Pharmalogical activation of AMPK and glucose uptake in cultured skeletal muscle of ME/CFS patients

Demepivo

Dolores Abernathy
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There is a transcript of Chris Armstrong's Stanford presentation here along with various diagrams showing healthy & low energy states

https://www.melbournebioanalytics.org/metabolism-chris-armstrong-written-transcription/

"AMPK (adenosine monophosphate-activated protein kinase) is important to note. It is a major protein metabolic switch within cells"

"First off, AMPK detects that there are low nutrients and energy. It turns on like a switch and, once the switch is on, AMPK prioritises the use of mitochondria for efficient energy production, and diverts resources away from other processes, because it sense the low energy environment.

The body wants to make energy in the most efficient way per molecule that it can. So, fats and amino acids, which would usually be used for cell proteins and cell fats, are diverted to make energy. This process requires oxygen and the end-products of glycolysis will also be used to make energy this way. When nutrient deprivation continues for a longer period then glucose becomes important for fuelling muscles and the brain, in this instance the end-products of glycolysis are increasingly used to form glucose via gluconeogenesis instead of being used to make ATP by mitochondria."
 
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nanonug

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There are now two "data points" that contradict Chris Armstrong's conclusions: the first one is the use of rapamycin to apparently improve SEID; the second one is the study published in this thread. At this point, my inclination is to qualify Chris Armstrong's conclusions as simply wrong.
 

nanonug

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Together with DCA, I'm going to give high dose resveratrol a try to see what happens.
Well, this sucks! It seems that resveratrol also lowers ATP production by inhibiting ATP synthase. It is possible that due to resveratrol myriad actions, it ends up being a net positive but at this point I need a "clean" AMPK activator for testing purposes.
 

nanonug

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The attached image is from the article "Resveratrol as a calorie restriction mimetic: therapeutic implications."

AMPK activation depends on the action of cyclic AMP. An increase in cAMP leads to an eventual increase in AMPK. However, production of cAMP depends on the conversion of ATP by adenylyl cyclase. In a permanent state of ATP depletion - which is purportedly a characteristic of SEID - not much cAMP is going to be produced. This will thus result in a persistent state of low AMPK, contrary to Chris Armstrong's conclusion.
 

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Are any of these “clean” @nanonug ?


I’ve been thinking about my very fluctuating ME journey over the last 20 years. I’ve been around 10% and around 95% on the Bell Disability Scale and everything in between up and down at different times. This week I’ve been thinking about when I went from 10% to 30% in a couple of weeks (with the help of a nutritionist). It could be a number of things but I started this supplement (Fast & be clear) at that point



My understanding is Quercetin, alpha lipoic acid, grapes and green tea are AMPK activators. I wonder if this was part of the benefit of taking this supplement?
http://ampkactivator.net/quercetin/
http://ampkactivator.net/a-lipoic-acid/
 

nanonug

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Are any of these “clean”@nanonug ?
I don't know, I'd need to research each individually. For now, I think I'm going to stick to what I've been doing which is forskolin (adenylyl cyclase activator => higher cAMP), caffeine (non-selective PDE inhibitor => higher cAMP), nicotine patch (induces catecholamines release) and dichloroacetate (higher ATP production.)
 

alex3619

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Cellular ATP content was unaffected by treatment although ATP content was significantly decreased in ME/CFS compared to controls.
To me this implies these treatments do not work. They fix one issue but its peripheral or has co-complications.

My last trial of Metformin was a total disaster. I almost lost my left foot and it took four months before the large areas of dead skin grew back.

I have a long history of using Resveratrol, at 600mg dosage every three to four days. It does not help my ME symptoms. It helps with my breathing problems, being a PDE4 inhibitor. It does however increase my tolerance to sleep deprivation, even though it makes my sleep worse.
 
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The attached image is from the article "Resveratrol as a calorie restriction mimetic: therapeutic implications."

AMPK activation depends on the action of cyclic AMP. An increase in cAMP leads to an eventual increase in AMPK. However, production of cAMP depends on the conversion of ATP by adenylyl cyclase. In a permanent state of ATP depletion - which is purportedly a characteristic of SEID - not much cAMP is going to be produced. This will thus result in a persistent state of low AMPK, contrary to Chris Armstrong's conclusion.
The Wikipedia for AMPK says "It should not be confused with cyclic AMP-activated protein kinase (protein kinase A).[2]"

I believe cAMP can be an input to a process that raises AMPK but is not the key way. As far as I understand it, AMPK works by binding AMP/ATP/ADP to its sensors, and the ratios it discovers decide whether it turns on or not.
 

pattismith

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nanonug

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T3 and 3.5 T2 activate AMPK in muscles by non genomic action
AMPK has got to be one of the most complicated beasts out there. The amount of stuff that either activates or inhibits AMPK boggles the freaking mind. No wonder it is so easy to screw it up. AMPK appears to be a wonderful example of Natural Selection's suboptimal solution finding.

Looking at that picture (I haven't read the article yet), I'm liking the effects T2 has on SIRT1 and AMPK. Something worth exploring, for sure.
 

nanonug

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I believe cAMP can be an input to a process that raises AMPK but is not the key way. As far as I understand it, AMPK works by binding AMP/ATP/ADP to its sensors, and the ratios it discovers decide whether it turns on or not.
Sure, but wasn't it you that showed that AMP is low/normal in people with SEID? (https://forums.phoenixrising.me/ind...nified-me-cfs-theory.55801/page-4#post-931517)

This would mean that a high AMP/ATP ratio couldn't be a trigger for AMPK activation with people with SEID, no?
 

Demepivo

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Sure, but wasn't it you that showed that AMP is low/normal in people with SEID? (https://forums.phoenixrising.me/ind...nified-me-cfs-theory.55801/page-4#post-931517)
*In the Newton paper it mentions studies which have shown ATP is lower in muscle cells taken from ME/CFS patients.

*Think of AMP as used up ATP. M stands for mono-phosphate. ATP has 3 phosphate groups hence the T for Tri.

*Phosphate groups are broken off from ATP releasing energy, so it becomes ADP (di-phosphate) then AMP

*you get AMPK activation in healthy people when there is more AMP and less ATP. It tells the cell take in more glucose to make ATP.
 

Wishful

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Resveratol makes my symptoms worse. Maybe it's for a reason involving ATP, but I think it's too complicated an issue to figure out.

If anyone does deeper reading into the T2 actions and finds something to explain why it has a positive effect on me that lasts a precise and consistent 21 days, please let me know. That sort of abrupt effect following that timing should mean something.
 

Wishful

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Pattismith's link says that T2 binds directly to subunit-A of cytochrome C oxidase. That seems a likely possibility for causing ME symptoms. Mitochondria turnover rate depends on the tissue they're in. I can't find a number for brain cells, but a 21-day cycle isn't unreasonable. However, a half-life doesn't seem to match the abrupt, precise, consistent change I observe. More thinking needed...
 

nanonug

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*you get AMPK activation in healthy people when there is more AMP and less ATP. It tells the cell take in more glucose to make ATP.
I'm not aware of any evidence (published research) that shows a high AMP-to-ATP ratio in people with SEID. The data from Naviaux et al, as extracted by @Murph, doesn't show that kind of high ratio, either.
 
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Sure, but wasn't it you that showed that AMP is low/normal in people with SEID? (https://forums.phoenixrising.me/ind...nified-me-cfs-theory.55801/page-4#post-931517)

This would mean that a high AMP/ATP ratio couldn't be a trigger for AMPK activation with people with SEID, no?
1. Excellent memory!!

2. The mistake I was making in that post (I believe) is considering extracellular measurements (for future passersby, that refers to outside the cell) not intracellular (inside the cell).

AMPK is inside cells and so Naviaux's extracellular serum measurements, while intriguing, don't give us a definitive answer on whether AMPK might be activated..

That weird ratio of ATP to AMP outside the cell needs explaining though. How do you get normal extracellular ATP and low extracellular AMP? One answer is @necessary8's theory of a failure in the cd39 enzyme that is supposed to break down extracellular ATP to AMP...

(Also for future passersby, note that outside the cells ATP is a danger signal, while inside the cell it is an energy molecule. Kind of makes sense that if you start throwing out the things you need to survive, the body takes that danger signal seriously.)

If you wanted to get highly speculative, you could ask if it is perpetually *leaking* ATP out of the cells that might leave us with perpetually low intracellular ATP and thereby activating AMPK. (Leaking ATP is exactly what Naviaux's purinergic signalling theory is. ATP is a purine, and outside the cell it works as a signal hence the term purinergic signalling.)

The problems with this theory of course, are that a) we have similar extracellular ATP levels as the healthy; and b) in an unexpected finding, ATP outisde the cell can somehow activate AMPK inside the cell.

tl;dr cellular biology is too damn complicated. it breaks my brain.
 
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