Metabolic profiling indicates impaired pyruvate dehydrogenase function in myalgic encephalopathy/CFS

JaimeS

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Today's longshot: Could this be something worth trying out for Christmas?
Don't think it could hurt.

My daughter was shown to have autoantibodies to the pyruvate kinase receptors in the basal ganglia.
PDH kinases would inhibit the activity of PDH enzymes.

If your daughter had antibodies to these, the most direct result -- all other things being equal -- is that her PDH enzyme activity would increase. This paper is talking about a decrease in PDH enzyme activity.

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 males increase amino acids in their diet? Whitney seemed to benefit from amino acid supplementation.
This is at least decent evidence that women should lean on protein-rich diets, because we appear to be relying on amino acids for energy. Men don't seem to have the same issues with depleted aas -- could they be 'leaning' on fatty acid oxidation in a similar manner to the way that women are 'leaning' on aas? This paper doesn't address the latter one way or the other.

Considering it's a very low-risk intervention, though, I don't see the harm in giving it a try.

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
This study wouldn't contradict that women store fat long-term, so they're breaking down their proteins for energy, and men use fat more readily. I'm not sure whether this is correct in the slightest, but the study as it is would agree with you, not disagree.

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.
Ooooooooh! <3 <3 <3 @alex3619 this is why you are my favorite. ;)

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).
n=2. Same.

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?
Specifically, they said that there were no correlations between aa levels and dietary intake, I think.

Just because you've got a good amount of protein for a normal human, though, doesn't mean we wouldn't need more -- as the recommendation to supplement with certain amino acids in more traditional PDH deficiency implies. Fluge and Mella's tentative conclusion is that we are using aas as an energy reserve. Just because we are eating the same diet as others doesn't mean it's the right diet for us.

I think it was dietary intake, and there was something about BMIs being the same as well. Please correct me if this is wrong.

Personally being overweight and having attempted an atkin's type of diet and gained 10 lbs in the first week, I would be stupid to try this.
If it doesn't work for you, it doesn't work for you. :)

How would this be likely to show up on a Nutreval test if at all? Would the pyruvate levels (urine) be increased if it's not being converted into acetal CoA?
@ChrisArmstrong 's paper showed that pyruvate was decreased in the urine. This showed up on his older results (2015) and newer results (just came out). There was no change in the pyruvate in the blood shown in his most recent study. I'm not sure that Fluge and Mella measured it in the blood in this study. (Can anyone help w/that? I'm pretty fried.)

-J
 

Tuha

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Regarding this paper I would like to share my experiences. I tried ketogenic diet and I got 20 % more energy already after 2-3 days. I didnt have any problem to follow this diet but after 4 months I suddenly started to feel hypoglycemic so I had to put more carbs into my diet (but I still eat less carbs then before).

What was good that even if i put more carbs it seems that the energy level stayed the same. So I ask myself if it was ketogenic diet which had positive impact on my energy level or it was just more proteins which I put into my diet. Before I wasnt vegetarian but I didnt eat too much meat.

So maybe what is important is not to reduce carbs but to eat more proteins. What do you think about?
 

Hip

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I wonder whether we can couple these Fluge & Mella et al findings of inhibited pyruvate dehydrogenase function with the Myhill, Booth and McLaren-Howard (MBM) studies on energy metabolism dysfunction in ME/CFS?

The MBM studies found several energy metabolism dysfunctions in ME/CFS patients; in particular, they found that mitochondrial translocator protein is blocked in most patients. Translocator protein (also called the adenine nucleotide translocator) is the mechanism by which ATP generated in the mitochondria is transported out of the mitochondria and into the cytosol of the cell, where the ATP is used as energy. Translocator protein also transports ADP (= the spent ATP) back into the mitochondria for recycling.

In the MBM 2012 study, they say:
If TL [translocator protein] is not working properly, oxidative phosphorylation will be inhibited, pyruvate dehydrogenase becomes inhibited and also the Krebs cycle [14].
So MBM are saying that if the translocator protein is blocked, pyruvate dehydrogenase automatically becomes inhibited.

So might the impairment of pyruvate dehydrogenase function that Fluge & Mella found be a knock-on effect, resulting from the blocked and dysfunctional translocator protein that MBM found in ME/CFS patients?

Seems feasible to me.



Grand Unifying Theory of ME/CFS

I am interested in mitochondrial translocator protein, because it might be the basis of a Grand Unifying Theory of ME/CFS, which is as follows. This myocarditis study (full paper here) on coxsackievirus B infections of the heart muscle found that CVB appears to triggers an autoimmune attack on translocator protein. This appears to be due to the fact that the VP capsid protein from coxsackievirus B has cross-reactivity to mitochondrial translocator protein.

The study also determined that the virally-triggered translocator protein autoantibodies in these heart muscle infections blocked the functioning of the translocator protein. And remember that blocked translocator protein was observed in many ME/CFS patients in the MBM studies.

Now we all know that chronic coxsackievirus B infections of the skeletal muscles are linked to ME/CFS, but it is not clear how such infections could cause the autoimmunity that Fluge and Mella found in ME/CFS, nor the energy metabolism dysfunctions that MBM, Fluge and Mella, and other research groups have found.

But that single CVB myocarditis study could be the link: it could explain how these 3 observed facets of ME/CFS — the viral infection, the autoimmunity, and the energy metabolism dysfunction — all tie together to create a Grand Unifying Theory of ME/CFS:

CVB infection triggers translocator protein autoantibodies which whack the mitochondria leading to ME/CFS

Note that translocator protein is also called the adenine nucleotide translocator (ANT).

More information about translocator protein autoantibody theory of ME/CFS here.
 
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Hip

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Yes, that sodium dichloroacetate is DCA. Regarding safety, see here:
The Medicor Centre has treated over 1,500 patients with DCA (28), with no deaths or non-reversible side effects due to DCA.

The balance of evidence is that DCA is safe, if:

The correct DCA dosage is observed;
Caffeine intake is monitored;
Nerve neuropathy is controlled using vitamin B1 (thaimine);
Sufficient water is taken to avoid Tumor Lysis Syndrome (TLS); (9)
The dosage schedule has regular breaks.

It says here that:
Side effects to DCA are all reversible. With oral DCA, the most common side effects include: peripheral neuropathy (numbness in an area of the body, with or without associated nerve pain; experienced in 15% of patients), fatigue (15%) and confusion/reduced memory (15%).
It says here about side effects:
Neurological:
Nerve injury in the hands and feet (“peripheral neuropathy”). Neuropathy typically takes several weeks to months to develop, and is reversible if it is caught early. In the existing literature, neuropathy from DCA has always been shown to be reversible.

We use vitamin B1 (benfotiamine or thiamine), acetyl L-carnitine and R alpha lipoic acid to prevent and reduce the severity of peripheral neuropathy. These medicines can be given orally or intravenously depending on the degree of neuropathy.

Published data clearly demonstrates all of these medicines can help chemo and/or diabetic neuropathy, and our own extensive experience confirms that these supplements are effective for DCA neuropathy as well.

Sedation, confusion, hallucinations, memory problems, mood changes, hand tremors. These side effects are temporary and appear to be dose-dependent and age-dependent. This finding is consistent with existing human research on DCA that we have reviewed. We use benfotiamine (a type of vitamin B1), acetyl L-carnitine and R alpha lipoic acid to prevent/reduce these side effects.

Sedation, confusion, hallucinations, memory problems, mood changes, hand tremors. These side effects are temporary and appear to be dose-dependent and age-dependent. This finding is consistent with existing human research on DCA that we have reviewed. We use benfotiamine (a type of vitamin B1), acetyl L-carnitine and R alpha lipoic acid to prevent/reduce these side effects.

Gastrointestinal:
Heartburn, nausea, vomiting, indigestion. These side effects may occur with DCA, and we prescribe a “proton pump inhibitor” antacid medication (e.g. pantoprazole) as needed to treat them.

Other Side Effects:
Some patients experience pain at the sites of their tumour(s) within the first few days of starting DCA. This may be an indicator of the effectiveness of DCA. About 1-2% of patients have mild liver toxicity (increase in liver enzymes noted without symptoms). We have not observed any drop in blood cell counts due to bone marrow toxicity, or any other significant organ toxicity. Note that leukemia patients may see a drop in their high white blood cell count, indicating destruction of the cancerous white cells.
So a good insurance against DCA neuropathy might be say: benfotiamine 300 mg + acetyl L-carnitine 500 mg + alpha lipoic acid 200 mg taken two or three times daily.

And if any signs of neuropathy do occur, they are apparently reversible in the early stages, so provided you stop taking DCA if you get any neuropathy symptoms, the neuropathy should fix itself.



In the UK, you can buy 25 grams of sodium dichloroacetate for £32 on Amazon here.

Note that diisopropylamine dichloroacetate (DADA) has a carcinogenicity question mark next to it, whereas sodium dichloroacetate (the one usually found for sale online) apparently does not.


Note: if you see my post above, perhaps the issue with many ME/CFS patients may be a translocator protein blockage, which as a knock-on effect then causes pyruvate dehydrogenase inhibition. If so, then perhaps DCA may not help that much.
 
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ash0787

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It might not be antibodies, I think that idea became popular because the main function of those particular white blood cells is to make antibody, but it seems like these scientists think there is possibly other roles that they have. It would make sense to me if it wasn't antibodies because I always had a 'feeling' that it was unlikely to be that, even though there are some things that suggest precedence for them traversing cell walls and a reason they might choose to attack mitos. With these theorized 'signalling' molecules it does sound like they are having to break new ground in trying to find out how exactly the metabolism is controlled, so it seems they don't already know this in great detail.
 

Hip

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some things that suggest precedence for them traversing cell walls and a reason they might choose to attack mitos.
According to the CVB myocarditis study I mentioned above, the autoantibodies that target the mitochondrial translocator protein have cross-reactivity to the VP capsid protein from coxsackievirus B. So it looks like the immune system has made antibodies which target this viral VP protein, in order to attack the virus; but it turns out that these same antibodies also unfortunately target the translocator protein, thus whacking the mitochondria and creating an energy shortage.

So it could well be that the molecular similarity between Coxsackie B virus VP protein and the mitochondrial translocator protein is the whole basis for why this virus can trigger ME/CFS.
 

TreePerson

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Sorry can't cope with the quoting thing. Does anyone in this thread who has been discussing higher protein diets know if in theory l carnatine would help? At this stage in the energy process?
 

Marco

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It's worth noting that these findings are consistent with mechanisms for muscle fatigue proposed by Julia Newton's team :

The phenotype of fatigue exhibited by CFS/ME patients closely mirrors that seen in fatigue associated primary biliary cirrhosis patients (PBC). For example, Hollingsworth et al. [81] reported PBC patients to exhibit significant acidosis due to an overutilisation of the lactate dehydrogenase pathway, following a low-level repeat exercise protocol [81]. Furthermore, the authors postulated that the increased dependence on anaerobic pathways of energy production resulted in the fatigue associated with PDC. The idea that impaired PDC function leads to an overutilisation of the lactate dehydrogenase pathway is in agreement with other studies.
https://www.hindawi.com/journals/jar/2016/2497348/
 
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So might the impairment of pyruvate dehydrogenase function that Fluge & Mella found be a knock-on effect, resulting from the blocked and dysfunctional translocator protein that MBM found in ME/CFS patients?
I don't think so. To start with, it doesn't agree with the cell culture results of this study various biopsy studies, or this study of mitochondria.

Fluge & Mella showed the reduction in PDH activity was likely due to PDH kinases 1, 2, 4 and in turn, regulated by PPARδ. This provides a potential link with the other metabolism studies out recently, noting some differences in fatty acid metabolism (note the Hanson study found increased palmitate which is known to activate PPARδ).

 
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Yes, dichloroacetate (DCA) will up-regulate the pyruvate dehydrogenase complex. Detailed in this post.

Someone a few years ago on this forum tried DCA — see this thread — and got some positive results.
Clinical trials have revealed that DCA is ineffective in some patients with mitochondiral diseases and noted some nerve toxicity in some patients.

https://en.wikipedia.org/wiki/Dichloroacetic_acid#Lactic_acidosis

I don't recommend trying this drug outside of a supervised medical intervention (eg clinical trial).
 

Barry53

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According to the CVB myocarditis study I mentioned above, the autoantibodies that target the mitochondrial translocator protein have cross-reactivity to the VP capsid protein from coxsackievirus B. So it looks like the immune system has made antibodies which target this viral VP protein, in order to attack the virus; but it turns out that these same antibodies also unfortunately target the translocator protein, thus whacking the mitochondria and creating an energy shortage.

So it could well be that the molecular similarity between Coxsackie B virus VP protein and the mitochondrial translocator protein is the whole basis for why this virus can trigger ME/CFS.
Very interesting. What sort of study/trial would therefore be needed to prove/disprove this hypothesis?
 

Gijs

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All these metabolic studies are inconsistent. This is not a cause but secondary. First it must be replicated. I don't think this or any metabolic study at this point is the smoking gun.
 

Marco

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Hopefully this isn't too much of a digression.

Working on the basis that neuroinflammation/microglial activation plays a key role in ME/CFS, for some time I've been looking for an immune signal that might be induced by the various everyday 'stressors' that exacerbate symptoms and microglial priming/activation.

The ubiquitous signalling protein HMGB1 I believe is a strong candidate (for more reasons than I can go into right now). What I've been unsure about has been why HMGB1 would be higher (some sort of gain of function?) or have a greater effect in ME/CFS and whether or not ongoing peripheral input was necessary to maintain neuroinflammation.

This paper suggests that impaired pyruvate dehydrogenase function could be the necessary peripheral stressor :

PKM2 regulates the Warburg effect and promotes HMGB1 release in sepsis

http://www.nature.com/articles/ncomms5436

In short metabolic control of inflammation.

Inhibition of PDH complex function by pyruvate kinase induces the Warburg effect (aerobic glycolysis) which in turn releases HMGB1, an inflammation 'accelerant' resulting in sepsis (and in my model would feed 'neuroinflammation).

Bearing in mind that @ChrisArmstrong has compared the metabolic state in ME/CFS to the Warburg effect (and sepsis/starvation) while Montoya stated that in gene expression studies the closest match to ME/CFS is sepsis/SIRS.
 

Manganus

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It would make sense to me if it wasn't antibodies because I always had a 'feeling' that it was unlikely to be that, even though there are some things that suggest precedence for them traversing cell walls and a reason they might choose to attack mitos.
I really wonder if the mitosis as such may be attacked. Actually, I would doubt it.

It's an energy-dependent process, very much so in some parts, so when the availability of ATP is low, the process would be halted or hampered anyway, without any certain kind of attacks against for instance DNA replication, chromosome condensation, chromosome separation, extra lipid and protein synthesis, etc., etc.
 

Hip

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What sort of study/trial would therefore be needed to prove/disprove this hypothesis?
I would guess that the first step would be to check and see if ME/CFS patients have autoantibodies which target the mitochondrial translocator protein (also called the adenine nucleotide translocator, or the ATP-ADP translocator).

As far as I know, there have not been any studies which have checked for translocator protein autoantibodies in ME/CFS patients.

Chronic coxsackievirus B infection of the heart muscle (CVB myocarditis) can give rise to these translocator protein autoantibodies (since the VP capsid protein from coxsackievirus B has cross-reactivity to mitochondrial translocator protein); so it is quite possible that the chronic CVB infections of the skeletal muscles found in ME/CFS patients might also produce the same translocator protein autoantibodies — thus neatly explaining why in ME/CFS the muscles are so short of energy.



One of the best ME/CFS biomedical researchers in the UK, Professor Peter Behan, back in 1985 — in the days when UK ME/CFS research had not yet been usurped by the psychobabblers — said in this paper that:
an autoantibody, such as the anti-mitochondrial antibody recently identified in patients with viral myocarditis, might be involved
Here Behan is saying that autoantibodies like the mitochondrial translocator protein that, at that time, had just been discovered in viral myocarditis might be responsible for ME/CFS. translocator protein is also called the adenine nucleotide translocator (ANT).

So Prof Behan, even back in 1985, was already on to the idea that ME/CFS could be caused by an autoimmune attack on the mitochondria, leading to energy metabolism dysfunction.

More info on Professor Peter Behan's ANT autoantibody theory of ME/CFS here.
 
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Hip

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Fluge & Mella showed the reduction in PDH activity was likely due to PDH kinases 1, 2, 4 and in turn, regulated by PPARδ.
But do we know whether the increase in PDH kinases is a cause or consequence of the reduction in PDH activity?


I wonder whether there might be an autoantibody in ME/CFS that targets the mitochondrial pyruvate carrier, the protein located on the inner mitochondrial membrane that is responsible for transporting pyruvate into the mitochondria. Without this carrier, pyruvate cannot get into the mitochondria.

If the mitochondrial pyruvate carrier was whacked by autoimmune attack, that could explain why pyruvate dehydrogenase (PDH) function is inhibited in ME/CFS — because there would be very little pyruvate being carried into the mitochondria for PDH to process.
 
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