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

anni66

mum to ME daughter
Messages
563
Location
scotland
According to this Life Extension article, the Chinese herb Gynostemma pentaphyllum (jiaogulan) and trans-tiliroside from rose hip powder increase AMPK activation.

The drug metformin also activates AMPK.

The articles says:
@Hip
Our ATP profiles test showed -
inefficient oxphos
uncoupling of ATP/ADP supply and demand - literally chucking ATP into cytosol at alarming rate - could this be the initial mechanism for ATP signalling to activate AMPK?
 

Murph

:)
Messages
1,799
As a random thought: failure of AMPK activation as a result of ATP depletion by exercise could be an explanation for post-exertional malaise, no?

PEM definitely could be extreme, prolonged AMPK activation because of crazy low ATP; or failure to activate AMPK because AMPK is broken; or an attempt to activate MPK that is partially successful because the AMPK is already hyperactivated by chronic low ATP.

Not sure any of these can explain delayed PEM tho.

Side note while we are all here: There is an interesting genetic condition where the body can't break down AMP that could therefore give you high AMP/ATP ratios that activate AMPK. Suprise, surprise, people with this condition feel very very tired.

Adenosine monophosphate (AMP) deaminase deficiency is a condition that can affect the muscles used for movement (skeletal muscles). In many affected individuals, AMP deaminase deficiency does not cause any symptoms. People who do experience symptoms typically have fatigue, muscle pain (myalgia), or cramps after exercise or prolonged physical activity (exercise intolerance). Following strenuous activity, they often get tired more quickly and stay tired longer than would normally be expected. In rare cases, affected individuals have more severe symptoms including severe muscle weakness, low muscle tone (hypotonia), and muscle wasting (atrophy), but it is unclear whether these symptoms are due solely to AMP deaminase deficiency or additional health conditions. Exercise intolerance associated with AMP deaminase deficiency usually becomes apparent in childhood or early adulthood.

The only suggested treatment is eating d-ribose. I don't know why I haven't been tested for this tbh.
 

anni66

mum to ME daughter
Messages
563
Location
scotland
regenerating ATP from ADP and AMP is an energy intensive process ( via Cori cycle). You are in energy deficit to do this - for someone already compromised, making ATP this way is like having a permanent loan shark
 

nanonug

Senior Member
Messages
1,709
Location
Virginia, USA
Adenosine monophosphate (AMP) deaminase deficiency

Genetic mutations in AMPD1 happen in around 10% of Caucasians. Of these, 10 to 20% exhibit symptoms. In short, it is common enough to affect a substantial number of people here on PR. That being said, one characteristic of this condition is elevated extracellular and circulating adenosine, which is not consistent with the results obtained by Naviaux et al. One common symptom, particularly after exercise, is hypersomnolence (due to very high levels of circulating adenosine.) A neurologist is the specialist to visit for a diagnosis.
 

nanonug

Senior Member
Messages
1,709
Location
Virginia, USA
I'm still trying to understand what could lead to AMPK activation failure under muscle contraction. Looking at this paper entitled "Regulation and function of AMPK in physiology and diseases", one can see on Fig. 2 that circulating free fatty acids, lipopolysaccharides, TNF-alpha and IL-6 indirectly inhibit AMPK. Interestingly enough, IL-6 is released by contracting muscles. IL-6 has previously been discussed here on PR: https://forums.phoenixrising.me/index.php?threads/myokine-il-6-as-muscle-anti-inflammatory.34962/. I wonder if a disproportionate release of, or sensitivity to IL-6, could be a reason behind AMPK activation failure under muscle contraction.


emm201681f3.jpg
 

Wishful

Senior Member
Messages
5,665
Location
Alberta
As a random thought: failure of AMPK activation as a result of ATP depletion by exercise could be an explanation for post-exertional malaise, no?

I'd say no. I don't think it can explain the 24-hr delay. Also, my observations is that--at least for me--PEM is triggered by immune-system activation following muscle damage, not by increased physical demands. My guess is that the positive feedback loop of ME/CFS is quite complicated, involving a lot of interactions.
 

necessary8

Senior Member
Messages
134
Since a few people tagged me I guess I have to make a comment about this.

So.

First of all, two things.

1. As some of you already noticed, the intracellular signaling network that AMPK is a part of, is really fucking complicated. Its nowhere near as simple as "we're sick because AMPK is low, we need to take drugs that will make it higher". I mean, technically, it could be something like that, but it also could be a 100 different things.

2. While I really like this paper's findings, I still believe that they do not explain any of our symptoms in any even remotely direct way. I said it before and I will say it again: your cells not having enough energy does not directly make you tired. At least not to my knowledge (if someone can prove me wrong on this, PM me).

Now, with that said:
This is very good research. Very important, in my opinion. Not the study discussed in this thread specifically, but the one to which it is a continuation - the study from 2015 where they demonstrated impaired AMPK activation and glucose uptake in cultured muscle cells. This study: http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0122982 I somehow missed it earlier, and it has only come to my attention recently, when the continuation was published.

The reason why I believe it to be very important is that this is the first study that I've seen that demonstrates altered cellular energy homeostasis in muscle cells. That last part is important. I explained why here: http://forums.phoenixrising.me/inde...nic-fatigue-syndrome.55689/page-2#post-929359

And because of this research, and because of a few other things that were brought to my attention recently, the AMPK angle was bumped up to the top of my list of stuff to consider, and I am now extensively looking into the relevant literature. I will try to find a way to tie this to the symptoms, and maybe an actual hypothesis will emerge from it. Im not sure if I will post about it like I did with the CD39 hypothesis - explaining this so that everyone can understand takes a loooot of energy. So probably I will go straight to the researchers with my findings. But maybe I will give you guys a short summary. We'll see. It probably wont be anytime soon though. Lots of papers to read, very little energy.
 

Wishful

Senior Member
Messages
5,665
Location
Alberta
I said it before and I will say it again: your cells not having enough energy does not directly make you tired. At least not to my knowledge (if someone can prove me wrong on this, PM me).

I totally agree with that. When I first joined this forum, I was a bit bothered by the simplistic arguments I was seeing, such as 'exercise increases lactic acid, therefore that's why I feel tired!' My guess is that 'feeling fatigued' is probably quite complex, involving signalling to specific neuron groups. When I went for a long snowshoe trek recently, I noticed that I was feeling 'pleasantly fatigued' from the muscle use, rather than the unpleasant fatigue of ME. It's hard to explain the difference, but the two types of fatigue are different.

My ME also gives me perceived muscle aches. I'm convinced that there isn't anything wrong with those muscles, but that the perception of pain is due to altered chemistry in a group of neurons in my brain.
 

anni66

mum to ME daughter
Messages
563
Location
scotland
Since a few people tagged me I guess I have to make a comment about this.

So.

First of all, two things.

1. As some of you already noticed, the intracellular signaling network that AMPK is a part of, is really fucking complicated. Its nowhere near as simple as "we're sick because AMPK is low, we need to take drugs that will make it higher". I mean, technically, it could be something like that, but it also could be a 100 different things.

2. While I really like this paper's findings, I still believe that they do not explain any of our symptoms in any even remotely direct way. I said it before and I will say it again: your cells not having enough energy does not directly make you tired. At least not to my knowledge (if someone can prove me wrong on this, PM me).

Now, with that said:
This is very good research. Very important, in my opinion. Not the study discussed in this thread specifically, but the one to which it is a continuation - the study from 2015 where they demonstrated impaired AMPK activation and glucose uptake in cultured muscle cells. This study: http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0122982 I somehow missed it earlier, and it has only come to my attention recently, when the continuation was published.

The reason why I believe it to be very important is that this is the first study that I've seen that demonstrates altered cellular energy homeostasis in muscle cells. That last part is important. I explained why here: http://forums.phoenixrising.me/inde...nic-fatigue-syndrome.55689/page-2#post-929359

And because of this research, and because of a few other things that were brought to my attention recently, the AMPK angle was bumped up to the top of my list of stuff to consider, and I am now extensively looking into the relevant literature. I will try to find a way to tie this to the symptoms, and maybe an actual hypothesis will emerge from it. Im not sure if I will post about it like I did with the CD39 hypothesis - explaining this so that everyone can understand takes a loooot of energy. So probably I will go straight to the researchers with my findings. But maybe I will give you guys a short summary. We'll see. It probably wont be anytime soon though. Lots of papers to read, very little energy.
@necessary8 - have you looked at the Myhill, Booth et al papers?
Correlation of fatigue energy score and Bell scale, has been suggested that PEN dye to bidy having to make DiRibose from scratch due to AMP imoact on ATP recycling...
 

ljimbo423

Senior Member
Messages
4,705
Location
United States, New Hampshire
I'm convinced that there isn't anything wrong with those muscles, but that the perception of pain is due to altered chemistry in a group of neurons in my brain.

You could be right about that. I've been feeling more and more like my flu-like symptoms and my fatigue are more centered in my brain than in my body. From the research I've done flu-like symptoms are centered in the brain.

Caused by activated microglia, which are immune cells in the brain. Just like when someone gets a flu or bacterial infection, like bronchitis, they get flu-like symptoms, from activated microglia in the brain.

My flu-like symptoms and my fatigue seem very much intertwined though. That's why I'm thinking both my fatigue and flu-like symptoms are probably centered in my brain. Most likely caused by low grade neuro-inflammation and mitochondrial dysfunction. Which seem to feed each other.

A recent big increase in my coq10 intake has completely stopped the flu-like flares I use to get from exercising and increased my energy levels. That tells me that dysfunctional mito. were/are, causing both the fatigue and flu-like symptoms. The coq10, by increasing oxidative phosphorylation in the mito in my brain, stopped the flares and reduced my fatigue.


Jim
 

Wishful

Senior Member
Messages
5,665
Location
Alberta
My baseline symptoms are worsened by tryptophan transport into the brain, so I believe that kynurenines are at least partly responsible for the symptoms. Viral infections produce the same symptoms, involving elevated kynurenines, so it seems reasonable to me. CoQ10 might influence kynurenine production.
 

Mary

Moderator Resource
Messages
17,321
Location
Southern California
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.

I've been taking resveratrol at night for sleep for over a year I think - I don't know how long actually, it's a blur. I started taking it because I was tapering off of lorazepam and read that resveratrol is a glutamate scavenger (along with calcium pyruvate and high dose vitamin c). it did help but something is draining my energy now and I'm wondering if it's the resveratrol - i'm going to try stopping it (I've been totally off the lorazepam for over a year now) and see what happens - A little bit of knowledge ... dang! :bang-head:
 

Wishful

Senior Member
Messages
5,665
Location
Alberta
It's important to retest the effects of supplements, drugs, and anything else we do 'to feel better', because some of them just stop working after a while, and some might sneak in unpleasant side effects. We are terrible at noticing slow changes.

A related problem is: 'when should we give up on something?' If someone says that 'x' reduces their symptoms, or hypothesis 'y' suggests that 'z' should help, how long should we continue taking it before we accept that it doesn't work for us? Some of the suggestions, such as antiviral treatments, can take a couple of years before having an effect...if they have an effect at all. I admit I'm really terrible at judging when to say 'enough'.
 

pattismith

Senior Member
Messages
3,930
Conclusions
Pharmacological activation of AMPK can improve glucose uptake in muscle cell cultures from patients with ME/CFS.
This suggests that the failure of electrical pulse stimulation to activate AMPK in these muscle cultures is due to a defect proximal to AMPK.

Further work is required to delineate the defect and determine whether pharmacological activation of AMPK improves muscle function in patients with ME/CFS.

I wonder if Valacyclovir improves ME/CFS by fighting Herpes virus or by improving muscle glucose uptake via pyruvate kinase/AMPK activation...

This key study was just released in september 2022:
Key findings
Acyclovir, an antiviral nucleotide analog, alleviates insulin resistance by reducing blood lipids as well as oxidative stress and elevating insulin sensitivity on diabetic mice, which is in accord with results in the insulin resistance model of HepG2 cells.
Mechanically, acyclovir stimulates pyruvate kinase M1 (PKM1) directly to activate adenosine 5′-monophosphate (AMP)-activated protein kinase (AMPK)/Sirtuin1 (SIRT1) signaling pathway, thus improving insulin resistance.




Acyclovir alleviates insulin resistance via activating PKM1 in diabetic mice - ScienceDirect
 
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