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The Adenosine - Phosphatidic Acid Hypothesis

Iritu1021

Breaking Through The Fog
Messages
586
Important!

Sadly, I have to inform you that I've found a critical flaw in this hypothesis. There are still many pieces to it which I would consider valuable ideas, but the whole no longer works together.

I have stated that "after activating the A1 receptors, a significant portion of this adenosine is actually brought into the cell by CNT2 transporters, and proceeds to activate AMPK. The exact mechanism by which it accomplishes that is not known, but my speculation is that it’s a different mechanism from the one AMP uses, and therefore serves as a fallback activation route in muscle exertion." - this is not fully correct. The andenosine is transported into the cells, and does activate AMPK, but the mechanism is not unknown. The adenosine turns into AMP, which activates AMPK in the usual manner. Meaning, this cannot be an alternetive, fallback activation route for AMPK in contracting skeletal muscle. Unfortunately, this is one of the very few places where an error like this means the whole hypothesis falls apart. The two halves of this hypothesis - the systemic part with the anti-beta2 antibodies, and the intracellular part, with the phospatidic acid - no longer fit together, as they were tied by this idea of adenosine constituting a fallback activation route.

This is fully my mistake, I missed an important part in one of my sources. I apologize terribly for wasting your time. The irony of working on this for half a year only to discover a critical flaw days after going public, would be funny to me if I wasn't so embarassed by this.

The above will be edited in at the beginning of the text of the hypothesis itself, and the untrue statement marked red.
Hey, no worries and no need to be embarrassed. This is what we are all here for - to brainstorm ideas off each other and to get the discussion going. Many of us here (and in science world) have invested a lot of time and effort and feelings into theories that didn't hold out in the end - but that's all part of the process. I'm sure that all the knowledge you've gained and all the connections you've made in your brain will come in handy at some point later.
Keep it up! As Thomas Edison put it: "I failed my way to success".:)
 

Murph

:)
Messages
1,799
Important!

EDIT 17/09/2018
Sadly, I have to inform you that I've found a critical flaw in this hypothesis.

Kudos for your intellectual approach and total transparency!

I will admit I didnt understand how the whole fitted together so I'm not grieving this like you would be, but I think there's some salvageable pieces you've highlighted, not least the ideas about ASIC and about low levels of adenosine meaning we are unable to tamp down an immune reaction to exercise.
 

Diwi9

Administrator
Messages
1,780
Location
USA
@necessary8 - Do not be embarrassed. Your willingness to share ideas and your ability to compile research results is huge for this community. It's not about being right, but getting to the right solution...step-by-step. Thank you so much for your contribution, I should have thanked you earlier. I look forward to how your ideas continue to evolve with new research.
 

kelly8

Senior Member
Messages
191
Are you talking about phosphatidylcholine as an oral supplement addition or iv? I used some oral phosphatidylcholine at one point which seemed to help a bit but I wasn't just adding that at the time.
 

frozenborderline

Senior Member
Messages
4,405
Also there are quite a few of us here who feel improved with caffeine which is adenosine receptor antagonist.
I was going to bring this up, but I wasn't sure that other people had the same experience. It's not just that it gives me "energy" in the sense of most stimulants--amphetamines or methylphenidate don't help me and make me worse since being sick. It helps with all symptoms, even helps with sleep. More of a "relief" than stimulation.

It seems that xanthines are mast cell stabilizers so maybe this is part of that, although coffee has a number of effects including acetylcholinesterase inhibition (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3676818/) and mitochondrial uncoupling (https://www.ncbi.nlm.nih.gov/pubmed/22710994), so it might not help directly via adenosine antagonism.
 

Iritu1021

Breaking Through The Fog
Messages
586
I was going to bring this up, but I wasn't sure that other people had the same experience. It's not just that it gives me "energy" in the sense of most stimulants--amphetamines or methylphenidate don't help me and make me worse since being sick. It helps with all symptoms, even helps with sleep. More of a "relief" than stimulation.

It seems that xanthines are mast cell stabilizers so maybe this is part of that, although coffee has a number of effects including acetylcholinesterase inhibition (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3676818/) and mitochondrial uncoupling (https://www.ncbi.nlm.nih.gov/pubmed/22710994), so it might not help directly via adenosine antagonism.

Or intracellular calcium release - as we've been discussing in the other thread about T3/caffeine/intracellular Ca. Or phosphodiesterase inhibition. That's the problem - everything has at least a hundred different effects.
 

frozenborderline

Senior Member
Messages
4,405
Or intracellular calcium release - as we've been discussing in the other thread about T3/caffeine/intracellular Ca. Or phosphodiesterase inhibition. That's the problem - everything has at least a hundred different effects.
Yeah. The interesting thing is that if we ascribe any kind of unifying theory of life in terms of structure and energy, maybe the fact that drugs are "dirty" and have too many different effects can be explained... e.g. by the whole than the parts. I'm getting a little speculative here but part of this comes from the difficulty of parsing biology piece by separate piece. I'm not suggesting vulgar vitalism, but something like Szent-gyorgyi describes as a relationship between structure and energy in the living state. Maybe the multiple effects/targets of something like coffee or chaga are in concert rather than discordant.
 

JaimeS

Senior Member
Messages
3,408
Location
Silicon Valley, CA

JaimeS

Senior Member
Messages
3,408
Location
Silicon Valley, CA
Important!


Sadly, I have to inform you that I've found a critical flaw in this hypothesis. There are still many pieces to it which I would consider valuable ideas, but the whole no longer works together.

I have stated that "after activating the A1 receptors, a significant portion of this adenosine is actually brought into the cell by CNT2 transporters, and proceeds to activate AMPK. The exact mechanism by which it accomplishes that is not known, but my speculation is that it’s a different mechanism from the one AMP uses, and therefore serves as a fallback activation route in muscle exertion." - this is not fully correct. The adenosine is transported into the cells, and does activate AMPK, but the mechanism is not unknown. The adenosine turns into AMP, which activates AMPK in the usual manner. Meaning, this cannot be an alternative, fallback activation route for AMPK in contracting skeletal muscle. Unfortunately, this is one of the very few places where an error like this means the whole hypothesis falls apart. The two halves of this hypothesis - the systemic part with the anti-beta2 antibodies, and the intracellular part, with the phosphatidic acid - no longer fit together, as they were tied by this idea of adenosine constituting a fallback activation route.

This is fully my mistake, I missed an important part in one of my sources. I apologize terribly for wasting your time. The irony of working on this for half a year only to discover a critical flaw days after going public, would be funny to me if I wasn't so embarrassed by this.

The above will be edited in at the beginning of the text of the hypothesis itself, and the untrue statements as well as my ideas directly stemming from this misunderstanding, will be marked red.

The honest correction is what's important.
 

Iritu1021

Breaking Through The Fog
Messages
586
Yeah. The interesting thing is that if we ascribe any kind of unifying theory of life in terms of structure and energy, maybe the fact that drugs are "dirty" and have too many different effects can be explained... e.g. by the whole than the parts. I'm getting a little speculative here but part of this comes from the difficulty of parsing biology piece by separate piece. I'm not suggesting vulgar vitalism, but something like Szent-gyorgyi describes as a relationship between structure and energy in the living state. Maybe the multiple effects/targets of something like coffee or chaga are in concert rather than discordant.
That seems to be the case with marijuana since the pharmaceutical industry has been trying to bottle the active ingredient but it doesn't seem to work the same way as the whole plant.
 

frozenborderline

Senior Member
Messages
4,405
That seems to be the case with marijuana since the pharmaceutical industry has been trying to bottle the active ingredient but it doesn't seem to work the same way as the whole plant.
Yeah. Well it's true for a lot of things and it comes back to this debate about if there is a telos in substance itself, some kind of striving toward organization.
Back when I was just a casual drug user who was into pharmacology and I wasn't sick at the time, I was mystified that coca was not cardiotoxic even in heavy chewers, but cocaine is insanely cardiotoxic even used a few times. And it's not just dose at all, i'm talking people that would chew an equivalent amount of coca to doing 50 mg bumps of cocaine once an hour.
 

pattismith

Senior Member
Messages
3,930
ED

The feeling of fatigue is facilitated by synergistic activation of ASIC, TRPV1 and P2X3 receptors on certain nociceptive neurons. The main receptor is ASIC, with TRPV1 and P2X3 working to sensitize it, to activate more easily. The metabolites required for this activation are lactic acid and extracellular ATP (both of which are released from muscle cells during exercise).[source1][source2] And it just so happens that extracellular cAMP attenuates this process.[source] Meaning, if those neurons activate in healthy people in presence of lots of extracellular cAMP, and that gets you normal fatigue, then it makes sense than in ME/CFS patients, with much lower cAMP efflux, they activate more strongly and easily, resulting in intense fatigue. Certain levels of LA and ATP are present there even at rest, so without the inhibitory action of cAMP they could very well be activating even at rest.

I am interested in the ASIC hypothesis after reading a bit about small fibers neuropathy (SFN or SFPN)
SFN was shown to be associated in some cases with hyperexcitability of the small fibers by gain of function of sodium channels.
SFN produces hyperalgesia, hypersensitivity, muscle pain, burning skin, tingling, but also autonomic symptoms.
Small nerves (A delta and C fibers) to the muscle may be the fibers were ASICs acid sensors are located (just a speculation from me, as I can't find too much information on it).
So we could imagine that a small fiber neuropathy affecting particularly the small fibers going to the muscles would provoke hyperexcitation of the ASICs sensors, with only minimal lactic acid change.
Is this making sense?

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ED

This mechanism is interesting for a few reasons. Firstly, the autoantibodies in ME/CFS cause gain of function of the beta2 receptors - they make them activate more. That should mean more extracellular adenosine. And yet, looking at the metabolomics data from Robert Naviaux, andenosie is actually one of the most decreased compounds. It is extremely low.[source] There are, obviously, other sources of adenosine in the bloodstream, but my impression is that GPCR desensitization is one of the largest ones, if not the dominant one. This leads me to believe, that what happens in ME/CFS patients, is the cells after prolonged constant stimulation of their beta adrenergic receptors, take compensative measures to offset this.

Last study ( https://www.sciencedirect.com/science/article/pii/S2666354620300120 ) showed that IgG from ME patients with high beta2adrenergic Ab fails to activate the beta2adrenergic receptors. Maybe this explains why so few extracellular adenosine?
 
Last edited:

Rufous McKinney

Senior Member
Messages
13,249
This is fully my mistake, I missed an important part in one of my sources. I apologize terribly for wasting your time. The irony of working on this for half a year only to discover a critical flaw days after going public, would be funny to me if I wasn't so embarrassed by this.

Well, good for you- you acknowledge a flaw instead of hiding it.
 

necessary8

Senior Member
Messages
134
So we could imagine that a small fiber neuropathy affecting particularly the small fibers going to the muscles would provoke hyperexcitation of the ASICs sensors, with only minimal lactic acid change.
Is this making sense?
This is an interesting idea. You could probably explain fatigue with it. But I don't think you could explain PEM. Right? Also, do we have any data showing SFN in CFS already? I know studies on it are underway but do we have results yet?
Last study ( https://www.sciencedirect.com/science/article/pii/S2666354620300120 ) showed that IgG from ME patients with high beta2adrenergic Ab fails to activate the beta2adrenergic receptors. Maybe this explains why so few extracellular adenosine?
This is really interesting as well. When I talked with Alan Light about this a few years back, he was saying that the aabs in CFS cause gain of receptor function, not loss. I guess he was wrong.
 

frozenborderline

Senior Member
Messages
4,405
Also, do we have any data showing SFN in CFS already? I know studies on it are underway but do we have results yet?
I don't know but I do know many physicians are running with the idea already , and think that neuropathy could cause preload failure which could cause PEM. Systrom, Farhad , those are the two I know that believe this.
 

frozenborderline

Senior Member
Messages
4,405
In sickle cell I believe a lot of the pain is caused by lack of oxygen getting to tissues. Something as simple as hypoperfusion seems like it could explain many me/cfs symptoms but I think the real problem is probably upstream from the hypoperfusion
 

necessary8

Senior Member
Messages
134
I think the idea is that exertion dependent hypoperfusion and hypoxia could cause all of the symptoms of PEM. And that preload failure can cause all the hypoperfusion and hypoxia.
Okay but then how does the delay work? In most cases PEM is delayed, usually by something like a day, sometimes even two. How would preload failure cause someone to get worse not immediately during the exertion but the next day instead?
 

frozenborderline

Senior Member
Messages
4,405
Okay but then how does the delay work? In most cases PEM is delayed, usually by something like a day, sometimes even two. How would preload failure cause someone to get worse not immediately during the exertion but the next day instead?
That part would probably be above my pay grade but we already know that people perform worse on the second day of 2day cpets. We just don't know why. Systrom presumes the poor aerobic performance on repeat testing is based on preload failure.

There are lots of conditions , including congestive heart failure, that cause exertion intolerance and abnormal recovery to exertion. I'm not sure that PEM always has to be delayed , either. I mean I think th exertion intolerance in me/cfs causes somewhat delayed crashes , but the abnormal fatiguability probably starts immediately with exertion.

So, I think wed have to know the cause of th preload failure to know why the hypoperfusion is delayed or why it's effects are delayed. But preload failure involves an inability to properly fill the heart on recovery from the last beat , so maybe that has something to do with it