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Ampk dysfunction and ME/CFS

Discussion in 'General ME/CFS Discussion' started by Frenchguy, May 29, 2018.

  1. Frenchguy

    Frenchguy Senior Member

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    Hi everyone,

    I wonder if the dysfunctional enzyme added by Robert Phair to his Metabolic modeling could be the AMP-activated protein kinase.

    This enzyme is present in every cells in our body.

    At the Unrest screening in France, Ph De Korwin (the president of the French scientific CFS research) said that they are certain that an enzyme was responsible for all the problems found in many studies (immunes abnormalities with lack of T cell regulation, metalobic finding ...).

    He works with a team specialized in data analysis from studies publied on pubmed. This type of massive analysis looks for similar finding/abnormalities in studies.
    He didn't said that the enzyme which he think responsible for our symptoms is AMPK, but I wonder if he supposes that.

    Given the finding of this study
    https://www.ncbi.nlm.nih.gov/pubmed/29654166

    AND

    After reading this article :
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4855276/#!po=17.5000

    I wonder if DIRECT Ampk activators (not metformin) can help.
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4855276/table/tbl2/?report=objectonly

    INDIRECT Ampk activators works by increasing AMP/ATP ratio by the complex 1 mitochondrial respiratory chain for the majority, which seem problematic in ME.
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4855276/table/tbl1/?report=objectonly
     
  2. raghav

    raghav Senior Member

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    I am a diabetic and the first medicine I tried was metformin and within half a day it made me miserable. I tried pioglitazone and within half an hour I was bed ridden. My heart felt like it was going to stop. What could be the reason ? Any expert explanation.
     
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  3. Murph

    Murph :)

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    I feel sure AMPK is implicated in the disease. Whether the problematic process flows through AMPK (after all it is a major energy regulator) or the problem starts with AMPK is a different question.

    I did an analysis of Naviaux's metabolite findings and found that ATP is not unusually low in our blood but the chemicals into which it degrades (AMP and Adenosine) are low. This could be evidence that ATP in the blood is not being broken down properly.

    There is an enzyme called cd39 which is supposed to break down ATP to AMP and Adenosine (adenosine has an immune suppressing role). cd39 could be broken. This is a theory by @necessary8 that is the first post in the thread I just linked. If ATP:AMP ratios are wrong for a long time AMPK could get hyper-sensitised and maybe turn itself off? (this is just a vague idea).

    I'm curious about this reference :

    >wonder if the dysfunctional enzyme added by Robert Phair to his Metabolic modeling could be the AMP-activated protein kinase.

    Can you show me where you see Phair referencing a dysfunctional enzyme. I want to read more!
     
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  4. Murph

    Murph :)

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    Interestingly AMPK may also affect red blood cell (aka erythrocyte) integrity, which Ron Davis is looking at as a possible biomarker

    The AMP-activated protein kinase beta 1 subunit modulates erythrocyte integrity
    Emma L. Cambridge,a Zoe McIntyre,a Simon Clare,a Mark J. Arends,b David Goulding,a Christopher Isherwood,a Susana S. Caetano,a Carmen Ballesteros Reviriego,a Agnieszka Swiatkowska,a Leanne Kane,a Katherine Harcourt,a The Sanger Mouse Genetics Project,a David J. Adams,a Jacqueline K. White,a and Anneliese O. Speaka,∗
    Author information ► Article notes ► Copyright and License information ► Disclaimer
    Go to:
    Abstract
    Failure to maintain a normal in vivo erythrocyte half-life results in the development of hemolytic anemia. Half-life is affected by numerous factors, including energy balance, electrolyte gradients, reactive oxygen species, and membrane plasticity. The heterotrimeric AMP-activated protein kinase (AMPK) is an evolutionarily conserved serine/threonine kinase that acts as a critical regulator of cellular energy balance. Previous roles for the alpha 1 and gamma 1 subunits in the control of erythrocyte survival have been reported. In the work described here, we studied the role of the beta 1 subunit in erythrocytes and observed microcytic anemia with compensatory extramedullary hematopoiesis together with splenomegaly and increased osmotic resistance.

    Screen Shot 2018-05-30 at 2.13.12 PM.png
    Red blood cells from normal mice (left) and mice engineered for dodgy AMPK (right)
     
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  5. Frenchguy

    Frenchguy Senior Member

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    Hi raghav,

    I don't know the reason, but since others people have reported to feel worse with AMPK activators (principally Metformin), I don't think it's unusual for an ME/CFS.

    This fact with the speech of Ron Davis who said that if the metbolic trap is confirmed, the treatment likely produce an increase of symptoms before people get cured, I wonder if AMPK activation can be the treatment mentioned.
    This enzyme is so central, like a metabolic modulator, i think it can be the perfect therapeutic target to breakdown the vicious cycle of ME/CFS.
     
  6. Frenchguy

    Frenchguy Senior Member

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    Hi Murph,

    In the article on the metabolic trap written by Cort :
    "When Phair added the impaired enzyme functioning to his metabolic modeling to determine if it could account for the strange metabolomic finding, he found that it could."

    I don't know if the problem start with AMPK but it is possible we have a mutation of the gene which code AMPK and that the genetic suceptibility mentionned by many authors show that.

    I am puzzled when I see the multiple dysfunctional pathways in our disease. Each major system seem involved (metabolic, immune system, blood, brain). I can't see an other major "switch". To my view AMP is central and could be a target to break the cycle.

    I will read the CD39 hypothesis, can you send me the link for Naviaux metabolics results ,

    Thanks
     
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  7. mariovitali

    mariovitali Senior Member

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    I wanted to give you some info relevant to this Thread.

    CC : @perrier @Hip

    1. Snapshot from the document i sent to several ME/CFS Researchers in October 2017 :


    Screen Shot 2018-05-30 at 12.52.54.png
    Please Note : AMPK is associated with Autophagy.


    2. From the Wikipedia Entry of AMPK we read :

    Regarding PGC-1a aka PPARG1a, from February 8, 2016, Phoenix Rising :


    https://forums.phoenixrising.me/ind...e-treatment-for-cfs.37244/page-70#post-694400

    Special cc : @perrier , PGC1a is associated with NRF1

    https://en.wikipedia.org/wiki/PPARGC1A

    Also we have the following entry from Wikipedia :

    Please note the word Glucokinase. From the same doument we read :

    Screen Shot 2018-05-30 at 13.08.33.png


    Given the above, please search PR and you will find many mentions regarding Thiamine and Biotin having positive effects to ME/CFS Patients.

    Finally you can see Network Analysis identifying Pgc1 as well which is also included to the document i circulated (Right from Urea_Cycle node):

    [​IMG]

    Looking forward to your comments.
     
    Last edited: May 30, 2018
  8. pattismith

    pattismith Senior Member

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  9. Hip

    Hip Senior Member

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    I was looking at AMPK boosters for treating my fatty liver (I was diagnosed with non-alcohol related fatty liver a few years ago, as a result of a slightly raised liver enzyme ALT).

    Fatty liver is common in adults, around 25% of the population have it. In my case, I think it is related to the abdominal obesity I developed after catching my viral infection.
     
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  10. mariovitali

    mariovitali Senior Member

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    cc @JaimeS @perrier

    From the Link @Hip provided it says about AMPK being a "Master Switch" :

    But if you scroll a bit down to the AMPK Activators, you will see Gynostemma pentaphyllum aka Jiaogulan :


    Interestingly Jiaogulan is an LXR Agonist.

    The importance of LXR has been previously described here (worth a read):


    https://forums.phoenixrising.me/ind...sted-research-on-cfs.51283/page-6#post-899305

    and also LXR can be found below :


    [​IMG]
     
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  11. Frenchguy

    Frenchguy Senior Member

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    Top athletes are doping for some (not a surprise).

    AICAR is used to over-activate AMPK. This over-activation makes it possible to maintain the effort longer but especially to recover more quickly.

    https://extremepeptides.com/product/aica-ribonucleotide-aicar-50mg/

    AICAR is a direct AMPK activator, I don't know if this way to activate AMPK is clean.
     
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  12. mariovitali

    mariovitali Senior Member

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    NutMeg which i use is also one :

    cc : @perrier

    https://www.ncbi.nlm.nih.gov/pubmed/20541406


    more (posted earlier today) :

    https://forums.phoenixrising.me/ind...ted-research-on-cfs.51283/page-10#post-980188
     
  13. raghav

    raghav Senior Member

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    Can acetyl salicylic acid (prodrug of aspirin ?) help. It is in that list mentioned by Frenchguy
     
  14. Rossy191276

    Rossy191276 Senior Member

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    All very interesting... I may be mistaken but I thought in Chris Armstrong’s hypothesis they thought that ampk might be over activated?
     
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  15. Wally

    Wally Senior Member

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    Here is a study from 2014 regarding AMPK and thyroid cancer. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3986867/

    Since, thyroid dysfunction and thyroid cancer have often been suggested to have a link to ME/CFS, I thought this study might provide some additional insight into this discussion.

    @Rossy191276 - This study also provides some discussion related to the up regulation of this enzyme.
     
  16. Wally

    Wally Senior Member

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    @raghav - I don’t have an answer to your question, but I found this discussion online regarding aspirin and AMPK that you might be interested in looking at. http://www.longecity.org/forum/topi...es-ampk-but-whats-the-minimum-effective-dose/

    You also might like to review the linked article below, which discusses the positive and negative effects of AMPK on viruses. http://www.hal.inserm.fr/inserm-01171763/document

    *Edit to add the following link. Perhaps it is the AMPK activity of aspirin that might have been the missing link in this study? https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5155651/

    It would be fascinating if something as simple as aspirin or Willow Bark could hold a key to treatment of this illness.
     
    Last edited: May 30, 2018
  17. raghav

    raghav Senior Member

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    Thanks @Wally But at the high doses mentioned in that thread in longecity it may cause gastric bleeding. We do get gastro resistant aspirin, but will it be safe for the intestines ?
     
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  18. raghav

    raghav Senior Member

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  19. pamojja

    pamojja Senior Member

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    Depends on the person. For example, I take dozens of supplements all allegedly being risky in causing excessive bleeding. Never had any from them. However if I add only one baby aspirin (81 mg) I do get immediately bloody stools and much more fluid blood (as seen by finger-pricking for blood-glucose).
     
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  20. Frenchguy

    Frenchguy Senior Member

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