i think i figured it out (the cause of cfs ) i will pass on the baton

[Mohawk1995]

I believe all people are capable of getting cfs if the stressors are intense enough and of enough duration . I believe the mechanism that I describe happens in healthy people too

I would agree that theoretically all people are capable of getting ME/CFS. It may not even depend entirely on the intensity or duration of the stressor. Certainly in our son's case it had nothing to do with his health prior to onset or his mental health. He was a typical, although highly driven and competitive 7th grader. He did have a viral onset FYI.

Although I may not be able to completely follow the metabolic pathways you are talking about, I believe that ME/CFS is most likely a normal protective and/or metabolic process that has gotten turned on but then not shut off when "normal" physiology would suggest it should. More specifically a "threat response" (could be an exertional issue) that then does not turn off when the threat has been mitigated. This would be supported by a hypothesis that it is an upregulated process.

In my thinking it would be several if not many processes that are upregulated beyond their normal usefulness. To address the metabolic issue in the form of a new treatment, would help but if the cause of the upregulation is not changed there will simply be another pathway that crops up as problematic. Still it is not a wrong thing to address metabolic processes in hope that by turning them down, it might allow for the upregulation to "down shift".

It is the downregulating of this protective/metabolic response that I feel was the difference maker for our son. It just happened to be that he responded to Anti-viral medication (there are likely many ways to turn this off). I believe it was the downregulation of the Nervous system more than the decrease of the viral load that created this open window to recovery, but that is literally impossible to prove based on current knowledge.

 

[livinglighter]

I would caution against this line of thinking with ME/CFS. It has been this type of thinking in medicine that has created many issues with patient care (PACE for instance). There is a difference between having an explanation of a mechanism in a disease and actually understanding the root cause of the disease. Not denying that what you have proposed may be accurate, but it is a description of a mechanism at play in ME/CFS and not the root cause. The ultimate question is why does this system become mal-adaptive in some and not in other people who experience the same distress (disease, trauma, emotional stress, etc....). When we know that answer, then perhaps we can boast just a little.

Could it be some form of immunodeficiency? I've been reading about this being a possible reason for severe COVID19 cases.

 

[livinglighter]

@phillybadboy I recently proposed involvement of PKM2 in my thread along with OAT testing, see here:
https://forums.phoenixrising.me/thr...ults-do-we-all-show-the-warburg-effect.80662/

The impairment of glycolysis is an interesting and unproven hypothesis in ME/CFS. So far I think only one researcher (McGregor) is supporting it, while many others have demonstrated impairment of PDH but without impairment to glycolysis. I'm confused by this because impairment of PDH is typically associated with high pyruvate or lactate, whereas OAT tests of PwME typically show low pyruvate and lactate. In my thread to date, you'll see all but one OAT result contributor show this result, so based on this short survey I'm in the camp that supports something isn't right with glycolysis.

As explained in my thread, PKM2 is the rate limiting step of glycolysis and ubiquitously expressed in sepsis and cancer. Its plausible therefore PKM2 is a good candidate for involvement in ME/CFS if glycolysis is impaired.

no glycolysis is not impaired , at rest the lactate levels are are low , but during physical activity the lacate levels are higher than normal people . if glycolysis was impaired you wouldn't have high lactate levels . It is actually oxidative phosphosphorylation that is inhibited . so we try to make energy by aerobic glycolysis similar to how cancer cells do . the reason this abnormality is PKM2 expression in muscle cells ( normally PKM1 is expressed in muscle cells ) PKM2 helps you with antioxidant system . but PKM2 inhibits p53 activity , p53 is very important for oxidative phosphorylation (sco2) .

Sounds like a possible mechanism for the disease. I spent a few years as a patient of a chartered physiotherapist with specialist knowledge of ME/CFS, they explained somethings to me verbally that I didn't quite understand at the time like ME/CFS being like cancer (I couldn't understand how I could be alive for so long, although I often felt like I was dying, if the illness is somewhat comparable to cancer and be receiving NHS recommended GET and CBT).

I came across the subject of oxidative phosphorylation approx. 20 yrs ago. In my notes I have that NAC, glutathione, L-glutamine, ALA, C0q10, B-vitamins, Magnesium, potassium help support oxidative phosphorylation.

The same therapist recommended some form of Magnesium injections for the energy impairments I would always complain about.

Makes me think how they knew all this but was made to deliver GET therapy...........

 

[phillybadboy]

Livinglighter , I didn't wana say the C word (because I didn't wana be sensational but its the same mechanism and the same enzymes involved, whats important for cancer is cell proliferation , cancer produces high amounts of ROS so they upregulate their antioxidant system , and they also depend on aerobic glycolysis ) p53 is low in cancer . p53 is also low in cfs ( very important for oxidative phosphorylation (to make energy) . The same mechanism that is happening in cancer is happening in muscle cells of cfs .

What is throwing the researchers off is they are testing mononuclear cells . The mechanism is not happeneing in the mononuclear cells . Even though they find an abnormality in mononuclear cells , what's causing the problem in the mononuclear cells is 2,3 dpg ( just a downstream metaboliste of what's happening in the muscles). 2.3dpg inhibits certain glycolytic enzymes in mononuclear cells, giving them the abnormal results . Ron Davis study found downregulated glycolysis because they tested in serum which contained 2,3dpg . Another group out of Stanford found an opposite result(upregulated glycolysis and high atp) because they tested without serum that did not contain abnormal 2,3dpg levels . Normalizing 2,3dpg levels is not gona fix cfs , 2,3dpg is just downstream metabolite of what is happening in cfs patient muscles , where the mechanism causing cfs is actually happening.

The way to fix cfs is normalize what is happening in the muscle cells , There are many enzymes that upregulated and many that are downregulated . But to keep it simple i'm gona mention PKM2 and P53 . Normalizing the aerobic glycolysis and normalizing the upregulated antioxidant system and normalizing p53 (p53 to have normal oxidative phosphorylation )is what i'm looking to do .

 

[phillybadboy]

Livinglighter i'm looking to test for pkm2 and 2,3dpg .

 

[Methyl90]

I tell my experience.

I have experienced "cell hunger" since I was very little ...

To date, 30 years, some things have changed for the better while some have definitely changed for the worse.

I was growing up but in no way could I accumulate some lean muscle tissue ... I was filled with water / fat with a very high mental latency (what I now call cerebral ataxia).

In 2014, after a positive year of weight training, I lost about 12kg of weight without any logical and demonstrable explanation ... in a short time ... all my muscles were lost.

Since 2014 I have started my autonomous experimentation when even today, despite the symptoms, I do not have a medical diagnosis in Italy.

I have done numerous tests that show low pyruvate and low blood lactate.

What I can tell you is that GALACTOSE is truly exceptional for fueling oxidative phosphorylation.

No supplements ... and again, none ... helped me as much as that week when I only consumed HONEY, SKIMMED MILK, YOGURT, FRUIT, no starch.

The protein was very high and the fat was very low.

I still didn't understand why I had so many benefits ... then AFTER I saw this study:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3613401/

ALA R inhibits PDK in pyruvate dehydrogenase and gave me a slight head start probably by increasing insulin signaling ... but after a week the collapse:

It lowers both lactate and pyruvate ... so ALA R lowered it further for me.

This made me realize that the PDH was probably working while the problem had started earlier.

Vitamin E and Vitamin C are doing a lot for me ... E is an HDAC inhibitor. (Niacinamide, ALA R, Biotin, short chain fats are too).

 

[percyval577]

@phillybadboy

You might be interested in the following (self-) observation, although I am currently not able to understand the theory you provided.

In 2015 I found low manganese to be of a huge effect. Sadly the effect disappeared after three months, and since then I though improve slowly and under new difficulties.

Now, one crucial action of Mn is in the MnSOD inside the mt. MnSOD transforms superoxide radicals, which are mostly actively produced but to a certain extend also build up during normal respiration. The product is H2O2 which can leave the mt.

H2O2 then can get further degraded by GSH (I think, it was to water and something). GSH works with selenium, and taking it, is a major positive influence on my symptoms as well.

So I conclude, that in my brain, there is too much H2O2, though it could be both, only relative to some other structures, or absolute (I think it should be in the putamen).


If it is indeed absolute too high, then it may be because of too low GSH or too high MnSOD.

MnSOD has been shown to be intertwined with p53. Here, I think, high MnSOD downregulates p53, a problem in advanced cancers cells (at least roughly, in early ones is the other way around, roughly), so this would go along with your considerations, if I am not wrong.

 

[alex3619]

I would agree that theoretically all people are capable of getting ME/CFS. It may not even depend entirely on the intensity or duration of the stressor.

Unless it requires specific genetic predispositions, several of which have been hypothesized, including IDO2 mutations. These hypotheses are still undergoing testing, we do not know if this valid yet.

 

[vision blue]

I just sent you a quick PM, but have you submitted this anywhere yet officially? It may be easier to get careful analyses in an official capacity just because it's so time consuming to do so when there's a serous contender (as this is) on the table. (didn't explain that properly but i'm tired...)

 

[phillybadboy]

I'm gona make a better presentation , and post here on the forum and bring it to a doctor as well , (haven't seen her in maybe five to ten years ). Its slow going right now reading over this stuff . Will include pictures ( diagrams ) this time .

 

[vision blue]

i meant in a journal. like here's a quick comment. It may be in your best interst to back off a claim that glutathione levels have to be higher. there's many reasons for this and will just give one - if people are depleting it because of great need, could turn out lower, even in the cells. But there are others.

anyway, it's stuff like this. Why not do it properly and send it to a journal?

 

[phillybadboy]

no , oxidative stress is higher in cfs muscle cells , but so is an upregulated antioxidant system , so total glutathione will be high in cfs muscle cells .

Mononuclear cells and red cells will have lower total glutathione because those cells are inhibited by 2,3dpg . 2,3dpg is released by cfs muscles into the blood stream and taken up by mononuclear cells and red blood cells . 2,3 dpg inhibits glycolytic enzymes in mononuclear cells and red blood cells . 2,3dpg in red blood cells inhibits hexokinase 1 hk1 (important for glucose uptake ) , pfk , and gapd , this results in less glucose available for red blood cells and some steps in glycolysis are also inhibited in red cells because of 2,3dpg . This results in less glucose 6 phosphate (for the pentose phosphate pathway) and atp production (through glycolysis) in red blood cells , without adequate pentose phosphate pathway activity and atp , which are needed to synthesize glutathione in red blood cells . So that's how you'll find low glutathione in red cells of cfs .

but the mechanism causing abnormality in red cells is not the mechanism causing cfs . Its the mechanism inside muscle cells that's causing cfs ( the mechanism probably is happening in brain, heart and lung of cfs also , because these organs like muscles are high energy demanding and high energy producing so therefore have the potential trigger the initial oxidative stress and antioxidant reposnse , and now the cfs patient is stuck in this cycle of oxidative stress and antioxidant upregulation.

 

[vision blue]

Even in the muscles, glutathione production will require cysteine. if ther'es no cysteine, there's no glutathione no matter how upregulated this particular anticoxidant defense system is. But this isn't the forum for this.

If you are going to say stuff like this "have most complete and probably the only correct guess out here right now . as far as explaining the mechanism of cfs I think I've gone farther than any researcher all around the world" then you should back it up. Submitting your theory to a peer reviewed journal will reveal if this is true or not.

Btw, you are not the first person (in the published cfs literautre) to suggest oxidative stress and cfs go together, not even the second. Others have pointed out this as well in their posts as well as other cautions and things that might help you develop this into something good.

 

[phillybadboy]

Others pointed at oxidative stress while implying an INADEQUATE antioxidant response ,hence they recommend antioxidants as supportive therapy . I'm saying something opposite , that there is oxidative stress but also an UPREGULATION of the antioxidant system that is more than adequate and i'm also saying antioxidant supplement aren't necessary or helpful ( in this instance ) .

 

[gregh286]

I tell my experience.

I have experienced "cell hunger" since I was very little ...

To date, 30 years, some things have changed for the better while some have definitely changed for the worse.

I was growing up but in no way could I accumulate some lean muscle tissue ... I was filled with water / fat with a very high mental latency (what I now call cerebral ataxia).

In 2014, after a positive year of weight training, I lost about 12kg of weight without any logical and demonstrable explanation ... in a short time ... all my muscles were lost.

Since 2014 I have started my autonomous experimentation when even today, despite the symptoms, I do not have a medical diagnosis in Italy.

I have done numerous tests that show low pyruvate and low blood lactate.

What I can tell you is that GALACTOSE is truly exceptional for fueling oxidative phosphorylation.

No supplements ... and again, none ... helped me as much as that week when I only consumed HONEY, SKIMMED MILK, YOGURT, FRUIT, no starch.

The protein was very high and the fat was very low.

I still didn't understand why I had so many benefits ... then AFTER I saw this study:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3613401/

ALA R inhibits PDK in pyruvate dehydrogenase and gave me a slight head start probably by increasing insulin signaling ... but after a week the collapse:

It lowers both lactate and pyruvate ... so ALA R lowered it further for me.

This made me realize that the PDH was probably working while the problem had started earlier.

Vitamin E and Vitamin C are doing a lot for me ... E is an HDAC inhibitor. (Niacinamide, ALA R, Biotin, short chain fats are too).

Hi @Methyl90
Real interesting
Did you ever try only galactose diet since?
Yea good supplement pack there....e ....ala and biotin

 

[sometexan84]

I respect what you're doing. But I think your theory is a bit messy and presumptuous.

I believe infections, autoimmunity, and epigenetic modifications are the cause (plus perhaps stress and genetic predisposition).

A simpler explanation for the energy metabolism dysfunction you're describing is autoimmunity. ANT antibodies can cause myocardial energy metabolism dysfunction.

 

[gbells]

Chronic fatigue patients have higher activity of nfkb and lower activity of p53.

Yeah because they are infected with HHV6 and EBV. Antioxidants don't solve the problem. I think you are confusing palliation with cure. Many people report that while strong antioxidants can temporarily make them feel better it causes them to crash later.

 

[Badpack]

Can ppl please stay on topic and not just copy paste their idea all over the forum into every thread ?

 

[phillybadboy]

sometexan84, gbells. I meant to say nrf2 is high and p53 is low. ( didn't mean to write nfkb )

 

[Badpack]

Interesting to think about that the Rituximab trial in Norway started with 3 cancer patients, who all got a big relief during chemo but it stoped working with the end of treatment. It always bugged me, that they got a full blown CHOP regime and Fluge and Mella picked single agents to reproduce the same effect. But as we know now, it didnt work out. So clearly it isnt one agent that works, but the full blown cancer treatment. Kinda would also explain why cyclophosphamide seems to work better than Rituximab, from what they have hinted.

So acting on p53 could really be something worthy to explore. Besides, cancer fatigue seems to have the same level of fatigue when asked in questionnaires.