Ampk dysfunction and ME/CFS

Frenchguy

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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
 

raghav

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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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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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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)
 

Frenchguy

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Hi raghav,

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.
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.
 

Frenchguy

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Hi Murph,

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!
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
 

mariovitali

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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 :

AMPK activates autophagy by directly and indirectly activating ULK1.[11] AMPK also appears to stimulate mitochondrial biogenesis by regulating PGC-1α which in turn promotes gene transcription in mitochondria.[11] AMPK also activates anti-oxidant defenses.[11]
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 :

ERRalpha and PGC-1α are coactivators of both Glucokinase (GK) and SIRT3, binding to an ERRE elements in the GK and SIRT3 promoters.
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):



Looking forward to your comments.
 
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pattismith

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Hip

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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.
 

mariovitali

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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.
cc @JaimeS @perrier

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

Over the past 30 years, scientists have been investigating the properties of an enzyme called AMPK, which is a “ master switch” that, in many ways, controls how our cells behave.
But if you scroll a bit down to the AMPK Activators, you will see Gynostemma pentaphyllum aka Jiaogulan :

Gynostemma pentaphyllum is a plant distantly related to the cucumber.

In traditional Asian medicine, it’s used to promote longevity.81 Today’s scientists have discovered why Asian doctors prescribed G. pentaphyllum to address age-related health issues: It promotes AMPK activation.78,82

G. pentaphyllum not only activates AMPK, but it also shuttles excess fats into the mitochondria to be utilized for energy and safe disposal.82 The result is efficient energy production and a sharp reduction in unnecessary fat storage.

Results of G. pentaphyllum-induced AMPK activation include increased fat burning, as well as an increase in cellular glucose uptake.78,82 Extracts of G. pentaphyllum have other beneficial properties as well, including the ability to prolong cellular life in the face of stresses induced by oxidation, fat accumulation, and diabetes.83,84

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 :


 

mariovitali

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NutMeg which i use is also one :

cc : @perrier

AMP-activated protein kinase (AMPK) is a potential therapeutic target for the treatment of metabolic syndrome including obesity and type-2 diabetes. As part of an ongoing search for new AMPK activators from plants, this study found that the total extract of Myristica fragrans (nutmeg) activated the AMPK enzyme in differentiated C2C12 cells. As active constituents, seven 2,5-bis-aryl-3,4-dimethyltetrahydrofuran lignans, tetrahydrofuroguaiacin B (1), saucernetindiol (2), verrucosin (3), nectandrin B (4), nectandrin A (5), fragransin C(1) (6), and galbacin (7) were isolated from this extract. Among the isolates, compounds 1, 4, and 5 at 5 microM produced strong AMPK stimulation in differentiated C2C12 cells. In addition, the preventive effect of a tetrahydrofuran mixture (THF) on weight gain in a diet-induced animal model was further examined. These results suggest that nutmeg and its active constituents can be used not only for the development of agents to treat obesity and possibly type-2 diabetes but may also be beneficial for other metabolic disorders.
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
 

Wally

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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.
 
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raghav

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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 ?
 

pamojja

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We do get gastro resistant aspirin, but will it be safe for the intestines ?
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).