Metabolic profiling indicates impaired pyruvate dehydrogenase function in myalgic encephalopathy/CFS (Fluge et al., 2016)

[Hutan]

In ME/CFS, multiple studies have found increased numbers of Tregs in patients (and no studies with decreased Tregs, I believe), indicating that we are more likely immunosupressed rather than immunoactivated.

In 2015 I saw an immunologist and had a blood test that showed high levels of 'T- suppressor total'. The immunologist made no comment about it (and I just had a phone call with her to discuss the results, which seemed to her to all be fine, so I didn't get to go into any detail).

Are T-suppressor cells the same as T-reg cells?

I read this paper
Special regulatory T-cell review: A rose by any other name: from suppressor T cells to Tregs, approbation to unbridled enthusiasm
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2433291/

that appeared to be suggesting that 'T-suppressor cells' is an out-dated concept. So, I'm quite confused as to why that term would be showing up on my blood test results in 2015.

So, T-regs reduce autoimmune processes? And possibly pathogens/parasites encourage the existence of T-regs to create a less aggressive immune system so that they can thrive?

 

[nandixon]

Are T-suppressor cells the same as T-reg cells?

Yes, it should be. (Different labs may look at different markers for what actually identifies the particular Tregs they're interested in, though, as there are several different varieties. Not sure how that factors into things. May not matter if a person's results are being compared to others from the same lab.)

I read this paper
Special regulatory T-cell review: A rose by any other name: from suppressor T cells to Tregs, approbation to unbridled enthusiasm
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2433291/

that appeared to be suggesting that 'T-suppressor cells' is an out-dated concept. So, I'm quite confused as to why that term would be showing up on my blood test results in 2015.

It may just be a holdover of the use of old nomenclature. I have a test from a couple years ago that also uses that term.

So, T-regs reduce autoimmune processes?

Yes, although it's very complicated and the type of Treg is probably important (along with a lot of other stuff I'm not familiar with).

And possibly pathogens/parasites encourage the existence of T-regs to create a less aggressive immune system so that they can thrive?

Some apparently can do that, yes.

 

[Sing]

@MeSci, The cimetidine started working within a day or two after I started using the 50 mg dosing, but I think I had been experimenting with higher doses first for about a week. So I'm not sure how long it might take starting with the lower dose at the outset.

Just to mention too, another member posted about her experience on an old cimetidine thread, and she apparently found that a single dose of 200 mg every other day worked best for her. I thought it was interesting that the two different dosing methods each averaged out to 100 mg per day.

Also, I have a progressive version of ME/CFS, and even though cimetidine took me from entering into a bedridden state to a more moderate level, my illness has continued to be slowly progressive in spite of the cimetidine these last couple of years since I began taking it. I do still notice less energy when I forget to take it, though.

What do you think the cimetidine is doing that helps your condition? I understand of course that it is an antacid and also has an antihistamine effect, but what else is going on?

 

[nandixon]

What do you think the cimetidine is doing that helps your condition? I understand of course that it is an antacid and also has an antihistamine effect, but what else is going on?

It works as an immunostimulant by decreasing Treg activity and it activates the Akt/mTORC1 pathway in the process. See this post for more info.

 

[Sing]

@nandixon Thank you for sharing your knowledge with us, and also the information about what has helped you. I want to give the cimetidine a try in the small doses you found helpful to see what happens. I like that this is an OTC medication with additional effects beyond that of an antacid, and that these were helpful for you and some others here.

 

[MeSci]

@nandixon Thank you for sharing your knowledge with us, and also the information about what has helped you. I want to give the cimetidine a try in the small doses you found helpful to see what happens. I like that this is an OTC medication with additional effects beyond that of an antacid, and that these were helpful for you and some others here.

Just to say - maybe try 50 mg a day to start with? I seemed to find 100 mg a day too much, at least so far. But then it's so hard to ascertain what is doing what, and I'm about to go into a spell of a year of worsening mental symptoms and am not sure of anything. Still - better safe than sorry? (Occasionally I feel quite well for an hour or 2, but I did before starting the cimetidine.)

 

[Sing]

Just to say - maybe try 50 mg a day to start with? I seemed to find 100 mg a day too much, at least so far. But then it's so hard to ascertain what is doing what, and I'm about to go into a spell of a year of worsening mental symptoms and am not sure of anything. Still - better safe than sorry? (Occasionally I feel quite well for an hour or 2, but I did before starting the cimetidine.)

Thanks for chiming in with your experience. I haven't started my experiment yet with cimetidine but will bear it in mind that the dosage could need adjusting.

The immune system numbers that I do have on myself show immunosuppression--"hypogammaglobulinemia". I wonder if cimetidine would affect that? Anyway, I will see how I feel on it and start with that.

 

[nandixon]

@nandixon

Since exercise activates the Akt/mTOR pathway, why doesn't GET work, according to your theory?

Probably because an inappropriate response to exercise, or often just increased activity really, is the fundamental problem in ME/CFS. Not only might we not be properly activating the Akt/mTOR (mTORC1) pathway with exercise, but we may in fact be de-activating it with what for healthy people is relatively minimal exertion.

Exercise, specifically resistance training/anaerobic exercise, has been found to activate Akt/mTORC1 in healthy people, but maybe it doesn't in ME/CFS.

Note that endurance training/aerobic exercise does not activate Akt/mTORC1, healthy or not.

And over-training (e.g., marathon running) in healthy people actually de-activates the Akt/mTORC1 pathway. You see this manifested, for example, in marathon runners being found to be immunosuppressed (e.g., having increased Treg activity) after a race. (Under-activation of Akt/mTORC1 leads to immune suppression by increasing Treg activity.)

So maybe in ME/CFS, doing what in healthy people is a normal level of exertion, for us is the equivalent of over-training, and that's why Akt/mTORC1 appears to be under-activated.

I don't know what the cause of that is. The under-activated Akt/mTORC1 pathway theory doesn't tell us what the cause is. It just shows how the cause/problem is mediated along what may be the most important downstream pathway (because it leads to the impairment in the PDH complex that Fluge & Mella found).

 

[kangaSue]

I don't know what the cause of that is. The under-activated Akt/mTORC1 pathway theory doesn't tell us what the cause is. It just shows how the cause/problem is mediated along what may be the most important downstream pathway (because it leads to the impairment in the PDH complex that Fluge & Mella found)

Two-pore sodium channel channel dysfunction perhaps?
https://www.ncbi.nlm.nih.gov/pubmed/23394946

 

[Tunguska]

i.e. muscles challenged by exercise do not appear to get stronger or fitter. Just a thought.

Was always the same here (basics like low testosterone ruled out). Along with poor to nonexistent healing ability. And the rest that's been mentioned fit me too, as in poor alcohol response and fluid retention issues. I like to add terrible skin composition as well (sphingolipids).
...
The mTor being a major player in both body and brain makes it a profoundly attractive target, to me anyway (as in including but well beyond the PDH). And it's got to be the most urgent to restore, because although other aspects of daily processes will be impaired, and you'll get some relief from addressing them (including through things like fasting), upregulating processes even conservatively catabolic while mTor is not functioning sufficiently is setting up for slow degeneration. Also meaning anything on the anti-mTor side has to be used more strategically than the liberal advice the rest of the population gets, on quite a lot of supplements that fall on that side. I personally took too many too often and I think I screwed the pooch on that one.

I'm not in a position to do tons of experimenting, but I've been trying combining tianeptine with whey (+ juice) and at 50+ grams whey they seem to synergize effectively on my brain (fog + other), acutely, albeit it's not perfect, and not long enough experiment. (May not try further because tia is too troublesome and have to ditch it again ultimately) Also got like a mild fever from it.

Doesn't seem they sell tagamet OTC here, another adventure. Good luck the rest of you.

 

[gregh286]

@nandixon is the hpa axis implicated in Mtorc pathway.....does it have a role in this metabolic function....thanks.

 

[wastwater]

Pyruvate dehydrogenase deficiency in its inherited genetic form is extremely rare.
Also saw pyruvate carboxylase deficiency at gene location 11q13.2 another rare inherited metabolic deficiency
A rieger syndrome gene pax6 is at 11p13 close but on a different arm.
Pax6 seems to be related to trpm3

 

[jump44]

Think I read where dhea activates or increased mtor activity as well.

 

[RogerBlack]

It struck me this might also explain the failure of anabolic responses which I noticed all the time (30y) I have been ill. i.e. muscles challenged by exercise do not appear to get stronger or fitter. Just a thought.

At least for me, this is definitely not the case.
Muscles seem to respond - if not normally, at least somewhat to exercise.
When I'm feeling 'well' during a day, I have the normal expected power limits, and if I exert myself to the point where I'm doing something I barely can - lifting a heavy object, for example - even only a few times daily, then over a few weeks I get stronger.

 

[nandixon]

@nandixon is the hpa axis implicated in Mtorc pathway.....does it have a role in this metabolic function....thanks.

Yes, there are many studies on this. See, e.g.:

Hypothalamic mTORC1 Signaling Controls Sympathetic Nerve Activity and Arterial Pressure and Mediates Leptin Effects (2013 - Full text)

and

Hypothalamic roles of mTOR complex I: integration of nutrient and hormone signals to regulate energy homeostasis. (2016 - Abstract)

 

[nandixon]

Two-pore sodium channel channel dysfunction perhaps?
https://www.ncbi.nlm.nih.gov/pubmed/23394946

The authors indicate in the full text that this would likely be a problem that is downstream of mTORC1. (Might explain some ME/CFS symptoms, though.) They state:

These data suggest that mTOR does not require TPCs for its function and places lysoNaATP downstream of mTOR in the signaling cascade.

 

[eljefe19]

Think I read where dhea activates or increased mtor activity as well.

All About mTOR here

 

[Tunguska]

All About mTOR here

There is good information but that page along with his AMPK one are the kind of articles poised to lead people down the wrong lane if they rely on his personal takes and selectivity.

 

[Sing]

@nandixon @MeSci I have been trying Cimetidine 50 mg twice a day over the past several days. It causes so much dryness of mouth when I am sleeping that it interferes with maintaining sleep, so I will back off to just taking it once a day an hour or so after breakfast. This must be its anti-histamine aspect which is causing the excessive dryness. Otherwise it didn't cause any problems. On the positve side I had a feeling of more pressure. Can't say for sure if blood pressure improved--went up but it seemed I could walk better. I will continue in a longer trial. From the post #675 above, it seems that improved mTorc1 signalling might be linked to improved sympathetic nerve activity and blood pressure? The science here is above my level, but @nandixon do you think that cimetidine could improve, raise, low blood pressure? Thanks!

 

[nandixon]

@Sing, I wouldn't have guessed cimetidine (Tagamet) would cause dry mouth. But it can definitely have interactions with other drugs or supplements and cause side effects that way. I think the interaction is usually to decrease the clearance of the other drug, in which case it can sometimes be possible to decrease the amount of the other drug to offset this (if the effect is a bad effect). Of course a person would want to check with their doctor, though, regarding doing that with any prescription drugs. I'm not sure about the other positive effect you've noticed regarding blood pressure.