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ME/CFS metabolic question

MAOAr297r

Senior Member
Messages
113
Location
Seattle
Hey guy,

So we know from the great research in Norway that a big driver of our disease is that pryruvate dehdrogenase is inhibited. This nearly shuts down glycolysis and then there is not enough acetyl-CoA the go into the Krebs i believe. In a nut shell this results in a big lack of ATP and we all know what that does to us.

My question to you is does anyone have any remote idea why the heck this enzyme is shut down!??? I know too much NADH will shut it down when there is plenty of it in supply but I think thats not the case because I've heard NADH is low in us and it's way, way too simply. Does the mTOR gene expression maybe have something to do with this. I know it's a hard question but I'm dying to hear your thoughts.
 

MAOAr297r

Senior Member
Messages
113
Location
Seattle
Oh wow thats so interesting! Thanks for sharing :) Also I found this on wiki. There may be some kind of link between mTOR and our inhibited glycolysis enzyme friend. I've think in an update video Dr. Davis mentioned this. He also said antibiotics and antivirals inhibit this gene even more. I'm looking up autoantibodies right now in my text books, Thanks again.

*Update I just looked it up. This is what they appear to be finding antibodies against. Hmmm I'm going to study this hard tonight and see if my doctor can run a test to see if I have these. Apparently disruptions in acetylocholine result and it gets super messed up. I'm looking this up and studying these receptors in a neuroscience textbook of mine. I want to see if they takl about autoimmuninty against these and what it can manifest as. I'm already over my head but If I find something cool I'll tell you*
β adrenergic and muscarinic cholinergic receptors



the mTOR pathway is inhibited and ATP consuming protein synthesis is downregulated, since mTORC1 initiates a phosphorylation cascade activating the ribosome.[16] Hence, the proportion of damaged proteins is enhanced. Moreover, disruption of mTORC1 directly inhibits mitochondrial respiration.[71] These positive feedbacks on the aging process are counteracted by protective mechanisms: Decreased mTOR activity (among other factors) upregulates glycolysis[71] and removal of dysfunctional cellular components via autophagy.[70]

Brain function[edit]
 
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Jesse2233

Senior Member
Messages
1,942
Location
Southern California

pattismith

Senior Member
Messages
3,931
Oh wow thats so interesting! Thanks for sharing :) Also I found this on wiki. There may be some kind of link between mTOR and our inhibited glycolysis enzyme friend. I've think in an update video Dr. Davis mentioned this. He also said antibiotics and antivirals inhibit this gene even more. I'm looking up autoantibodies right now in my text books, Thanks again.

Did you find any evidence that other any antibiotic inhibit mTOR (I mean other than Rapamycin, which is a Macrolide ATB)
 

Nickster

Senior Member
Messages
308
Location
Los Angeles, CA
That's right, but to throw a curve ball at you patients have been reporting benefit from mTOR inhibitor Rapamycin

Ron Davis is aware of this paradox and is investigating
I have heard the drug Rapamycin come up a few times. Has anybody heard of a person using it and what the outcome was?
 

Wishful

Senior Member
Messages
5,684
Location
Alberta
I remain unconvinced that low ATP is the prime cause of the symptoms we feel. I think it's more complicated than that. The low ATP might just be a side-effect, or something that affects other processes that actually do cause the symptoms. Low ATP doesn't fit my observations of results of physical activity. T-cell activity seems far more important.
 

Jesse2233

Senior Member
Messages
1,942
Location
Southern California
I remain unconvinced that low ATP is the prime cause of the symptoms we feel. I think it's more complicated than that. The low ATP might just be a side-effect, or something that affects other processes that actually do cause the symptoms. Low ATP doesn't fit my observations of results of physical activity. T-cell activity seems far more important.

Interesting, id be interested to hear more of your thoughts on this. Are you implicating cytokines?
 

MAOAr297r

Senior Member
Messages
113
Location
Seattle
I remain unconvinced that low ATP is the prime cause of the symptoms we feel. I think it's more complicated than that. The low ATP might just be a side-effect, or something that affects other processes that actually do cause the symptoms. Low ATP doesn't fit my observations of results of physical activity. T-cell activity seems far more important.
I agree. I think low ATP is just one factor. The autoantibodies come to mind as a bigger thing. I guess that would result in cytokines big time and perhaps microglia being heavily activated. I just don't know enough though yet.
 

Wishful

Senior Member
Messages
5,684
Location
Alberta
Cytokines definitely seem to be important. If it was simply low ATP production, going for a 6 hr bike ride, or digging soil for a few hours should noticeably deplete ATP and cause significant symptoms. For me, it didn't. However, a few minutes of using muscles in ways that would cause cell damage--and thus t-cell activation and cytokine release--does cause PEM. Likewise, a viral infection has the same effect on my symptoms as muscle damage. That's why I say that my observational evidence indicates that cytokines are directly involved, while ATP levels might just be a side issue.

The mitochondrial dysfunction might be affecting t-cell production and function, which could cause a feedback loop. For treatments, my feeling is that targeting the immune system is more likely to be effective than targeting ATP production. The problem with the pyruvate mechanism looks serious, but if that was critical for our symptoms, shouldn't a ketogenic diet bypass that, and make us feel healthy again? Since it doesn't, I'd guess that it's just a side issue.

I don't know enough about autoantibodies to even guess about their importance in ME/CFS.
 

unicorn7

Senior Member
Messages
180
Cytokines definitely seem to be important. If it was simply low ATP production, going for a 6 hr bike ride, or digging soil for a few hours should noticeably deplete ATP and cause significant symptoms. For me, it didn't. However, a few minutes of using muscles in ways that would cause cell damage--and thus t-cell activation and cytokine release--does cause PEM.

The problem with the pyruvate mechanism looks serious, but if that was critical for our symptoms, shouldn't a ketogenic diet bypass that, and make us feel healthy again? Since it doesn't, I'd guess that it's just a side issue.

Could you explain a bit further what you mean with using muscles in ways that would cause cell damage?
I do have the feeling that ATP production is my problem. I can not go for a 6 hour bike ride or dig soil, because my muscles just become weaker and weaker, until I have to quit. A few hours to a day later, I feel the damage that that activity has done (extreme soreness, exhaustion and illness) and it lasts a few days until I gain muscle strength again. To me, it does feel like an ATP shortage could be the problem.

I don't think the pyruvate dehydrogenase blockage is the only problem, but I don't think that problem would be solved on a ketogenic diet. You will always need glycolysis (and pyruvate) to start the krebs-cycle, so you can't burn fats without a little bit of anaerobic glycolysis.
 

Learner1

Senior Member
Messages
6,305
Location
Pacific Northwest
I'm thinking oxidative stress may play a part. I've been experiencing IVIG side effects that were very frustrating... my forearms and legs felt depleted and jittery and if I tried to exercise at all (I normally can exercise some) I just felt weak and fell apart.

Yesterday, I had an IV of curcumin and another one of nutrients - methylB12, folinic acid, magnesium, taurine, and carnitine, and bounced right back to my normal self. I was able to exercise this morning, and though I was a little weaker due to a week of feeling awful, I was able to get through a normal workout.

I need to discuss what exactly happened with my doctors, but it made a dramatic difference.
 

Wishful

Senior Member
Messages
5,684
Location
Alberta
If you rarely use a muscle, then do something that strains it, you damage the cells, and t-cells activate to clean up the debris, meanwhile other chemicals released cause the growth of more/stronger muscle cells. So, my leg muscles were fine with the strain and motion of cycling, but when I strained them past those limits, such as by climbing a ladder, that caused tissue damage. There must be at least two subgroups of ME/CFS, because I don't seem to have uncommon exhaustion from activity.

I don't think a ketogenic diet can drop the blood glucose level to absolutely zero, so that's not an issue. Just shifting a significant part of ATP production from glucose to ketones should make a significant difference to symptoms if the pyruvate mechanism inefficiency was critical. If it is critical, it's certainly not obvious about it.
 

frozenborderline

Senior Member
Messages
4,405
I've been trying to read up on cell biology and molecular biology to try and understand some of the research i've been following, especially the stuff on mitochondrial dysfunction. Right now I realized i think I need to start with chemistry, I can't understand the kreb's cycle without it. It seems like this is at the heart of a lot of the new research--certainly ron davis thinks so and i've seen other people say so. So if I can just understand this, I should be able to start guessing about cures. Have any tips for going from being a total humanities/arts person to actually understanding this science? I got Cs in high school chem and bio and now I'm kicking myself!!
 

Learner1

Senior Member
Messages
6,305
Location
Pacific Northwest
I feel the need to learn because a) maybe i could find a cure and b) maybe i could pick through the pseudoscience vs science on this shit a little better
The desire to learn can get you far. Good for you for wanting to try!

Just keep reading. Look at the same topic from different angles. Read different levels of material. If you read studies, read the abstract, the conclusion, and look through the illustrations. Look at simple definitions and illustrations - use Google images. And ask questions.

Once you've seen the same material several times, it'll become more familiar. You'll start to understand, and be able to use what you've learned to help yourself.

Good luck!