Mitochondrial and Energy Metabolism Dysfunction in ME/CFS — Myhill, Booth and McLaren-Howard Papers

[frozenborderline]

Thanks, that's good to know.

You're not wrong there and I've been umming and ahhing over trying their products for that reason. I did manage to find my way to the shop in the end though but still debating with myself whether or not to give this a shot.

Let me know here if you try this one, and I'll do likewise.

I have ordered this product. I don’t expect miracles, but there is some interesting literature on Ethyl pyruvate. @Hip if you get around to trying it, would be curious what you think

 

[Hip]

I have ordered this product. I don’t expect miracles, but there is some interesting literature on Ethyl pyruvate. @Hip if you get around to trying it, would be curious what you think

I will be curious to hear about your results with ethyl pyruvate.

In this paper about using ethyl pyruvate to treat Trypanosoma brucei infection (sleeping sickness) they suggest ethyl pyruvate may kill this parasite by cutting off its ATP energy supply, which is achieved by inhibiting pyruvate kinase, an enzyme involved in the final step of glycolysis.

The authors say:

We have shown that ethyl pyruvate effectively kills trypanosomes most probably by net ATP depletion through inhibition of pyruvate kinase

Our results present ethyl pyruvate as a safe and fast acting trypanocidal compound and show that it inhibits the enzyme pyruvate kinase. Competitive inhibition of this enzyme was found to cause ATP depletion and cell death. Due to its ability to easily cross the blood-brain-barrier, ethyl pyruvate could be considered as new candidate agent to treat the hemolymphatic as well as neurological stages of sleeping sickness.

Whether ethyl pyruvate has any effect on human pyruvate kinase and glycolysis I am not sure.


Ron Davis thinks pyruvate kinase might be inhibited in ME/CFS:

Fluge and Mella suggest pyruvate dehydrogenase is probably blocked. We have not investigated that, but it is consistent with glycolysis being shutdown. We also think that pyruvate kinase might be shutdown. Those are not inconsistent and it is possible there are blocks in both of them. This may be the heart of this disease.

Source: here.

 

[frozenborderline]

I will be curious to hear about your results with ethyl pyruvate.

In this paper about using ethyl pyruvate to treat Trypanosoma brucei infection (sleeping sickness) they suggest ethyl pyruvate may kill this parasite by cutting off its ATP energy supply, which is achieved by inhibiting pyruvate kinase, an enzyme involved in the final step of glycolysis.

The authors say:



Whether ethyl pyruvate has any effect on human pyruvate kinase and glycolysis I am not sure.


Ron Davis thinks pyruvate kinase might be inhibited in ME/CFS:

So I’m short, you’re urging caution?
I wasn’t thinking about pyruvate kinase, what reaction does that catalyze? In fluge/Mellas paper they suggest pyruvate dehydrogenase being impaired by upregulation of pyruvate dehydrogenase kinase.

In the thread I posted earlier, the argument is made that pyruvate helps increase the expression of pyruvate dehydrogenase, which almost seems to simple and good to be true—I had assumed that if pyruvate dehydrogenase is impaired the pyruvate would just be reduced to lactate. But there are a lot of studies cited there. And Ron Davis has good results in the nano needle by adding pyruvate. It seems Ethyl pyruvate is also helpful in ischemia and a number of inflammatory diseases

 

[Hip]

So I’m short, you’re urging caution?

I could not find anything to suggest ethyl pyruvate inhibits pyruvate kinase in humans, so I don't think its going to be an issue, but I thought I'd mention it.

In fact one study I came across found that in experimental rat ischemia, ethyl pyruvate increased ATP levels and prevented oxidative injury.

 

[frozenborderline]

I could not find anything to suggest ethyl pyruvate inhibits pyruvate kinase in humans, so I don't think its going to be an issue, but I thought I'd mention it.

In fact one study I came across found that in experimental rat ischemia, ethyl pyruvate increased ATP levels and prevented oxidative injury.

I’m excited. Do you have any thoughts on the other constituent , acetoacetate ?

 

[ljimbo423]

In the thread I posted earlier, the argument is made that pyruvate helps increase the expression of pyruvate dehydrogenase, which almost seems to simple and good to be true—I had assumed that if pyruvate dehydrogenase is impaired the pyruvate would just be reduced to lactate.

As I understand it, NAD, Pyruvate and CoA (pantethine is a precursor to CoA) block the Pyruvate Dehydrogenase Kinases, which activates PDH. NADH and Acetyl-CoA activate the Pyruvate Dehydrogenase Kinases which inactivates PDH. Alpha Lipoic Acid inhibits the Pyruvate Dehydrogenase Kinases, which helps to activate PDH.

https://www.google.com/search?q=dca..._AUICigB&biw=768&bih=366#imgrc=fv7p8ik5RmT5UM:

 

[frozenborderline]

As I understand it, NAD, Pyruvate and CoA (pantethine is a precursor to CoA) block the Pyruvate Dehydrogenase Kinases and activate PDH. NADH and Acetyl-CoA activate the Pyruvate Dehydrogenase Kinases and inactivate PDH. Alpha Lipoic Acid inhibits the Pyruvate Dehydrogenase Kinases, which helps to activate PDH.

View attachment 31464



https://www.google.com/search?q=dca..._AUICigB&biw=768&bih=366#imgrc=fv7p8ik5RmT5UM:

I believe thiamine is also a pdk inhibitor

 

[ljimbo423]

I believe thiamine is also a pdk inhibitor

I think it's also a cofactor in the PDH complex, as it's coenzyme, Thiamine pyrophosphate-

https://en.wikipedia.org/wiki/Pyruvate_dehydrogenase_complex

EDIT- I just want to add that all 3 of the enzymes listed on the left of the diagram make up the PDH complex.

 

[Hip]

Do you have any thoughts on the other constituent , acetoacetate ?

Don't really know much about acetoacetate, apart from the fact it's one of the three ketone bodies produced during a ketogenic diet. But beta-hydroxybutyrate is the ketone body normally sold as a supplement (and which some ME/CFS patients have benefitted from).

 

[leokitten]

@Hip @debored13 @ljimbo423

I haven’t read much yet on ethyl pyruvate though I have some concerns regarding its depletion of GSH. Ray Peat and followers believe GSH levels can also be pathogenic, not sure what to say about that.

 

[frozenborderline]

@Hip @debored13 @ljimbo423

I haven’t read much yet on ethyl pyruvate though I have some concerns regarding its depletion of GSH. Ray Peat and followers believe GSH levels can also be pathogenic, not sure what to say about that.

Is GSH the reduced form of glutathione ? If so it should be somewhat easy to supplement to make sure this doesn’t happen. I actually have intranasal glutathione for this situation

 

[Learner1]

@Hip @debored13 @ljimbo423

I haven’t read much yet on ethyl pyruvate though I have some concerns regarding its depletion of GSH. Ray Peat and followers believe GSH levels can also be pathogenic, not sure what to say about that.

That looks correct:

https://www.ncbi.nlm.nih.gov/m/pubmed/14569076/

Is GSH the reduced form of glutathione ? If so it should be somewhat easy to supplement to make sure this doesn’t happen. I actually have intranasal glutathione for this situation

GSH is the reduced form, not the oxidized form.

I'd wonder how ethyl pyruvate and GSH actually interact. I also wonder if vursmin C wluld get depleted.

 

[frozenborderline]

Of course anything that revs up metabolism can increase the need for other nutrients but in my cursory glance through pubmed Ethyl pyruvate looks promising and I don’t see any major safety concerns. Didn’t Ron day he tried pyruvate in the nano needle test w good results?

 

[Learner1]

As I understand it, NAD, Pyruvate and CoA (pantethine is a precursor to CoA) block the Pyruvate Dehydrogenase Kinases, which activates PDH. NADH and Acetyl-CoA activate the Pyruvate Dehydrogenase Kinases which inactivates PDH. Alpha Lipoic Acid inhibits the Pyruvate Dehydrogenase Kinases, which helps to activate PDH.

You might find this interesting - DCA and ALA or PolyMVA are used together:

http://www.townsendletter.com/AugSept2018/metabolic0818.html

 

[Learner1]

Of course anything that revs up metabolism can increase the need for other nutrients but in my cursory glance through pubmed Ethyl pyruvate looks promising and I don’t see any major safety concerns. Didn’t Ron day he tried pyruvate in the nano needle test w good results?

I'm not sure why you'd use ethyl pyruvate? How would you know you need it?

My mitochondrial function changed dramatically (tests and symptoms) in 8 months. I added phosphatidyl choline, NAD, and liposomal glutathione to my program with PolyMVA, a lot of B5, B1, and vitamin C, folate and B12. The strategy of reducing peroxynitrites and repairing damage has beeen successful.

 

[frozenborderline]

You might find this interesting - DCA and ALA or PolyMVA are used together:

http://www.townsendletter.com/AugSept2018/metabolic0818.html

I read that and found it interesting. I’m less excited about pyruvate dehydrogenase than I used to be , no longer sure it’s the answer. But on the other hand it’s cool to see people talking about reductive stress in illnesses rather than always oxidative stress. Both have their place of course but I almost never hear the former mentioned. I would probably be open to trying this combo if it was affordable.

Yeah even though I doubt it’s a cure, after getting excited about Ethyl pyruvate over a year ago, now that there’s a product available I feel the need to try it

 

[frozenborderline]

I'm not sure why you'd use ethyl pyruvate? How would you know you need it?

My mitochondrial function changed dramatically (tests and symptoms) in 8 months. I added phosphatidyl choline, NAD, and liposomal glutathione to my program with PolyMVA, a lot of B5, B1, and vitamin C, folate and B12. The strategy of reducing peroxynitrites and repairing damage has beeen successful.

I believe that pyruvate dehydrogenase May be impaired in cfs patients. And I have had symptoms consistent w/ reductive stress , lactic acidosis , etc. of course I can’t afford the testing or time to figure out the details, and have to go based on theory and experimentation somewhat blindly. But some things that also increase PDH have helped me, like megadoses of thiamine

 

[ljimbo423]

I’m less excited about pyruvate dehydrogenase than I used to be , no longer sure it’s the answer.

I agree, that I don't think it's the answer. The Fluge and Mella paper says they think it's immune activation that's causing the PDH inhibition they found in ME/CFS. I thinks that's true. So I'm mainly focused on treating what I think is causing my immune system activation, causing it to inhibit PDH.

However, I am having a lot of success in supporting PDH with supps like b-1, ALA, etc. Also using BCAA's to bypass PDH and feed the krebs cycle directly. All of which increase the krebs cycle and oxidative phosphorylation to create more ATP and energy.

 

[Learner1]

In addition to glutathione, BCAAs are extremely helpful for avoiding or reversing PEM.

 

[ljimbo423]

This is a quote from the Fluge and Mella paper, where they explain how the immune system is causing the PDH inhibition in ME/CFS-

According to this model, ME/CFS is caused by immune interference with an unidentified target, potentially a signaling factor, which ultimately causes metabolic dysfunction and induction of secondary rescue mechanisms.

We hypothesize that aberrant PDK and SIRT4-mediated inhibition of PDH, and consequent obstruction(s) in central energy metabolism, occurs early during ME/CFS pathogenesis, followed by metabolic adaptations serving to maintain ATP production.

The result will be increased consumption of amino acids not depending on PDH to fuel oxidative metabolism via the TCA cycle.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5161229/