New Atmosphere, New Vision: Gibson and Whittemore Kick Off Invest in ME Conference 2016
Mark Berry reports on Dr. Gibson's introduction and Dr. Whittemore's keynote speech, at the 11th Invest in ME International ME Conference in London.
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Metabolic profiling indicates impaired pyruvate dehydrogenase function in myalgic encephalopathy/CFS

Discussion in 'Latest ME/CFS Research' started by deleder2k, Dec 22, 2016.

  1. Hip

    Hip Senior Member

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    Sorry, I meant to say above: "do we know whether the increase in PDH kinases is a cause or consequence of the reduction in PDH activity?" I have corrected my above post.


    So you say that increased PDH kinase activity will decrease pyruvate dehydrogenase function, but not likley the other way around? In other words, if pyruvate dehydrogenase activity were reduced because for example of a lack of pyruvate entering the mitochondria, you suggest that this would not affect the expression of PDH kinases?
     
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  2. ash0787

    ash0787 Senior Member

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    If you think its inconclusive then wait for Naviaux's follow up, thats the one with all the attention and scrunity on it

    Hard to argue with the other experiment they are doing though which is the same one that ron was doing,
    the design of the experiment is quite simple and there is no room for interpretation .
     
  3. A.B.

    A.B. Senior Member

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    That would reduce the expression of PDH kinases. At least that's how I understand it.
     
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  4. M Paine

    M Paine Senior Member

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    In all likelihood, the up regulation of PDH kinases is regulated by cytokine activity and is not abnormal. The PDH enzyme downregulation helps to explain the metabolic consequences of this disease state, but the upstream source(s) of the signal to switch gears away from oxidative phosphorolation, to instead sustrate-level phosphorolation, yet remains a mystery.

    It's worth mentioning that reducing oxidative phosphorolation is likely somehow protective in some situations involving pathogens.
     
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  5. alex3619

    alex3619 Senior Member

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    This is what ties into the hypothesis that its pathogen induced. The benefits are twofold. First, there is more energy for the immune system, and second, any intracellular pathogen, such as viruses, will find decreased energy and so its replication and spread in the body will be decreased.

    The issue that still remains is whether non-lytic infections are a big issue, or is it the hit and run idea where the infection sets this up and it does not turn off. My guess is that it might be both, which might mean there are subgroups where restoring energy is good, and others where restoring energy is bad. That is why its so important to wait for the science.

    Having said that I find that I am even considering yet more dietary and other changes outside of a clinical trial. Time waits for no patient.
     
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  6. Marky90

    Marky90 Science breeds knowledge, opinion breeds ignorance

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    Random thought: Would it not make sense to start omitting cells and the like from the blood of ME-patients until the muscle cells potentially dont react badly to our blood? I don`t know how possible that is, and obviously enormously tedious, but we dont have much else to do..
     
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  7. Navid

    Navid Senior Member

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    Can you share with the board what your ideas are around these changes : )

    Thanks!!
     
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  8. Kati

    Kati Patient in training

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    This is an important point: the metabolomics may point out to dysfunction but it would be too early to discuss causation. We may well be having a look at the downstream effect (metabolomics).

    Also: there may be individual variations in metabolomic patterns.
     
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  9. alex3619

    alex3619 Senior Member

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    I am still trying to figure it out. One idea I have played with for a long time fits this concept, which is low fat, low carb, high protein. I have done high protein with increased fat, and high carb with almost no fat or protein (I was vegetarian to see if it helped ... it didn't), but not the high protein, low carb, low fat.

    One thing that is very vital in something like this is to ensure you consume at least a tiny amount of essential fats, they are indeed essential. Its also important to have lots of low energy vegetables because keeping up the vitamins and minerals is important. I would also be considering going on a vitamin and mineral supplement because restricting diet can restrict nutrients. Finally I would want to pay attention to fat soluble nutrients, like CoQ10. I would want them to be boosted too. Just as lowering salt intake can impact iodine, lowering fat intake can impact vitamin A, CoQ10 etc.

    I wont be doing anything about this till some time January, and only after more consideration. I really like that there may be early steps at clinical intervention from some researchers next year.
     
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  10. Battery Muncher

    Battery Muncher Senior Member

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    Yes - in fact, I believe she had a PhD student working on something to do with PDC/PDH in ME/CFS. Gina Rutherford? I think. I didn't really keep up with it, but the project should have finished by now.

    I'm not sure if any research was published. Primary biliary cirrhosis was mentioned.
     
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  11. roller

    roller wiggle jiggle

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    if you want to starve the pathogens, allopurinol and likewise alfalfa may be good, for my findings and experiments.

    directly addressing the pyruvate-thing, i noted allanine and bh4, mainly.
    also diabetic drugs may help.
    but i dont know what was up-/downregulating what...
    its imo a dead end.
     
  12. Snow Leopard

    Snow Leopard Hibernating

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    It's almost as if I didn't post links to studies explaining how this stuff works a few pages ago.

    It's well established in many studies that PDH kinases reduce the activity of PDH. The expression of the kinases is known to be promoted by PPAR-delta (particularly PDK4). The current study shows an increase in PPAR-delta expression.

    It does not make sense that a decrease of PDH activity would have a negative feedback loop leading to further reduction in activity and any hypothesis along these lines would require a good explanation!
     
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  13. eljefe19

    eljefe19 Senior Member

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    Are there currently any ways to reduce PPAR-delta or is it way to early to even assume this would help?
     
  14. Snow Leopard

    Snow Leopard Hibernating

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    It is way too early to tell.
    PPAR-delta promotes multiple genes, so deliberately inhibiting it without understanding what is going on could cause problems too. More to the point, we need to understand why these genes are upregulated.
     
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  15. eljefe19

    eljefe19 Senior Member

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    Appreciate it. With this illness, sometimes it's hard to be patient, but you're right, knowing why the genes are upregulated in the first place probably is the smart before we start tinkering with things. Do you have any idea if there is any research currently underway to investigate this?
     
  16. Hip

    Hip Senior Member

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    The first study you posted earlier was this one:
    But I am not sure what you are referring to when you say "it does not agree." Could you explain what does not agree with what?



    Your view may well be right, but I am just offering an different explanation to consider. I am suggesting that a blocked mitochondrial translocator protein could well explain Fluge and Mella's findings of inhibited pyruvate dehydrogenase and activated pyruvate dehydrogenase kinases.

    If you want an explanation as to how, I'll have a stab at one: it says here that:
    So if you have a blockage in the translocator protein, I am guessing that this might lead to a build up of ATP in the mitochondria, because the translocator protein carries the ATP out of the mitochondria and into the cell.

    That ATP build up in the mitochondria would then activate the pyruvate dehydrogenase kinases, which would in turn inhibit the pyruvate dehydrogenase, which is what Fluge and Mella found.

    And since the translocator protein also carries the ADP back into the mitochondria, a translocator protein blockage would I presume lower the ADP concentration inside the mitochondria, which again would serve to activate the pyruvate dehydrogenase kinases.

    The MBM studies found translocator protein blockages in most ME/CFS patients.


    But this is just a suggestion, and I think your view is equally valid as an explanation.
     
    Last edited: Dec 25, 2016
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  17. M Paine

    M Paine Senior Member

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    I'm not sure why you're quoting me leopard, as I'm essentially in agreement with you.
     
  18. eljefe19

    eljefe19 Senior Member

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    @Hip Is there some explanation yet for why Rituximab would be helpful for some patients? In light of these recent discoveries.
     
  19. pogoman

    pogoman Senior Member

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    lol, I was wondering why the amino acids in the article weren't named either.

    Pyruvate dehydrogenase complex deficiency is one of the "inborn errors of metabolism" and there is quite a lot of info on treatments to reduce symptoms and lactic acid levels.
    The connection with encephalopathies has also been noted before.

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2771954/

    There is a test (I think its fairly new as I've never had it done until this month) called the anion gap test which along with the electrolyte panel can indicate lactic acid problems.
    Mine showed above normal high anion gap and below normal CO2 which points toward a metabolic acidosis.
    Some of the causes are the inborn errors of metabolism.
    Biotin, thiamine (B1) and baking soda are used in treatments for some of them.

    So I've been on high dose biotin along with normal B1 and sodium bicarbonate supplemtation for a week now to see if it would help.
    My nighttime neuro issues and muscle pain and stifness are improved, will see my neuro in Feb so I am going to discuss this with him then.
     
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  20. alex3619

    alex3619 Senior Member

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    There is no such hypothesis. The arguments are about immune regulation, and potential set points within the immune system that could lead to further pyruvate dehydrogenase problems. Its an unknown.

    My suggested dietary changes that I am thinking about are supportive, not aimed at correcting the core problem, but aiming for decreased secondary consequences. They are also hypothetical.

    Fixing the problem itself would ideally involve us understanding the cause. We don't, yet.
     

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