenase kinases in metabolic flexibility."
https://www.ncbi.nlm.nih.gov/pubmed/24520982

"CD36-dependent regulation of muscle FoxO1 and PDK4 in the PPAR delta/beta-mediated adaptation to metabolic stress."
https://www.ncbi.nlm.nih.gov/pubmed/18308721/

By the way, the above study is by @znahle and I first read it before Zaher was hired by the Solve ME/CFS Initiative...

I would be very interested to hear what Zaher has to say about this study.
 

eljefe19

Senior Member
Messages
483
Wait, did someone mention PPAR-delta and PDK4?

*dusts off my old hypothesis involving CD36 and fatty acid metabolism dysregulation*

"The pivotal role of pyruvate dehydrogenase kinases in metabolic flexibility."
https://www.ncbi.nlm.nih.gov/pubmed/24520982

"CD36-dependent regulation of muscle FoxO1 and PDK4 in the PPAR delta/beta-mediated adaptation to metabolic stress."
https://www.ncbi.nlm.nih.gov/pubmed/18308721/

By the way, the above study is by @znahle and I first read it before Zaher was hired by the Solve ME/CFS Initiative...

I would be very interested to hear what Zaher has to say about this study.
ELI5 please
 

Snow Leopard

Hibernating
Messages
5,902
Location
South Australia
ELI5 please

Dear 5 year old genius, here is a picture:

1743-7075-11-10-2.jpg

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3925357/figure/F2/

(PDC is the Pyruvate dehydrogenase complex)
 

alex3619

Senior Member
Messages
13,810
Location
Logan, Queensland, Australia
This might explain why SSRIs are so badly tolerated in ME. SSRIs raise Sirtuin 4, which suppresses PDH. See for example:

http://www.cell.com/cell/abstract/S0092-8674(06)01020-8?_returnURL=http://linkinghub.elsevier.com/retrieve/pii/S0092867406010208?showall=true&cc=y=

This research needs to be pursued and some of the implications ruled out because it suggests SSRIs might lead to early death. Its only suggestive however. It might already have been investigated too, this is not my area of expertise.
 

alex3619

Senior Member
Messages
13,810
Location
Logan, Queensland, Australia
Is this a small part of a bigger metabolic picture or could this be right at the heart of the disease? I have no way of understanding the significance of these results in the context of existing research.
Good questions. I think the argument they are providing is that this is the cause of the low energy, though perhaps not other issues. Indeed they hypothesize an immune mediated process, and this will have other impacts. In other words, we may have to fix the immune problems to fix this. However if we can restore PDH function we would still probably be sick but we would also have restored energy ... which in my view is a huge plus.

Now there is a lot of anecdotal evidence that ME patients do better on higher protein diets. A PDH problem would explain that.

What we do not know are the feedback loops. Its possible that doing things to try to restore PDH, outside of an experimental setting, might make the signals shutting down PDH increase in intensity. We just don't know.

I suspect from the anecdotal data that there is at least a large subset with ME who do better on higher protein. I was aware in the 90s that many docs in Australia found that higher protein was better, and together arrived at a decision that 1.5g/kg of body weight was about ideal. I don't know if this was ever published as it was based on informal investigation. I also cannot determine if this figure is reliable.

If restoring PDH function can lead to a cure or remission then we might find treating ME is even easier than we thought, but first we have to find the correct protocol.

PS I am currently reading the full paper.
 

roller

wiggle jiggle
Messages
775
Really?

This is exactly what OMF and Prof. Davis has been doing in his Severely Ill Big Data study.

I don't believe any pathogen has been found yet, using custom, cutting edge devices. Not just based on titres which are not always reliable.
@Ben Howell so, you dont believe...?

Naviaux findings point pretty strongly at parasites.
his findings are common in certain parasitic infections.
dont you think they should be ruled them out after those results?

so, which ones did he check the participants for?

which parasitic infections did he rule out?

can we have this list, please?
 

roller

wiggle jiggle
Messages
775
What a lot of people seem to be missing is that so far, from multiple studies, it seems to not necessarily matter what the initiating trigger is, the resulting metabolic consequences appear to be the same for patients.

i absolutely disagree.

that is exactly the problem with "medicine".
it DOES matter what the trigger is.

otherwise we are having band aids that just shift the whole mess.
it may go well for some time then symptoms change and mostly worsen.

we need to know the triggers and treat them.

it seems quite wrong to bomb (interfere with) the immune system as a solution.
 

roller

wiggle jiggle
Messages
775
we know that glycolyis, fatty acid metabolism go wrong.
pyruvate dehydrogenase dysfunction has been found in other diseases (alzheimers, parkinson and what not) as well.

iits old news.
it leads to nothing. zilch.

they may be just desperate in explaining their rituximab.

they have no clue and dont know what they are doing.
such sort of "research" just underlines that.
its aweful. scaring. horror. for us.
 

TiredSam

The wise nematode hibernates
Messages
2,677
Location
Germany
I suspect from the anecdotal data that there is at least a large subset with ME who do better on higher protein.
Here's an anecdote based on a sample of 1 - about 3 months ago I decided it was time to lose weight (6 kg so far, thanks for asking). So I switched from spreading the usual jams, peanut butter, cheese spreads etc on my bread in the evening to just putting slices of lean meat on them, or tuna, and eating more boiled eggs. In the same time period I have noticed a significant improvement in my ME symptoms and am now dangerously well (ie my biggest problem now is to stop myself from doing more because I feel ok. I still have my limits and will still crash, but it's getting harder to remember that because I don't have a headache all the time to remind me).

I thought the correlation between my change in diet and ME improvement could be due to just losing a bit of weight and generally eating more healthily, but now it looks like it may be due to my increased protein intake over the last 3 months?

Meat and red wine - I will continue experimenting with the Gout Diet and report back.
 
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Kati

Patient in training
Messages
5,497
One question to the biochemists here: do recent metabolic studies tell us what diet would be ideal? Should we try to increase consumption of certain nutrients? What's the story with males and amino acids? This study here says that males are breaking down proteins at increased rate in order to make energy. Should malesincrease amino acids in their diet? Whitney seemed to benefit from amino acid supplementation.

The paper specifically mentions that there is no nutritional deficiencies present in either patient or control groups, it is simply how the body utilizes the amino acid that is the difference. The experiment of introducing ME plasma to healthy muscle cells shows that that the muscle cells behave differently is most interesting and hopefully it will pique the curiosity of many more scientists.

I do not believe that the study said that male subjects were breaking down proteins any faster. The opposite actually, as all of these experiments yielded significant results for women but not in men, with the suggestion that the number of men was not sufficient enough to provide statistical power.

So take home message: eat well, eat varied and fund research.
 

Countrygirl

Senior Member
Messages
5,429
Location
UK
http://www.kon.org/urc/v10/rahim.ht

The above was posted elsewhere by our very own in-house God of Pleasure, but I don't think he has posted it anywhere here.

It is useful for those of us who don't have a spare PhD in biochemistry lying around.


Pyruvate Dehydrogenase Complex Deficiency (PDCD)
Zhilwan Rahim
Park University

Introduction
One of the most important molecules in the body undoubtedly is adenosine triphosphate (ATP). The process or pathways of making these molecules is considered even more important. This molecule is important to us, due to the vast requirement of it, which is involved in almost every reaction in the body. It is relatively clear the profound results that would yield in the absence and or decrease of production of this vital molecule. The process of producing ATP is similar to that of a domino effect; it consists of many metabolic pathways that ultimately lead to our product (9).
There are many different sites in this domino effect that are extremely important and necessary in order for things to run smoothly. The site, or rather complex that is going to observed, analyzed, and discussed in detail is the pyruvate dehydrogenase complex (PDC). PDC has a special job in the process of producing ATP. The conversion of pyruvate (product of glycolysis) to acetyl CoA (one of the starting products of the citric acid cycle), is accomplished by this very complex (10). As seen and discussed in great detail later on, this complex is composed of many different proteins and enzymes that work synergistically for the greater good (11).

The specific site (or transition state) in which intermediate products have to be converted for the domino effect to persist is going to be the target of this investigation. The main objectives of this paper is to highlight a specific abnormality at the E1 alpha subunit that can transpire, the mechanism for this abnormality, disorders related to them, differences and similarities in Prokaryotes verse Eukaryotes, and other pathways involved.

Specific Site (PDC)

Like mentioned above, the Pyruvate dehydrogenase complex is extremely important when it comes to ATP production. Although this complex doesn’t directly yield our product, the product that is fabricated by these enzymes have a major role in the proceeding metabolic pathways that lead to ATP production (12).

rahim_clip_image002.jpg

(Figure 1.1, central metabolic pathways – Lehninger Principle of Biochemistry, fifth edition)

So why is PDC so important? Well, one of the biggest functions of this complex is to perform oxidative decarboxylation of Pyruvate (7). In order to fully understand the importance of this complex, a brief discussion of glycolysis is necessary.

In glycolysis, one molecule of glucose (a 6 carbon molecule) is converted into two pyruvate (a 3 carbon molecule) molecules (refer to Figure 1.1). In that process (glycolysis), 2 molecules of ATP are invested to produce pyruvate, which is useless if PDC is not functioning properly.6 At this point, the pyruvate molecule has many fates. As you can see in figure 1.2, one of those paths includes the conversion of Pyruvate to ethanol or lactate (in the absence of oxygen, or abnormalities in the PDC). This occurs in a process called fermentation; the other pathway is the conversion of Pyruvate into acetyl CoA and the further oxidation of this molecule in the Citric Acid Cycle (this leads to the electron transfer chain and oxidative phosphorylation that ultimately synthesizes ATP).7,12

rahim_clip_image004.jpg

(Figure 1.2 Fates of Pyruvate, Biochemistry: A Short Course, 1st ed)

Components and Mechanism of PDC
PDC is located in the mitochondrial matrix. This complex is composed of 3 enzymes: pyruvate dehydrogenase (E1), dihydrolipoyl transacetylase (E2) and dihydrolipoyl dehydrogenase (E3).7 The complex also requires five cofactors (which are all derived from vitamins) that are vital for proper functioning of the enzymes.12 Furthermore, there are corresponding prosthetic groups that help support the PDC (refer to chart 1.3): TPP (thiamine pyrophosphate), Lipoamide, and FAD (flavin adeninedinucleotide).

rahim_clip_image006.jpg

(Chart 1.3 PDC. Lehninger Principle of Biochemistry, fifth edition)

The step by step process of how pyruvate is converted into acetyl CoA should be discussed in detail for clarification purposes.

In step 1, pyruvate reacts with the bound thiamine pyrophosphate (TPP) of pyruvate dehydrogenase (E1), undergoing decarboxylation to the hydroxyethyl derivative (see Figure 1.4). Pyruvate dehydrogenase is also responsible for carrying out step 2, the transfer of two electrons and the acetyl group from TPP to the oxidized form of the lipoyllysyl group of the enzyme, dihydrolipoyl transacetylase (E2), to form the acetyl thioester of the reduced lipoyl group. In Step 3 we have a trans-esterification in which the SH group of CoA replaces the SH group of E2 to yield acetyl-CoA and the fully reduced (dithiol) form of the lipoyl group. In step 4 dihydrolipoyl dehydrogenase (E3) promotes the transfer of two hydrogen atoms from the reduced lipoyl groups of E2 to the FAD prosthetic group of E3, restoring the oxidized form of the lipoyllysyl group of E2. In step 5, the reduced FADH2 of E3 transfers a hydride ion to NAD+, forming NADH. The PDC is now ready for another catalytic cycle (5).

rahim_clip_image008.jpg

(Figure 1.4 Mechanism of PDC. Biochemistry: A Short Course, 1sted)

To review of what has happened thus far, we took a glucose molecule and produced two molecules of pyruvate through a process called glycolysis. In an oxygen rich environment (and the proper functioning PDC), pyruvate is converted into acetyl CoA through a multi-step, multi-enzyme subunit complex and transferred into the mitochondria. Acetyl CoA is then put into the citric acid cycle (CAC) to propagate another pathway that ultimately leads to the production of reduced FADH+ and NADH2 (4). These electron carriers are going to run through the electron transport chain, which directs ATP synthesis. One can now see the importance of PDC and how it links the metabolic pathways together (8). If an abnormality were to occur, then the outcome would be profound.

E1 Alpha Gene Mutation
Frye and Benke1 state thatPyruvate dehydrogenase complex deficiency is one of the most common neurodegenerative disorders associated with abnormal mitochondrial metabolism.” Looking back at the metabolism of glucose, we observed the process by which pyruvate was produced at the
 

dannybex

Senior Member
Messages
3,561
Location
Seattle
The paper specifically mentions that there is no nutritional deficiencies present in either patient or control groups, it is simply how the body utilizes the amino acid that is the difference. The experiment of introducing ME plasma to healthy muscle cells shows that that the muscle cells behave differently is most interesting and hopefully it will pique the curiosity of many more scientists.

Perhaps I missed it (eyes are wiped out) but I couldn't find where it 'specifically' mentioned there were 'no nutritional deficiencies' between the two groups, especially of those that help may help improve mitochondrial function. Could you quote where they ruled out any specific nutritional deficiencies?

It's worth noting they didn't mention (that I could see) what might be interfering w/PDH, like heavy metals or other environmental toxins, not to mention toxic byproducts from bacterial, viral, fungal infections like acetaldehyde, just as one example. For some people oxalates can be a problem, and oxalate impairs both pyruvate kinase and pyruvate dehydrogenase.

I do not believe that the study said that male subjects were breaking down proteins any faster. The opposite actually, as all of these experiments yielded significant results for women but not in men, with the suggestion that the number of men was not sufficient enough to provide statistical power.

Quoting: "Concentrations of 3-methylhistidine (3-MHis), a marker of endogenous protein catabolism (e.g., muscle atrophy) (28, 29), were significantly higher in men with ME/CFS compared with healthy men."

Which unfortunately I can relate to. And the high lactate.
 

Snow Leopard

Hibernating
Messages
5,902
Location
South Australia
The paper specifically mentions that there is no nutritional deficiencies present in either patient or control groups, it is simply how the body utilizes the amino acid that is the difference. The experiment of introducing ME plasma to healthy muscle cells shows that that the muscle cells behave differently is most interesting and hopefully it will pique the curiosity of many more scientists.

I do not believe that the study said that male subjects were breaking down proteins any faster. The opposite actually, as all of these experiments yielded significant results for women but not in men, with the suggestion that the number of men was not sufficient enough to provide statistical power.

So take home message: eat well, eat varied and fund research.

I agree with most of what you said, and agree that these findings are unlikely to be due to nutritional deficiencies.

But the authors did explicitly find increased signs of muscle breakdown:
"Concentrations of 3-methylhistidine (3-MHis), a marker of endogenous protein catabolism (e.g., muscle atrophy) (28, 29), were significantly higher in men with ME/CFS compared with healthy men (P = 0.003 by t test, Cohen’s d = 0.80), while there was no corresponding difference in 3-MHis between female ME/CFS patients and healthy women (Table 2 and Figure 2, I and J)."
 

Kati

Patient in training
Messages
5,497
Perhaps I missed it (eyes are wiped out) but I couldn't find where it 'specifically' mentioned there were 'no nutritional deficiencies' between the two groups, especially of those that help may help improve mitochondrial function. Could you quote where they ruled out any specific nutritional deficiencies?

Sorry I can't copy and paste on my ipad, it was in the 'discussion' if I remember well, and they said that there was no nutritional amino acid deficiencies, meaning it's not caused by a protein-poor diet. Moreover they tested patients of all body weights (BMI) and they could see the differences across all body sizes in women.
 
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