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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. JaimeS

    JaimeS Senior Member

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  2. JaimeS

    JaimeS Senior Member

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    Don't think it could hurt.

    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.

    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.

    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.

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

    n=2. Same.

    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.

    If it doesn't work for you, it doesn't work for you. :)

    @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
     
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  3. alex3619

    alex3619 Senior Member

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    This might make sense as in an energy deficient state the body might be converting much of it to lactate.
     
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  4. Tuha

    Tuha Senior Member

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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?
     
  5. Hip

    Hip Senior Member

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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:
    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
     
    Last edited: Jan 11, 2017
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  6. Hip

    Hip Senior Member

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    Yes, that sodium dichloroacetate is DCA. Regarding safety, see here:

    It says here that:
    It says here about side effects:
    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.
     
    Last edited: Jan 25, 2017
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  7. ash0787

    ash0787 Senior Member

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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.
     
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  8. Hip

    Hip Senior Member

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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.
     
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  9. TreePerson

    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?
     
  10. Marco

    Marco Grrrrrrr!

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

    https://www.hindawi.com/journals/jar/2016/2497348/
     
  11. Snow Leopard

    Snow Leopard Hibernating

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    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).

     
    Last edited: Dec 24, 2016
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  12. Snow Leopard

    Snow Leopard Hibernating

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    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).
     
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  13. Barry53

    Barry53 Senior Member

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    Very interesting. What sort of study/trial would therefore be needed to prove/disprove this hypothesis?
     
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  14. Gijs

    Gijs Senior Member

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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.
     
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  15. Cheesus

    Cheesus Senior Member

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    How so?
     
  16. Marco

    Marco Grrrrrrr!

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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.
     
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  17. Manganus

    Manganus

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    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.
     
  18. Hip

    Hip Senior Member

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    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:
    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.

    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.
     
    Last edited: Jan 11, 2017
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  19. Hip

    Hip Senior Member

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    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.
     
    Last edited: Dec 24, 2016
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  20. A.B.

    A.B. Senior Member

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    Seems to be causal. The PDH kinases reduce PDH activity.
     

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