Invest in ME Conference 12: First Class in Every Way
OverTheHills wraps up our series of articles on this year's 12th Invest in ME International Conference (IIMEC12) in London with some reflections on her experience as a patient attending the conference for the first time.
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'Adding Pyruvate makes ME cells normal' - What questions does this prompt?

Discussion in 'General Treatment' started by AdamS, Apr 11, 2017.

  1. AdamS

    AdamS Senior Member

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    In Ron Davis's video, he says that adding pyruvate to their assays makes ME cells 'normal.' To me, this is a fascinating finding and gives us a strong clue/piece of the puzzle, (providing that the impedance test transfers well to real life of course, which i'm optimistic it will).

    Can we attempt to fill in any of the blanks here? Below are a few thoughts i've had...
    • If Pyruvate fixes ME patient's cells, does this suggest that it isn’t being made properly or that it is being made but not transported/utilised effectively?
    • Do any of our symptoms (e.g excess lactic acid buildup) give us any clues?
    • Could serum cytokines or an immune response affect pyruvate production/uptake or PDKs/AMPK?
    The purpose of this thread really is to try and spark some ideas and questions. All input welcome!

    Thanks, Adam
     
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  2. A.B.

    A.B. Senior Member

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    I'm a biochemistry amateur. My understanding is that it could be both. What this really shows is that energy production is a key problem. In the individual patient there could be both a problem with glycolysis (production of pyruvate) and PDH/PDK (utilisation of pyruvate). The recent research has highlighted that it's more a problem with utilisation. Last year Ron Davis also mentioned impairment of glycolysis but this was in severe patients and is unpublished research. A problem of utilisation of pyruvate would be consistent with excess lactic acid buildup during exertion.

    Some cytokines can suppress pyruvate dehydrogenase, but so far there isn't much evidence that this is actually what's happening in ME/CFS. Our researchers seem to think there's some different and possibly undiscovered mechanism at work.
     
    Last edited: Apr 11, 2017
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  3. AdamS

    AdamS Senior Member

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    Thanks for this @A.B.

    I'm certainly no expert myself. Great explanation, that was my thinking too, that it was to do with utilisation.

    I've often wondered if the underlying problem is the same for mild, moderate, severe and very severe patients. Interesting that Davis mentioned impairment of glycolysis in severe patients.
     
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  4. caledonia

    caledonia

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  5. A.B.

    A.B. Senior Member

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    The activity of pyruvate dehydrogenase is controlled by pyruvate dehydrogenase kinases which were increased:

    Metabolic profiling indicates impaired pyruvate dehydrogenase function in myalgic encephalopathy/chronic fatigue syndrome

    This would imply that there is a signal that tells the cell to inhibit PDH and it does so by making more of the relevant kinases.

    The article you're citing says that arsenic and mercury inhibit PDH by directly binding to it.
     
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  6. AdamS

    AdamS Senior Member

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    I'm going to add something else to the mix. PDK-1 is up-regulated in conditions of hypoxia, (in other words it increases in response to a decrease in cellular oxygen). My understanding is that in the context of ME, where our anaerobic thresholds have been found to be reduced, cellular hypoxia could theoretically occur at a lower level of exertion than in healthy people. If so, this could explain why the more we exert ourselves, the more PDH/energy production is deactivated and thus why we don't recharge properly after exertion. I could be wrong and i'm not suggesting that this is the sole cause of the problem, but it could be a contributory factor.
     
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  7. Tiger_Eyze

    Tiger_Eyze

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    Can you post a link to the video?

    I'm curious what criteria he used to define 'normal' & how much pyruvate had to be added to achieve the effect.

    Because, assuming blocked PDH is the problem, how would adding pyruvate normalize the cells if PDH is still being inhibited by PDK1, 2 & 4? By bypassing PDH and entering the TCA as OAA?

    Now if supra-physiological doses of pyruvate were added, perhaps the alternative pyruvate catabolism pathways (there are 5 or 6) were overloaded allowing a small fraction of the pyruvate to enter the TCA cycle using any low level remaining PDH function.

    Cytokines can affect glycolysis, PDKs, etc. via at least 1 route I am aware of -- inducing transcription &/or stabilization of Hif1a.

    F&M did not find increased mRNA for Hif1a in their study, so a sustained increase in transcription is less likely, but they did not check protein levels of Hif1a, so increased stabilization/decreased degradation of Hif1a could still play a role.

    NFkB & TNF-alpha are just 2 Cytokines that affect Hif1a levels.
     
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  8. halcyon

    halcyon Senior Member

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    It makes our immune cells (or a subset thereof) "normal" (i.e. makes them behave like immune cells from a healthy person). This is a novel assay and only a handful of ME patients have been tested against healthy people so far. The response seen in ME immune cells could be completely normal and expected for someone with white blood cells receiving immune activation signals from the serum, for example.

    It's really far too early to draw any conclusions about any of this.
     
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  9. kangaSue

    kangaSue Senior Member

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    https://www.jci.org/articles/view/90055
     
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  10. AdamS

    AdamS Senior Member

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    6m 16secs into the video he discusses pyruvate.


    Also at around 13m 45secs on this video he says 'in other words it would appear that pyruvate itself can cure the problem.'

     
    Last edited: Apr 12, 2017
  11. Aroa

    Aroa

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    Dr Davis said in his February video :

    " Fluge and Mella suggest pyruvate dehydrogenase is probably blocked. We have not
    investigated that, but it is consistent with glycolysis being shutdown. We also think that
    pyruvate kinase might be shutdown. Those are not inconsistent and it is possible there are
    blocks in both of them. This may be the heart of this disease "

    I presume this conclusion came from the severely ill study, but could this also be measured by the metabolomics validation study ?? ( sorry this may be too basic question but I am having a hard time trying to understand all these things)
     
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  12. AdamS

    AdamS Senior Member

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    @Aroa

    See below, this is from Fluge & Mella's study:

    For PDK1 gene expression, there were significant associations with ME/CFS disease severity (higher PDK1 mRNA level in moderate/severe versus mild/mild-moderate groups), with ME/CFS disease duration (higher PDK1 mRNA level with increasing duration), and with physical activity level assessed as the mean steps per 24 hours (higher PDK1 mRNA level with lower activity) (Figure 3, N–P). The corresponding associations were not found for PDK4 mRNA (Supplemental Figure 1, B–D), for PPARA (Supplemental Figure 1, F–H), for PPARD (Supplemental Figure 1, J–L), or for SIRT4 (Supplemental Figure 1, N–P).
     
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  13. Daffodil

    Daffodil Senior Member

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  14. AdamS

    AdamS Senior Member

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    @Daffodil Interesting angle, yeah good old brain fog, makes reading some of these studies tough!

    From the first paper:
    'Another important difference between glucose and pyruvate is that pyruvate can be produced by bacteria. This means that bacteria have the potential to protect themselves from acidic stresses by controlling glucose-derived generation of pyruvate, pyruvate-acetate efflux, or reversion from acetate to pyruvate.'

    I don't doubt that in the case of Chronic Lyme disease, persistent bacteria could potentially cause the problem, in ME i'm not so sure, I do however think that it could be one of many triggering factors which can lead to 'flipping the switch' or making the immune system attack and then fail to switch off or regulate itself. I could be wrong though, this is just an assumption based on what i've read. It's good to get different perspectives on it.
     
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  15. Tiger_Eyze

    Tiger_Eyze

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    @AdamS Thanks for posting the videos with the time to jump to for each!

    Do you know where the questions he answered in the first video were submitted, by chance? I posted my question on youtube, but not sure anyone reads that stuff.

    I want to ask if the ME/CFS serum stripped of antibodies still made the healthy cells function poorly. If not, it basically narrows ME/CFS down to an auto-antibody problem, which could explain the efficacy of Rituxan.

    @Daffodil - Interesting point, but if intracellular viruses/bacteria are stealing the pyruvate, how would ME/CFS cells start acting healthy when healthy person serum is added to them before testing? Maybe some antibiotic chemical or antibody in the healthy serum that kills intracellular bacteria really quickly? (Assuming they don't let the healthy serum sit on the cells too long before running the test.)

    I just can't imagine people with a raging intracellular infection benefiting from Rituxan, which wipes out your B cells - unless it has some antimicrobial effect we are unaware of. Though, I did hear somewhere that Ritux improves NKC fxn, but don't quote me on that.
     
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  16. Daffodil

    Daffodil Senior Member

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    @Tiger_Eyze oh gosh, i immagine there are many ways rituxan could help if its intracellular bacteria. B cells have a large part to play in our immune response, and its the immune response that's making us sick. I am too foggy at present to do some googling though lol

    Keep in mind there is a huge connection with the gut in this disease and gut flora affects B cells maturation

    ..I think...
     
  17. AdamS

    AdamS Senior Member

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    I found this today, an older study, but seemed relevant to the work that Naviaux and Davis are doing. Naviaux found that in males, over 50% (16/30) of the sphingolipids that were decreased were ceramides, and 47% (14/30) were sphingomyelin species. In females, 86% (18/21) were ceramides.

    I've bolded some of the bits that stood out about ceramides/pyruvate below:

    https://www.ncbi.nlm.nih.gov/pubmed/18981422

    I'd be interested to hear what @JaimeS thinks about this. I read a very insightful comment by her mentioning that Rituximab's action of disrupting lipid rafts could impact the 'defensive state' we see in ME/CFS moving responders' cells out of metabolic hibernation. Given Naviaux's work and Davis's findings about Pyruvate's ability to fix ME cells I certainly found the abstract above interesting.
     
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  18. adreno

    adreno PR activist

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    Calling @nandixon to take a look at the study above.
     
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  19. Hip

    Hip Senior Member

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    In his above videos Dr Ron Davis does not mention the abnormalities he found in ME/CFS patient's cells, which then returned to normal on treating the cells with pyruvate. So it's hard know exactly what he means by pyruvate returning the cells to normal, unless he simply means ATP energy production returned to normal.

    Presumably it relates to his group's current working hypothesis of ME/CFS being caused by a problem in glycolysis and in the pyruvate kinase enzyme. Cort's article details this working hypothesis:


    Pyruvate is the final output product from glycolysis, and pyruvate contains a lot of energy which can only be extracted if the pyruvate molecule is shuttled into the mitochondria, where when things are working normally, it gets converted into acetyl-CoA (via pyruvate dehydrogenase enzyme), and then enters the Krebs cycle to yield its energy.

    Fluge and Mella's study suggested an impairment in the pyruvate dehydrogenase enzyme in ME/CFS patients, resulting in a reduced ability to convert pyruvate to acetyl-CoA. So Fluge and Mella's work suggests impaired pyruvate dehydrogenase is the energy blockage in ME/CFS patients.

    In such a scenario, there is no shortage of pyruvate produced by glycolysis, and so adding extra pyruvate to the cells would probably not help restore the energy metabolism. The extra pyruvate will not help, because without the pyruvate dehydrogenase enzyme working properly, that extra pyruvate cannot be utilized.


    However, by contrast in Ron Davis's theory, it is thought there may be an issue with glycolysis and the pyruvate kinase enzyme. The pyruvate kinase enzyme is the final step of glycolysis: this enzyme manufactures pyruvate. Thus an impairment in pyruvate kinase functioning would result in a shortage of pyruvate. In this scenario, it makes sense that adding pyruvate to the cells would restore normal cell functioning, in terms of ATP energy production.



    If a dysfunctional pyruvate kinase enzyme is the blockage in energy metabolism of ME/CFS patients, then I guess we would want to uncover why pyruvate kinase function is impaired.

    According to the Wikipedia article on pyruvate kinase, glucagon, cyclic AMP and epinephrine inhibit pyruvate kinase, and thereby shut down glycolysis. Reactive oxygen species (ROS) inhibit the M2 isozyme of pyruvate kinase (PKM2) in human lung cells. Alanine inactivates pyruvate kinase. Fructose 1,6-bisphosphate is an activator of pyruvate kinase. So these are some factors that might be involved in down-regulating pyruvate kinase functioning.

    Some cyclic AMP boosters and inhibitors listed in this post.
     
  20. Hip

    Hip Senior Member

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    In terms of supplementing with pyruvate, this article looks at a few studies on pyruvate for weight loss, and in one of the studies, up to 44 grams of pyruvate was given to the participants.

    I read that high doses of pyruvate can cause stomach upset and diarrhea.
     
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