The 12th Invest in ME Conference, Part 1
Over the Hills presents the first article in a series of three about the recent 12th Invest In ME international Conference (IIMEC12) in London.
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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. Jesse2233

    Jesse2233 Senior Member

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    @Hip don't want to derail this thread, but I got test results today showing high levels of pyruvate and low levels of lactate, would those findings then validate Fluge/Mella and not Ron?
     
  2. Hip

    Hip Senior Member

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    I wouldn't know how to interpret lactate and pyruvate level test results, and what the results entail. There is some info on the lactate/pyruvate ratio test here, but I am not sure how this would connect to Fluge & Mella's and Ron Davis's hypotheses.
     
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  3. adreno

    adreno Homo neanderthalensis

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    I also showed high pyruvate on a urine amino acids test. So I doubt adding more would help.
     
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  4. AdamS

    AdamS Senior Member

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    Yeah from what i've read, the signs seem to point towards an inability to utilise pyruvate properly rather than a shortage of it. Your reply is quite timely actually because I was just reading @Jesse2233 's thread HERE which shows high levels of pyruvate from Genova CardioION test results. This would certainly suggest to me that pyruvate is being produced, but it is accumulating rather than being utilised.

    I'd be interested to know what % or ratio of pyruvate is accumulating in the cytosol vs in the mitochondrion. If it was all or mostly accumulating in the cytosol, one could assume that there could be a problem with the transport protein pyruvate translocase which facilitates the transport of pyruvate into the mitochondria. I'm not sure if this is the case though, the reason it came to mind was because of the action of 'adding' pyruvate described by Davis, if the pyruvate can't be 'added' or moved at a regular rate of flow into the mitochondria then I guess it can't be utilised or could in fact down-tune the cell, something we see in the hypometabolic state.

    [​IMG]
     
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  5. Hip

    Hip Senior Member

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    Nice image, AdamS. It's good to have a clear diagram to refer to when trying to understand these things through the veil of brain fog.

    I was looking at how pyruvate gets transported into the mitochondria when I was trying to learn about all this stuff a few months ago.

    I understand that pyruvate diffuses across the outer mitochondrial membrane just on its own, but pyruvate requires a dedicated transporter protein to ferry it across the inner mitochondrial membrane. The name I learnt for that transporter protein is the mitochondrial pyruvate carrier (MPC), but I think pyruvate translocase may just be another name for the MPC (though I am not entirely sure — the MPC phrase seems to be more commonly used).



    That's an interesting question. I wonder if there is any easy way to determine that ratio experimentally.

    There may of course be different subsets of ME/CFS patients, with each subset having a different sort of blockage in their energy metabolism.

    This is what they found in the Myhill, Booth and McLaren-Howard (MBM) studies on ME/CFS energy metabolism: the MBM studies discovered that there were different patient subsets, with blockages in different areas of energy metabolism.

    In MBM, the main blockage points were in: the mitochondrial translocator protein (aka ATP-ADP translocator, or the adenine nucleotide translocator), which is the mitochondrial membrane protein that transports the ATP generated in the mitochondria into the cytosol of the cell, as well as having the job of transporting the ADP (= the spent ATP) out of the cytosol and back into the mitochondria for recycling; and there were also blockages in oxidative phosphorylation itself (the mitochondrial process that recycles ADP back to ATP).
     
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  6. AdamS

    AdamS Senior Member

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    From Wikipedia:

    'PDK1 shunts Pyruvate away from the citric acid cycle to keep hypoxic cells alive' - I found this very interesting, it would explain the accumulation of un-used Pyruvate and also the low power state which keeps cells alive but leaves us functioning extremely poorly.

    From Fluge & Mella's paper:

    AMPK: We know that AMPK activation is abnormal in ME/CFS patients. AMPK is activated in response to stresses that deplete cellular ATP supplies such as low glucose, hypoxia, ischemia, and heat shock.

    HIF-1 - Can we target this and inhibit it? Would doing so downregulate/inhibit PDK1 and thus allow PDH to function more normally, resulting in more pyruvate getting into the citric acid cycle?

    From Cort's recent Stanford Paradox article on Health Rising:

    I'm piecing stuff together here, but it seems like hypoxia/low oxygen is pretty key here.
     
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  7. Jesse2233

    Jesse2233 Senior Member

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    Reminds of Dr Bell's findings on low blood volume. Tissues aren't getting enough oxygen because there's not enough blood. His solution was daily IV saline treatments for a year. Brought one woman from being bedridden back to work
     
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  8. melihtas

    melihtas

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  9. ljimbo423

    ljimbo423 Senior Member

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    Bacterial Lipopolysaccharides (LPS), like from a leaky gut, can cause an increase in HIF1, a decrease in oxygen consumption, an increase in PDK1 and therefore an inhibition of PDH.

    LINK
     
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  10. AdamS

    AdamS Senior Member

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    @ljimbo423 Interesting stuff, i've always wondered whether my gut has been responsible for ME all along. LPS certainly could be a factor!
     
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  11. ljimbo423

    ljimbo423 Senior Member

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    I think the gut is where it starts, but that's just the beginning. After 10 years of reading and research, I think the immune activation and oxidative stress from the LPS causes a domino effect. The results of which are, neuro-inflammation, mitochondrial dysfunction, methylation dysfunction, immune dysfunction and more.

    Treating the gut though, can be, and often is extremely difficult and complicated. Having said that, I feel better than I have in years, by treating my gut.
     
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  12. AdamS

    AdamS Senior Member

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    Glad to hear that you're feeling better than you have done in years! Yeah I wouldn't really know where to start with the gut, it does seem like a complex puzzle to crack. I tried eating lots of Sauerkraut and a range of expensive probiotics to begin with but noticed little difference in overall energy/functioning.
     
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  13. ljimbo423

    ljimbo423 Senior Member

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    You have to have the tenacity of pit-bull holding onto the last bone on earth!:D It really has been and is, a huge ongoing commitment.
     
  14. *GG*

    *GG* Senior Member

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    What are you referring to? Seems like my gut has gotten better, not sure why. Been on LDN since 2009, until relatively recently. Did raw milk years ago, that seemed to help some. Was taking Creon (script) because of diarrhea. Rarely have diarrhea now!

    GG
     
  15. alex3619

    alex3619 Senior Member

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    Do we have details of the pyruvate experiment? Two cautions come to mind without those details:

    1. Supra-physiological doses were used, and directly absorbed. No matter a patient's blood test its not relevant. The dose (concentration) used was far higher than the human body reaches. Ron is not planning to use this clinically, I think that says what we need to know.

    2. The outcome measure might not mean the cells are normal, just normal on that one measure.
     
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  16. Murph

    Murph :)

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    https://www.ncbi.nlm.nih.gov/pubmed/19364913

    When you talk hypoxia and ATP you're also straying into the vascular areas that can provide that involve the endothelium and can provide that POTS-ME/CFS linkage.

    http://www.sciencedirect.com/science/article/pii/S2211383512001669
    https://www.ncbi.nlm.nih.gov/pubmed/19364913

    For example:

    Autoimmunity/genetic problems -> endothelial problems -> Low vascular responsiveness -> Low ratio of blood volume to circulatory system volume -> low oxygen absorption -> failure to maintain homeostasis -> immune response including signalling molecules that start hypometabolism

    is just one of many possible linkage chains. Such chains may coexist and will interlink. It's going to be a network of cycles, not a one way street, of course.
     
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  17. kangaSue

    kangaSue Senior Member

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    Richvank made some comments a few years back that would have a bearing on this subject.

    http://forums.phoenixrising.me/inde...o-my-cells-brain-body.7501/page-2#post-147858

    [I would like to contribute my views on what is going on with oxygen, CO2, and breathing in ME/CFS.

    As I see it, the fundamental issue here is that the mitochondria in cells particularly of the tissues that are most depleted in glutathione are dysfunctional. A major fraction of the total cell mass is in the skeletal muscles, and they are glutathione-depleted. One result is that these tissues do not utilize oxygen at as high as normal a rate, and they also do not produce carbon dioxide at as high as normal a rate.

    The blood, of course, circulates to all the tissues, including those with serious mito dysfunction and those that are still operating more normally. The latter include the vital organs, which have complete transsulfuration pathways, and are thus able to make cysteine from methionine, while cells such as those in the skeletal muscles cannot. So when cysteine is in short supply, the vital organs are able to make cysteine to replenish their glutathione and continue to function to preserve life, while the skeletal muscles and some other types of tissues become dysfunctional.

    Here's the key point: The respiratory center in the brainstem controls the rate and depth of breathing by sending signals to the muscles involved in breathing. The respiratory center performs this regulation by monitoring the level of CO2 and the pH in the blood it receives. It pays attention to oxygen only when it becomes very low, and hits a trip point, which produces gasping. The CO2 level and pH of the blood represents an average of the effects of the mitochondria throughout the body, but they are dominated by the effects of the skeletal muscles, because of their large fraction of total cellular mass. So the respiratory center sees a low CO2 level in the averaged blood it receives, and it therefore slows and shallows the breathing, trying to raise the CO2 level. However, because the mitochondria are dysfunctional and can't produce CO2 very well, this doesn't work as well as normal, and that's why the rate and depth of breathing remain low.

    Unfortunately, other tissues that still have a normal oxygen demand, and which must share the same blood supply, may find that they are not able to get enough oxygen, because the shallowing and slowing of the breathing will also mean that the oxygen intake by the lungs into the blood will be lower than normal. This gives rise to the feeling of "air hunger" or "shortness of breath." In response, people take conscious control of their breathing and raise its rate and depth.

    When a person in this condition falls asleep, their normal ability to take conscious control of their breathing ("remind themself to breathe") is not present. Therefore, they can develop sleep apnea (not obstructive sleep apnea, but a central version, due to this confused signal getting to the respiratory center) and can awaken gasping periodically, as their oxygen level repeatedly drops down to the emergency trip point. This is just one more thing contributing to sleep problems in this disorder, added to things like abnormalities in cortisol, blood sugar level, melatonin, and others (all of which also stem from the same root vicious circle mechanism, in my view).

    Dr. Cheney's observation that the oxygen saturatioin level of the blood in ME/CFS does not drop as rapidly as normal on breath holding is a consequence of a lower rate of whole-body oxygen utilization because of the mito dysfunction in muscle cells and some other types of cells.

    His observation of oxygen toxicity is a consequence of the fact that if more oxygen is supplied to mitochondria that are dysfunctional, more of it is converted to superoxide ions, rather than to water molecules, as is normal. This exacerbates the state of oxidative stress that is already present, and that's why it feels "toxic."

    There have been at least four studies reporting hypocapnia (low carbon dioxide partial pressure in exhaled gas) in ME/CFS. This has been attributed (I believe wrongly) to hyperventilation. In fact, it is due to mito dysfunction, and PWMEs/PWCs in fact mostly have HYPOventilation. The one study that actually measured ventilation rate in ME/CFS did not find hyperventilation.

    I believe that all of this fits together, and it all comes back down to the vicious circle mechanism described by the GD-MCB hypothesis. This vicious circle mechanism is responsible for the mito dysfunction, and that's what brings on all the rest of what I have discussed here. This vicious circle also explains the other abnormalities in ME/CFS in straightforward detail, taking account of known biochemistry and physiology.

    Best regards,

    Rich

    richvank, May 17, 2011]
     
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  18. adreno

    adreno Homo neanderthalensis

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    If we are indeed hypoxic – and PDK1 prevents cell death by shunting away pyruvate – then preventing or interfering with this sounds like a very bad idea. HIF-1 is activated as a response to hypoxia. It would be more relevant to ask why we are hypoxic in the first place.
     
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  19. lansbergen

    lansbergen Senior Member

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    Good question
     
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  20. AdamS

    AdamS Senior Member

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    Great point.
     

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