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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. eljefe19

    eljefe19 Senior Member

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    I believe my anion gap was also high when last tested. What dosage of Biotin are you taking?
     
  2. pogoman

    pogoman Senior Member

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    About 50 to 70 mg (not mcg) total daily, one 10Kmcg every few waking hours.
    I already have been taking riboflavin and acety carnitine for a couple years now, they are also used in treatment of these diseases.
     
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  3. Snow Leopard

    Snow Leopard Hibernating

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    Here is my first post in this thread:

    http://forums.phoenixrising.me/inde...c-encephalopathy-cfs.48446/page-2#post-796671


    Fluge and Mella found increased expression of pyruvate dehydrogenase kinases. They did not show increased activation of pyruvate dehydrogenase kinases.

    It goes without saying it is activated by ATP, as that by definition how all kinases work. This is not quite the "increased activation" feedback system you are looking for...

    If the ATP translocator had any serious blockage (widespread across many cells), our symptoms would be quite different (along the lines of severe genetic mitochondrial diseases).
     
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  4. lansbergen

    lansbergen Senior Member

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    Maybe you should explain the difference between expression and activation.
     
    Last edited: Dec 25, 2016
  5. alex3619

    alex3619 Senior Member

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    Expression is about how much protein of a gene is made. In some cases this might be about mRNA, or messenger RNA, rather than protein. Activation is about how much of that is used, typically because some factor switches it on, or some factor does not switch it off enough. Often this can be as simple as some form of triphosphate, though there are several of these, and not just ATP. Indeed if there is low activation there can be higher expression if the body is trying to compensate.

    Its kind of like our NK cell issues. While some have low NK numbers, some also have normal NK numbers. The finding that is most consistent is that NK cell ability to function is low. They are not being activated like they should be. They just sit there.

    The body has lots of checks and balances, and key mechanisms that must be activated by something or they do not proceed. Take cancer, when I was studying biochem there were cases of cancer that required seven or so failures in regulatory mechanisms before there was uncontrolled growth. Its not one thing, its a bunch of things, a bunch of failures, that allow uncontrolled cell growth to be initiated.
     
  6. alex3619

    alex3619 Senior Member

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    PS I wonder how diagnostic we could make an NK cell function test in ME. If we test NK cells in our own serum, and isolated NK cells, and compare function, would this be diagnostic? Would that be an easy test? This would be a way to turn the inconsistencies in our NK cell tests to our advantage, presuming it works and is reliable.
     
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  7. lnester7

    lnester7 Seven

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    Is basically what klimas has been doing for years and some other old Cfs doctors.
    They measure Nk activities on special lab ( it is not a commercial test yet) and it is a bit tricky ( has to be done within 24h of collecting the blood). But so far they have success using this method.
     
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  8. eljefe19

    eljefe19 Senior Member

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    Where is Dr Klimas located? Is she still running this test for new patients?
     
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  9. lnester7

    lnester7 Seven

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    Is USA Miami Fl. Nova southwestern university (NsU)

    I don't know if they are taking new patients, call and ask. The university of Miami is the one doing the NK cell activity test.

    But this test is like ok you have it low and there is no much you can do. So not sure how helpful it is except for you to be sure you have Cfs.

    Mine has gone up on double dose of NK. I am on Imunovir and inosine ( just because I cannot tolerate Imunovir alone) and it has been like 6y and bearly gone up.
     
  10. alex3619

    alex3619 Senior Member

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    Actually it isn't. There are two types of tests. Normally you get the same result from both. In us you get opposite results. So I would like to know if that were diagnostic, as the tests are available NOW and have been for many years.
     
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  11. eljefe19

    eljefe19 Senior Member

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    I'm already interested in the 23andme genetic study Dr Klimas is doing, perhaps I will inquire about the NK testing at the same time.
     
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  12. lnester7

    lnester7 Seven

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    Can you pls rephrase this I don't understand about the 2 tests. I know they are very particular where they send ( lab) and only rely on one lab. They do numbers and activity. Is that the 2 tests you refer to?
     
  13. lnester7

    lnester7 Seven

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    The test is tricky like I said I have to travel to get it done there ( since the transit time is too long for me)
     
  14. Kati

    Kati Patient in training

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    I believe the issue regarding the NK cell function is that it is not specific to ME as other diseases also have this issue.
    the 2tests for NK cells are
    1) NK cell count. This test is usually within normal range in patients with ME. It can be done in most labs around the world. Not too expensive
    2) NK cell function or natural cell cytotoxicity. This is the test that is usually low for patients with ME. While it is true that dr Klimas's lab (actually Dr Mary-Ann Fletcher's) offers the test, Quest Labs in the US also offers the test. It is an expensive test, between 400-500$ USD last time I had it done and the sample needs to be tested within 24h of blood draw for accurate results.

    This is not an accepted or validated biomarker for ME as of yet (source: Institute of Medicine report) however experienced physicians will say that the function is reduced proportionally to the disease severity (more severe=lower cytoxicity of NK cells).
     
    Last edited: Dec 25, 2016
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  15. lnester7

    lnester7 Seven

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    Ahhh ok yes I agree the low activity might not be unique to ME. Klimas says that she thinks twice to give the diagnosis of Cfs if it is normal ( the activity) I think Peterson agreed. It was in one of those old videos.

    Yes the test is consoder reaserch.

    I don't know if I agree severity matches my NK levels since they are always low for me. Both number and activity in my case. I was for a while with activity low normal and numbers very low.

    For me the severity of disease had more to do with treating OI. When I treat it I am active if not I am bed ridden.

    Now I do get more infections when they are very low. I had ebv, hh6, coaxaxie and Parvo when I was first seen!

    I don't struggle as much w infections ( except for hh6) which I cannot seem to beat.
     
  16. Kati

    Kati Patient in training

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    The correlation with severity was published here.

    Myself I had a couple of instances when my NK cell function was very discordant with how I felt. It is sure frustrating when the numbers don't match.

    NK cells kill viruses and circulating cancer cells. So a low functin (or low cytotoxicity) would explain why we have trouble regulating viruses, especially the ones which usually remain dormant in the body. However the latest research does not seem to be interested in viruses or immune issues, but more metabolomics and mitochondria function. That puzzles me a bit because I got sick from a viral infection and continue 8 years later to experience sore lymph nodes and flu-like illness, seemingly on a daily basis.
     
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  17. alex3619

    alex3619 Senior Member

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    No, other diseases get identical results on the two types of tests.
     
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  18. alex3619

    alex3619 Senior Member

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    No. Sigh. This has been discussed, even came up at the IACFSME conference, but its not formally published.

    You might recall that NK function tests have had wildly variable results. It turns out that tests in our serum show low NK function, and tests out of our serum show OK NK cell function. That includes in the sera of healthy people. That appears to be potentially diagnostic to me. BOTH these tests are NK function tests, but done two different ways.

    This is about some factor in our blood, or lack thereof, turning NK cell function off.
     
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  19. eljefe19

    eljefe19 Senior Member

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    @alex3619 thanks for making sense of this stuff for those of us who's brain fog is real
     
  20. Hip

    Hip Senior Member

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    Good point. I guess I may have to concede this one, unless I can find a mechanism by which a translocator protein blockage increases pyruvate dehydrogenase kinase gene expression.



    However, if we assume that an inhibited pyruvate dehydrogenase is the only blockage in ME/CFS energy metabolism, that blockage alone would seem unlikely to account for ME/CFS symptoms, as far as I can see (but I may be wrong).

    This is because an inhibited pyruvate dehydrogenase will only serve to block the coupling of glycolysis to the mitochondria, and if this coupling is blocked, it means that you will be limited in the ability to process glucose from dietary carbohydrates in an efficient way via the glucose > glycolysis > pyruvate pathway into the mitochondria.

    But the failure to efficiently process glucose via the pyruvate pathway into the mitochondria should not lead to an energy shortage, because mitochondria can also process dietary fats and protein as alternative energy sources. As we know, people who undertake a ketogenic diet get nearly all their energy from dietary fats and protein.

    When you get your energy from dietary fats and protein, I believe you can bypass the glucose > glycolysis > pyruvate pathway into the mitochondria. Thus this pyruvate pathway could be substantially blocked, but that would not significantly affect the processing of fats and protein in the mitochondria. I think the fats and protein would still be processed with normal efficiency, and you would be able to derive a lot of energy from them.

    A ketogenic diet typically contains (ref: 1):

    60-75% of calories from fat (or even more)
    15-30% of calories from protein
    5-10% of calories from carbs

    When ketones-adapted runner Zach Bitter completed a 100 mile run in just under 12 hours, data showed that 98 percent of his energy came from fat, and only 2 percent from carbs. Ref: 1

    Thus just on fats and proteins, you can function pretty well, and have no symptoms of ME/CFS. In fact you can run 100 miles on more or less just fats!

    So how then could a blockage in the pyruvate pathway into the mitochondria cause ME/CFS symptoms? I cannot see that it could, not on its own at least.

    (Having said that, some ME/CFS patients do fare well on a ketogenic diet; so maybe in the light of this latest Fluge and Mella finding on pyruvate dehydrogenase inhibition, we might consider trying a ketogenic diet to see if it benefits ME/CFS).

    There would have to be some other blockages in the energy metabolism, alongside a pyruvate pathway blockage, if we are going to get the sort of major energy shortage that might underpin ME/CFS.

    These other blockages in energy metabolism could include a blockage in oxidative phosphorylation (which the MBM studies found many ME/CFS patients have), or a translocator protein blockage (which the MBM studies found most ME/CFS patients have).

    But a pyruvate pathway blockage alone I cannot see causing ME/CFS. (But note that my knowledge of energy metabolism pathways is not very good, so if anyone can see any flaws with the above argument, please do point them out).



    It's worth posting Figure 1 from the MBM 2009 study below, as this nicely shows the inputs and outputs of the mitochondria. Note how the glucose > glycolysis > pyruvate input to the mitochondria is separate to the fatty acids input.

    Screen Shot 2016-12-26 at 6.34.46 am.png



    I don't think you can predict in advance the symptoms that a mitochondrial translocator protein blockage might produce.

    And note that the MBM studies found that the translocator protein in ME/CFS patients is not completely blocked, but partially blocked to varying degrees. The "ATP Profiles" test measures the efficiency of translocator protein functioning, and provides a translocator protein efficiency figure from 0 to 1, which depends on the degree of blockage of the translocator protein (the more efficient, the less the blockage).

    If you look at Figure 2 from the MBM 2009 paper, the TL IN graph gives the efficiency of various ME/CFS patients' translocator protein as it transports ATP from the mitochondria into the cytosol of the cell; and the TL OUT graph gives the efficiency of the translocator protein as it transports ADP out of the cell, and back into the mitochondria.

    As you can see from those two graphs, ME/CFS patients have varying translocator protein efficiencies, with some as low as 0.1 (these are the most blocked patients), but others with higher efficiencies of 0.3 or 0.4, etc.
     
    Last edited: Dec 26, 2016
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