Cause of EBV Fatigue found + Biomarkers (Mitochondria “Cellular Chronic Fatigue")

[Hip]

From a quick look last night, it looks like AICAR can boost ATP-Synthase (Complex V), but likely indirectly through upregulation of AMPK:

Looks like you can buy AICAR (also called acadesine) at peptide suppliers:

https://www.peptidesciences.com/aicar-50mg
https://www.uk-peptides.com/aicar-50mg

 

[Hip]

AICAR seems interesting:

The drug, AICAR, mimics AMP, effectively tricking the body into thinking that it needs more energy and to begin producing more ATP – making more energy available for cellular action. — Source: here.

Apparently AICAR is touted as an exercise pill: it gives the benefits of exercise without having to actually move a muscle:

AICAR affects many organs and regulates a plethora of metabolic processes, in part by replicating the effects of exercise in both in vivo and in vitro studies. — Source: here.

EDIT: unfortunately it looks like AICAR is not viable unless you are wealthy: this Reddit thread suggests the human dose would be or 125 mg to 500 mg daily. Since 50 mg costs $60, that's very expensive.

 

[Learner1]

From a quick look last night, it looks like AICAR can boost ATP-Synthase (Complex V), but likely indirectly through upregulation of AMPK

This sounds like an unnecessary step then. Researchers have recognized that ME/CFS patients may need to boost AMPK.

My specialists have suggested MOTS-C and then metformin for this, however, MOTS-C made me extremely fatigued as it stops use of folate, while metformin impairs complex 1, which might be great if your robustly healthy for longevity purposes, but when one's complex one is going at 30 to 50%, might not be such a great idea.

However, resveratrol boosts AMPK as do quercetin, curcumin, zinc, anthocyanins, EGCG, alpha lipoic acid, and a whole bunch of other stuff. This has a good run down here, complete with references:

https://selfhacked.com/blog/natural-ampk-activators/

 

[Learner1]

This sounds like an unnecessary step then. Researchers have recognized that ME/CFS patients may need to boost AMPK.

My specialists have suggested MOTS-C and then metformin for this, however, MOTS-C made me extremely fatigued as it stops use of folate, while metformin impairs complex 1, which might be great if your robustly healthy for longevity purposes, but when one's complex one is going at 30 to 50%, might not be such a great idea.

However, resveratrol boosts AMPK as do NAD, quercetin, curcumin, zinc, anthocyanins, EGCG, alpha lipoic acid, and a whole bunch of other stuff. This has a good run down here, complete with references:

https://selfhacked.com/blog/natural-ampk-activators/

I suspect a lot of folks around here who have low ATP synthase activity may not be taking most of the things on that list. And, in the belief that most things work synergistically, based on the mitochondrial papers I've read, it's probably worth using at least five to eight things on the list together, and not just one and then saying it doesn't work

 

[Hip]

. @Hip none of your suggestions in yourvlinks say how to LOWER hyperactive complex IV.

I would not have thought over-efficient mitochondrial complexes would be a problem, only under-efficient complexes.

 

[wabi-sabi]

I would not think over-efficient mitochondrial complexes would be a problem, only under-efficient complexes.

It's my understanding that these complexes upregulate as a compensatory mechanism for problems elsewhere, so lowering them would only exacerbate things.

 

[Wishful]

I would not think over-efficient mitochondrial complexes would be a problem, only under-efficient complexes.

No, think of the electron transport chain as a pipe, and ATP synthase is the outlet. Plug that even partially and bad things happen. They're even worse if you build up the pressure (complexes I-IV more active). More ROS get released and signal that correction is necessary, but what if the correction mechanism isn't working properly?

 

[Wishful]

I looked up inherited mitochondrial diseases affecting ATP synthase, and was surprised at how localized some of them were. One would think that a mito mutation would affect all cells in the body, but some diseases affect just single organs, or parts of the brain, without affecting others. That could explain why my body doesn't show any signs of mitochondrial disease while parts of my brain aren't working right. It could still be mito dysfunction, just highly localized.

 

[Learner1]

I would not think over-efficient mitochondrial complexes would be a problem, only under-efficient complexes.

From what I've learned so far, it's not being overly efficient, more like frantically thrashing, maybe throwing off too many ROS??

It's my understanding that these complexes upregulate as a compensatory mechanism for problems elsewhere, so lowering them would only exacerbate things.

I was originally told high complex IV was compensating for low complex I, but correcting complex I hasn't fixed complex IV.

And, as I mentioned, my pyruvate/lactate are now below range, having steadily been dropping from high normal 5 years ago.

And, fatty oxidation is not functioning properly. So, there are more layers to this.

More ROS get released and signal that correction is necessary, but what if the correction mechanism isn't working properly?

Complex IV isn't usually tagged for releasing too many ROS, but inn wondering big that's indeed what's going on as oxidative stress is quite high even though several drivers have been worked on.

I looked up inherited mitochondrial diseases affecting ATP synthase, and was surprised at how localized some of them were. One would think that a mito mutation would affect all cells in the body, but some diseases affect just single organs, or parts of the brain, without affecting others. That could explain why my body doesn't show any signs of mitochondrial disease while parts of my brain aren't working right. It could still be mito dysfunction, just highly localized

A single mito mutation can even create different mito diseases, depending on how much it's being expressed. And they affect different parts of the body.

 

[sometexan84]

Sorry, I haven't been able to respond to any of this. I've been herxing, and stuck in bed for days now. Only now able to get on comp. I think I found a cure for Echovirus 11. But I'm still too tired to chat much on here. I expect to feel better tomorrow or the day after, then I'll be able to give more info on everything.

 

[sometexan84]

Also, as I'm skimming the responses here, y'all are missing the whole point. With thoughts like "how to fix Complex (whatever)", you're not helping yourself. You HAVE to see the bigger picture. It's about fixing what's causing that. After that, if you still happen to have biomarkers indicating problems, along w/ bad symptoms still, then take care of that, like B cell depletion therapy, or vagus nerve stimulation. But I really doubt many will need that if you get rid of the underlying condition.

All you guys who have been active in this thread throwing out your opinions, including you @Hip, all you're doing is muddying the waters. I'm too tired right now to spend the time to rebuttal all of y'alls BS. All I can say for now, you guys make me feel sometimes like this is pointless. And I should just cure myself and not worry about the rest of you. I mean, does everyone on here even want to be cured?

 

[Learner1]

You HAVE to see the bigger picture. It's about fixing what's causing that.

Totally agree.

After that, if you still happen to have biomarkers indicating problems, along w/ bad symptoms still, then take care of that, like B cell depletion therapy, or vagus nerve stimulation. But I really doubt many will need that if you get rid of the underlying condition.

I disagree on this one I've done a lot to get rid of a lot of underlying conditions, but was still sick. I do things that stimulate vagal nerve and have done B cell depletion to work on the autoimmunity destroying my quality of life which have been successful.

I mean, does everyone on here even want to be cured?

I do, and have made a huge amount of progress, working through a number of complex issues over time. This isn't easy and there are no quick fixes and shortcuts don't work too well. It's taken me three years to do this, and been well worth the effort to get the entire symphony playing. Getting only one instrument playing doesn't cut it...

 

[WantedAlive]

To understand what this research paper means, one has to really understand ATP Synthase (Complex V) and its function in context with this paper.

To date, we know ATP Synthase activity regulates (1) the state of flux of OXPHOS, (2) execution of cell death (3) mitochondrial signalling by ROS. The protein IF1 (ATPase inhibitory factor 1) referred to in the paper, is an inhibitor of ATP Synthase in normal physiological conditions - when dephosphorylated it binds to ATP Synthase and inhibits ATP synthesis. In the same manner, it also inhibits ATP hydrolysis, when ATP Synthase runs in reverse. ATP Synthase is a reversible turbine, each revolution yields 3 ATP but in reverse consumes 3 ATP. Essentially, IF1 acts just like a brake and could be the cause of downregulated ATP Synthase.

Inhibition of ATP Synthase by IF1 reduces ATP output by OXPHOS and rewires energy metabolism to enhanced glycolysis, and this paper suggests that non-mitochondrial oxygen consumption was enhanced. What I find strange here is this research finds no impairment of glycolysis, yet previous findings of a PDH deficiency, low pyruvate and normal lactate argue against this. Unless of course pyruvate is being converted to Acetyl-CoA and taken up by hypermetabolic mitochondria more rapidly than is being produced. A hyperactivated Complex I, as reported, might support this possibility, and perhaps glycolysis isn’t impaired after all. A study of the pyruvate kinase enzyme, the final rate-limiting step in glycolysis is needed to answer that question.

The question why ATP Synthase is insufficient remains unanswered, we can only speculate. ATP Synthase is pro-apoptotic whereas inhibition by IF1 is anti-apoptotic by inducing mitohormesis, cell survival and adaption to stress. The finding of proton leak might suggest inhibition of ATP Synthase by IF1 to increase mitochondrial membrane potential, by increasing the proton pool. This could all be a hypoxia response or Warburg effect. However, the paper proposes spare capacity of early complexes suggests this Complex V inhibition is unwarranted.

There are many other unexplored possibilities though. The cAMP / Protein Kinase A (PKA) signalling pathway is relevant in PKA’s ability to phosphorylate IF1 preventing it binding to and inhibiting ATP Synthase. PKA’s functions include regulation of glycogen, sugar and lipid metabolism, all thought to be disturbed in ME/CFS. Has cAMP activator Forskolin improved anyone or made them worse? A β-adrenergic agonist has been shown to phosphorylate IF1, Beta-Blockers do the opposite, and this may be relevant in the context of ME/CFS.

Similarly, we know SIRS metabolically resembles ME/CFS, and in septic shock ATP Synthase function is suppressed and IF1 depleted which favours ATP hydrolysis. Without IF1 to prevent ATP hydrolysis, early complexes would need to be hyperactive, as reported, to maintain the proton gradient. The SIRS/Sepsis model adopts the Warburg effect, whereby both glycolysis and OXPHOS are impaired, which may still be relevant for ME/CFS.

This paper is certainly significant progress to validating the crisis of ME/CFS patients, but also shows how much more research we desperately need. I'd love to know definitively if glycolysis is impaired or not, I'm not at all confident yet there's no problem there. Afterall, if glycolysis is impaired, would Complex V downregulate in order to to induce increased glycolysis as a normal response?

 

[Learner1]

I'd love to know definitively if glycolysis is impaired or not,

Neil.McGregor says it's definitely impaired.

 

[bread.]

I find it disturbing how long it takes the whole field and also patients to understand that this disease is driven by mitochondrial failure one way or the other. It is like people do not want it to be an issue with mitos and therefor look away. Severe ME patients can not stand up for gods sake, not because they are „fatigued“ but because they do not have the energy to do so. You do not even need to have any clear cut evidence for mitochondrial dysfunction yet, only looking at the disease alone and what is known about physiology in mammals must tell you it is a primary issue of energy generation - according to occam’s razor it is a necessity. Of course everybody can bullshit themselves for another 100 years.

 

[sometexan84]

Apologies for my rant before. If anyone's gone through a Herxheimer reaction, you might can relate to the legit agitation that goes along w/ it. This herx was my worst ever, lasting a full week. Just came out of it today.

Good news is, I believe I cured my Echovirus 11, which I'll create a new Post for in a sec. Also, it can't be verified until I retest my EV11 titres from ARUP, which will take about 2 weeks.

I disagree on this one I've done a lot to get rid of a lot of underlying conditions, but was still sick. I do things that stimulate vagal nerve and have done B cell depletion to work on the autoimmunity destroying my quality of life which have been successful.

You've been working hard my friend, if you've actually done B cell depletion therapy.

Did you mean to say "have been UNsuccessful"?

Regardless though.... what are your highest infection titres? Have you tested for all the major bacteria and viral infections associated w/ CFS? Have you had any conditions and/or symptoms that really stand out? For example, the fact that I had Guttate Psoriasis helped me discover a large portion of my condition. It's not something everyone has, kind of uncommon really.

Have you mapped out a timeline dating back to just before symptoms started? This helped me a lot as well, documenting symptoms, when they started, when they changed to severe, when I got diagnosed w/ this and that, noteworthy lifestyle changes, etc etc.

What drugs did you use for your highest titre infections?

 

[Learner1]

I've mapped out an extensive timeline and am pretty well aware of the issues. I had stage 3 cancer before the infections. Yes, I was tested thoroughly for the 7 infections - 2 viral and 2 atypical pneumonias, treated with IVIG, 20 months of Valcyte and 4 months of a triple antibiotic IV regimen. And B cell depletion for the autoimmune issues that arose. And a comprehensive nutrient and hormone program and HBOT.

Been pretty successful. However, each of us has a somewhat different path into and out of this disease.

 

[sometexan84]

To understand what this research paper means, one has to really understand ATP Synthase (Complex V) and its function in context with this paper.

To date, we know ATP Synthase activity regulates (1) the state of flux of OXPHOS, (2) execution of cell death (3) mitochondrial signalling by ROS. The protein IF1 (ATPase inhibitory factor 1) referred to in the paper, is an inhibitor of ATP Synthase in normal physiological conditions - when dephosphorylated it binds to ATP Synthase and inhibits ATP synthesis. In the same manner, it also inhibits ATP hydrolysis, when ATP Synthase runs in reverse. ATP Synthase is a reversible turbine, each revolution yields 3 ATP but in reverse consumes 3 ATP. Essentially, IF1 acts just like a brake and could be the cause of downregulated ATP Synthase.
....

 

[sometexan84]

this research finds no impairment of glycolysis

First off, remember this study used EBV infected cells. If you're referring to McGregor's paper on Glycolysis dysfunction, I'm pretty sure he just tested on "ME/CFS patients". Something to keep in mind.

Second, Glycolysis occurs outside the mitochondria. This study looked at dysfunction w/in mitochondria. It also acknowledged the older studies that propose a defect in glycolysis, or defect in pyruvate dehydrogenase (PDH).

And those are their words in the study, they were careful to use the term "defect". Because really, the other studies aren't wrong. I mean, there is dysfunction involving glycolysis and PDH and energy production. But where is the true defect. None of it is going to work to bring our bodies energy if Complex V is messed up.

Third, to be fair, I actually don't think McGregor's paper (or the healthrising blog post I read, I didn't seek out the actual study) really showed direct Glycolysis dysfunction. I mean, he used that glucose tolerance test (GTT) or whatever. But, that just showed CFS people suck at using glucose for energy, not why. Idk, the whole McGregor theory seems sort of presumptuous, to me at least.

#4!! They actually talked about Glycolysis a lot. Section 2.6. Glycolytic Rates Are Unaffected in blah blah blah.

This makes sense in my mind. Glycolytic Rate - Ok, so the rate at which glucose turns to pyruvate. If the dysfunction is IN the mitochondria, then yea, the glycolytic rate would be the same. It's just that once the pyruvate gets to the mitochondria, it doesn't get processed right.

I'd love to know definitively if glycolysis is impaired or not

So, I guess the answer at this point in time, appears to be no, it is not.

 

[sometexan84]

However, each of us has a somewhat different path into and out of this disease.

True. But there's a 100% chance I can't help if you don't give me more info.