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

Kati

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Although some (congenital) PDH deficiency disorders respond to thiamine supplementation and to a lesser extent a ketogenic diet.
For our patient group though, you'd hope that the fatty acid oxydation is going on normally, which is not necessarily a given for each and every patients.

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. i'm going to wait for more papers to come through and my doctor's advice. So much more research is needed.
 

dannybex

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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 woights (BMI) and they could see the differences across all body sizes in women.
I agree, they said no nutritional amino acid deficiencies, but didn't see any discussion of other deficiencies besides proteins. :)
 
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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)...
That's a good discovery. It dovetails nicely with observations that large-scale breakdown of collagen (the body's most abundant structural protein) is occurring in a group of PWME. The skin is home to large collagen stores and stretchy skin, indicating catabolism thereof, is a somewhat common symptom. (See also this thread.)
 
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ash0787

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no roller isn't trolling he is just fixated on one particular line of inquiry for some reason,
I understand his concern but I think if there is a persistent pathogen its likely to be one that doesn't cause a lot of damage / is relatively inactive or localized, otherwise it would be fairly easy to detect and the rituximab patients would become very ill no ?
 

thegodofpleasure

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Dr Karl Morten (Neurosciences Group, Institute of Molecular Medicine, Department of Clinical Neurology, University of Oxford) is evidently an expert in these matters:

Dichloroacetate stabilizes the mutant E1α subunit in pyruvate dehydrogenase deficiency

http://www.neurology.org/content/53/3/612

I know that Dr Sarah Myhill's research colleague, Dr Norman Booth (Dept of Physics, Oxford) has encouraged him to get involved in ME/cfs research.

He gave a talk to the Oxford ME Support Group earlier this year (introduced by @charles shepherd)

His opinion on these findings would be of considerable value.
To have him replicate them would be even better.
 

Deepwater

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For our patient group though, you'd hope that the fatty acid oxydation is going on normally, which is not necessarily a given for each and every patients.

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. i'm going to wait for more papers to come through and my doctor's advice. So much more research is needed.
I can't lose weight on Atkins either, but lost a lot of weight on the Dukan diet, which is Atkins minus fat. As soon as I added a moderate amount of fat and carbs and into my diet the weight went straight back on.
 

Barry53

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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
Yes, if closed loop control mechanisms have gone awry, and you unwittingly mess directly with a badly controlled variable rather than fix the underlying problem in the closed loop regulation itself, then you may just force its bad regulation to do even weirder things. Especially if there happen to be several interdependent control loops in play, possibly with several of them faulty.
 

Marky90

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so a bit like some of the computer viruses you sometimes get, you think you have found the main files of the virus and you delete it, only for it to reappear later because another part of the virus elsewhere in the system is monitoring what you did
Maybe we are programmed to be sick :nervous: #Westworld #reference

I have skimmed through the paper, not carefully read it, as I lack the sufficient understanding of metabolomics anyway. It gets me thinking that we probably do not know a whole lot about the whole picture when it comes to how the body can work, but obviously this is a conclusion that`s very easy to come to when you know jack all about the particular subject anyway.

I`m starting to be doubtful that antibodies are the main culprit for the majority, mainly because very few seemingly get fully recovered by rituximab and cyclo (based on the trials, and the cyclo patent). Is it because in a majority long lived plasma cells are hard to reach? Might there be some pathological immunological "castle" somewhere, like in sarcoidosis? May other immunological processes not yet known of, "mimic", what seemingly seems like a case of autoimmunity?

I`m asking, because there are other severely debilitating diseases like e.g sclerodermia, which looks like autoimmunity, but dont respond properly to the treatment of it. Even autologous stem-cell transplantation does not always impact the level of functioning in these patients.

I feel that the fact that cultured muscle cells react to being exposed with ME-blood is a big lead, perhaps more than the concrete metabolic findings. At the very least it is a reason for the researchers to be completely open minded about what may be causing the metabolic abnormalities, and the cause might even be due to processes unknown of.
 

Hip

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Anyone have any ideas how to upregulate PDH?
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.



We found significant mRNA upregulation of PDK1, PDK2, and PDK4 in PBMCs from ME/CFS patients.
...
The function of the PDKs is to inhibit PDH
Dichloroacetate (DCA) boosts pyruvate dehydrogenase function specifically by inhibiting the pyruvate dehydrogenase kinases (PDK), and DCA does this by the same mechanism that pyruvate inhibits PDK. See here.

So DCA would seem like a good drug to try in order to boost pyruvate dehydrogenase function in ME/CFS.



DCA is sold online as an alternative/experimental cancer treatment. If you Google search on "dichloroacetate cancer buy" you will find some suppliers. It is a little expensive, but not prohibitively so (it would be worth the money if it works).


The anti-cancer effect of DCA is thought to be due to its ability to:
"reactivate suppressed mitochondria in some types of oxygen-starved tumor cells, and thus promotes apoptosis.

DCA is known to be relatively safe, available, and inexpensive, and it can be taken by mouth as a pill."
Ref: 1
 
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Although some (congenital) PDH deficiency disorders respond to thiamine supplementation and to a lesser extent a ketogenic diet.
I'm excited to try a ketogenic diet. Providing ketones would bypass PDH, right? Ketones could maybe then provide an energy source and spare proteins. I've been considering trying it anyway.
 

Forbin

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Is the idea that autoantibodies are attacking PDH? This is apparently part of the etiology of primary biliary cirrhosis (PBC). According to the Wikipedia article on PBC, the disease is "strongly associated" with the presence of a bacterium that is "cross reactive" with liver cell mitochondria. Also...
"Most of the patients (>90%) have anti-mitochondrial antibodies (AMAs) against pyruvate dehydrogenase complex (PDC-E2), an enzyme complex that is found in the mitochondria."
I'm guessing that means that, in going after the bacteria, the immune system starts going after PDH enzyme as well [but I could be wrong].
In 2003 it was reported that an environmental Gram negative alphabacterium —Novosphingobium aromaticivorans was strongly associated with this disease [PBC]. Subsequent reports appear to have confirmed this finding suggesting an aetiological role for this organism. The mechanism appears to be a cross reaction between the proteins of the bacterium and the mitochondrial proteins of the liver cells

https://en.wikipedia.org/wiki/Primary_biliary_cirrhosis#Causes
If the immune system were going after PDH, might cells down-regulate the production of PDH as a defensive countermeasure?

[I could be misinterpreting the above, but, if this is going on, I wonder if other bacteria, say, from "leaky gut," could trigger a similar process. It seems as though "leaky gut" itself might be triggered by an altered microbiome, which, in turn, might be the result of a variety of strong immune responses to viruses, toxins, physical injury, etc... This might explain the multiple triggers, in that they funnel down to one cause, i.e. bacterial translocation from GI tract.]
 
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lansbergen

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http://m.worldpapercat.com/1766/Article3360782.htm

Regulation of Pyruvate Dehydrogenase Activity In Rat Fat Pads And Isolated Hepatocytes by Levamisole

. Levamisole at 1.5 mM and 2.0 mM were as potent as insulin (1.0 mU/ml) in adipose tissue and as dichloroacetate (2.0 mM) in isolated hepatocytes, respectively, in increasing the catalytic activity of the PDH complex.