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My Current Understanding of ME: Part 4 - Lactic Acid/PEM

Ok, since I haven´t got very far with this series of blogs, I have decided to skip straight ahead to the juicy stuff. I had two additional reasons for this: 1.) the stuff in the fourth episode is what motivated me to start writing this series; and 2.) I was worried someone on the forum might ´scoop´ me (it´s all about keeping/earning a reputation for relevancy in the cut throat world of PR). As I am skipping ahead to part 4, there will be a couple of parts missing (from my current understanding of ME), but seeing as the crucial one with regards to this part, the gut, has quite a lot of evidence already pointing towards what I am claiming (check out Lipkin´s, KDM´s and Hanson´s gut studies if you haven´t already), I thought I could get away with skipping to the end.

I was motivated to look into the metabolic problems in ME when I this read blog on Health Rising:
https://www.healthrising.org/blog/2017/04/18/stanford-paradox-elevated-energy-production-found-chronic-fatigue-syndrome-mecfs/

Basically, the studies authors found that immune cells free of serum were producing twice as much ATP in patients as in controls. If you are interested (and haven´t already) you can read the article or the study yourself, but to my mind the most important conclusion was this:

(Cort) I asked Dr. Wang if by-products of glycolytic production such as lactate could be causing issues in ME/CFS.

(Dr. Wang, the study´s lead author) That’s indeed my speculation. There might be some intrinsic triggers in the patients, such as activation of immune cells, and/or elevation of cellular activities, that promote glycolysis – a similar situation when we exercise too vigorously and we feel sore and tired.

Dr. Wang elaborated on this later in the interview:

It is possible that those immune cells (PBMCs) are activated, maybe due to a virus infection or other pathological conditions. It has been shown that when activated, immune cells shift from catabolism to anabolism which requires more energy, and become increasingly dependent on glycolysis for ATP production. This theory was raised by Dr. Maureen Hanson via personal communications.

So, being biologically ignorant as I am, I did not understand the full implication of these statements when I first read the article, and it was only after staying up late googling stuff on Pubmed that I understood them (at which point I thought I had come up with the basic idea myself, when clearly I hadn´t).

To make it clear for people as biologically ignorant as me: something is causing the serum-free immune cells in ME patients to increase glycolysis and produce lactic acid.

When Cort asked about the significance of the cells being serum-free, Dr. Wang said this:

It is difficult to directly compare our results from cultured PBMCs with those from patients in vivo. The reason is that the cells we studied were dissociated from the patients and thus they didn’t have the same environment as those cells inside the body. To be precise, other cells, serum, and the environment surrounding PBMCs were not present anymore.

And when she was asked about the possibility that the immune cells may be acting oddly both in and out of the serum she said this:

I’m not an expert in immunity so I’ll have to speculate. The immune cells undergo significant structural and signaling changes after activation – such as receptor binding to a ligand on the plasma membrane, intracellular transduction of signals, and eventually the signals end up in nucleus to change gene transcriptions. I don’t know how long these changes last once the cells are out of the body, but maybe the cells still keep some of the internal changes in our culture so we are able to detect it. It’s also entirely possible that these phenomena are responses of the cells after removing inhibitory factors in the serum – to prove this theory, a direct comparison with and without serum is needed.

I am going to assume that the first possibility (odd in and out of the serum) is true. Of course, this might turn out to be wrong, but since the first possibility fits so well with what we know about ME, I´m fairly confident in this prediction.


Ok, I will now stop just rehashing Cort´s article, and try to contribute myself to ME patients´ (and who knows, perhaps a couple of researchers´ too, I can dream, can´t I?) understanding of this glycolysis/lactic acid problem. Dr. Wang has already suggested where the problem is occurring (the immune cells) and by which mechanism (the switch from catabolism to anabolism when activated); I will try to illustrate why I think this this activation is occurring in the immune cells of people with ME.

To do this I have to go back to the blog on the gut that I haven´t wrote yet (oops). Briefly, first KDM reported (6 years ago, I think), and then Hanson last year showed that ME patients have higher levels of LPS in their blood than controls do. According to KDM, this was positively correlated with the severity of the patient´s condition, and since he was right on the LPS in general I am willing to bet that he is right on this too. This led me to look into whether LPS can cause the immune cell activation mentioned above.

The answer was an unequivocal ´yes´:

http://www.nature.com/cr/journal/v25/n7/full/cr201568a.html#bib2

This study is well worth reading in its entirety. I am not going to detail them all here, but there are several changes in the immune cells mentioned that seem to correspond to the results of Naviaux´s metabolic study.

I also found the following study very intriguing, particularly this statement:

The findings indicate that the early (2 and 6 h) elevation in muscle lactate concentration during LPS infusion was not attributable to limited muscle oxygen availability or ATP production (evidenced by unchanged ATP and phosphocreatine (PCr) concentrations) or to PDC inhibition, whereas after 24 h, muscle lactate accumulation appears to have resulted from PDC activation status limiting pyruvate flux, most probably due to cytokine-mediated up-regulation of PDK4 transcription.

https://www.ncbi.nlm.nih.gov/pubmed/18218678

I can feel everyone´s (and most importantly, my own) patience starting to wane, so I will just list the steps that I think probably make up an ME attack or PEM episode, and that are probably present to some extent all the time, at least in those with more severe ME.

1. Exercise or diet causes changes in intestinal permeability. This has been shown in healthy people in the first instance, and I willing to bet that when this is measured in people with ME, it will be found that not only do people with ME have leakier guts than controls, but that exercise makes them far leakier. I do not have a detailed explanation for this yet as the gut is a very complicated area, but in people like me (with those gut infections that Lipkin is looking at as the cause of the IBS present in some ME patients), it might be either a direct or indirect result of infection with one of these bugs. In others it may be an autoimmune process, or perhaps something else entirely. Regardless, I think we will see that there will be some separation between cases and controls with regards to measures of intestinal permeability (which would explain the differences observed by Hanson in levels of LPS) and that all of these measures (including the LPS) will show a much greater separation between patients and controls after exercise (as was suggested by the Vernon gut study).

2. The increased level of LPS ´aggravates´ the ongoing immune process in the blood whereby lactic acid is produced by these immune cells through the ramping up of glycolysis. This process also causes changes in cytokine production, which I believe account for the sleep disturbances (see the other blog I haven´t written yet), and also very likely other symptoms as well.

3. This increased production of lactic acid by the immune cells results in increased amounts in the blood (I´ve forgotten which study it was, but I found good evidence that the increased glycolysis in the immune cells result in changes in blood lactate levels).

4. This increased level of lactic acid in the blood results in changes in the lactate gradient between the muscles and the blood, resulting in lactate levels increasing in the muscles as well (see the unpublished observations in the second study I posted).

5. The early LPS-induced increase in TNF-a results in a delayed upregulation of PDK4 in the muscle (see the second study for a proposal for how this might work).

6.This upregulation of PDK4 results in the inhibition of PDC, contributing further to muscle lactate accumulation.


Things this might explain
  • Observed increases in blood lactate levels in ME patients, both before and, more dramatically, after exercise.

  • Some of the metabolic changes observed in Naviaux´s study.

  • The delayed onset of PEM. I do not have a explanation yet for why the delayed, possibly PDK4-induced inhibition of muscle PDC activity should be more disabling in ME patients than in controls (if indeed it is), but if I had to guess I would go back to the mooted intestinal permeability changes (and the suggestion of longer lasting changes in the blood microbiota after exercise in the Vernon study). In rats, the PDC inhibition did not compensate fully for the ramping down of the first mechanism (suggested to be the change in the lactate gradient), but perhaps in ME patients this situation is reserved, with lactate levels climbing not falling. The delayed onset could of course be caused by something other than increasing lactate levels, but it definitely feels like there is more lactate in my muscles a day or two after exercise than there is immediately afterwards.
Things that this does not explain because I couldn´t be bothered/had forgotten why I came to that conclusion, but which may be the true anyway
  • The contradiction between the seemingly well-founded assumption that mTOR is downregulated in ME patients, and the fact that some people seem to improve on mTOR inhibitors such as Rapamycin and Azithromycin. I forgot exactly how I came to this conclusion, but it seemed to me when I stayed up late researching this (sleep deprivation might be a factor here) that the Akt-mTor-HIF-1a pathway may be downregulated in the muscle*, but upregulated in the immune cells in the blood. A possible mechanism for the positive effects of mTOR inhibitors (one I mentioned in one of the mTOR threads, although not explicitly with reference to LPS-induced activation of immune cells), could then be that these mTOR inhibitors suppress the LPS-induced increase in glycolysis in the immune cells.

* I think this quote from the second study may have had something to do with it:

In the context of cytokines, it has recently been demonstrated that TNF-α decreases Akt protein levels and/or signalling in apidocytes (Medina et al. 2005) and human skeletal muscle (Plomgaard et al. 2005) thereby presumably activating (dephosphorylating) the family of FOXO transcription factors.

EDIT (2020):
I found myself a little thrown by Hanson's recent finding that glycolysis in immune cells in ME is downregulated, but then I realized that this does not necessarily mean that the hypothesis I outlined above is incorrect, since while it may be true that, individually, glycolysis in each immune cell is downregulated, the immune system as a whole may still be producing too much lactic acid due to being more activated than a healthy person's (even though a healthy person's would be producing even more with the same stressor). The fact that glycolysis is downregulated might even suggest chronic exposure to such a stressor, i.e. this finding may be a type of immune exhaustion.

Edit: just had a read through of Hanson's article, seems like they are thinking along similar lines (i.e. immune exhaustion):

"Other cytokines of interest had unique relationships with ME/ CFS and healthy control T cell metabolism. IL-10, which was also negatively correlated with ME/CFS CD8+ T cell glycolysis, is an immunosuppressive cytokine that has previously been linked to chronic infection, immune cell exhaustion, and inhibition of T cell activation (46, 63, 67). In these examples, diminished T cell metabolism would be predicted so that the negative correlation with glycolysis in ME/CFS CD8+ T cells is expected. Nonetheless, the absence of this correlation in healthy controls is notable."

"It is clear that the immune system plays a role in ME/CFS. Our data indicate that there are existing reductions in resting T cell metabolism in patients. In particular, CD8+ T cells had altered mitochondrial membrane potential and an impaired metabolic response to activation. Both CD4+ and CD8+ T cells had significant reductions in glycolysis. This hypometabolism in T cells aligns with other findings of hypometabolism in ME/CFS cells (50, 51, 59). Furthermore, patients with ME/CFS appeared to have altered relationships between plasma cytokine abundance and T cell metabolism, in which proinflammatory cytokines unexpectedly correlated with hypometabolism. Such a dysregulation may indicate that ME/CFS T cells have lost responsiveness to some proinflammatory cytokines. Along with hypometabolism in immune cells, this is consistent with a possible ongoing infection (42), though such an infectious agent has not yet been identified. A high priority moving forward will be to determine the mechanism behind hypometabolism in ME/CFS T cells as well as how altered metabolism affects the function of these cells. "

https://dm5migu4zj3pb.cloudfront.ne...-covered-253bed37ca4c1ab43d105aefdf7b5536.pdf

Interestingly, only CD8, not CD4 cells had downregulated glycolysis upon activation. So the CD4 cells would react to the proposed stressor just as strongly as a healthy person's cells, and it seems that both types of cells actually produce more extracellular acidity (ECAR) than healthy control's cells. So I would say the hypothesis summarized in this blog is still a viable one.


And Most Importantly:

1200-3600 mg of ALA has got rid of my lactic acid problems, allowing me to work and exercise like a normal person. So whether the hypothesis is correct or not, it has led me to find a effective solution to the problem.

Second Update for 2020:

I have found something that is much more effective than ALA: Chinese skullcap. When I wrote above that ALA allowed me to exercise like a normal person, this was only true in a certain sense: I could manage a fairly strenous one hour work out, but I would have to be careful with cardio, and would use the breathing exercises popularized by Wim Hof (actually the less stressful alternative where you breathe in and out deeply). Anyway, with Chinese skullcap I do not have to be careful anymore, as long as I take it beforehand, and do not need to do the breathing exercises to keep my heartrate within a certain limit, while working out actually feels healthy now, like it does for normal people, rather than something that I am pushing my body to do.

Rationale: I started taking Chinese skullcap on the basis of the recent article that showed that people with ME only have a problem with the fifth step in the energy chain, and discovered that ALA only affects the downstream ones, while Chinese skullcap exerts its effect on the fifth. The analogy I came up with for this is that ALA in ME is like putting higher-grade fuel in a faulty engine: it will increase the performance but the engine is still inefficient; while Chinese skullcap basically corrects the problem with the engine itself.

Things to be aware of: Just as with DCA and ALA, overuse of Chinese skullcap seems to make my peripheral neuropathy flare up again. So far, it seems to fit between DCA and ALA in terms of this effect, so I think I will try to reserve Chinese skullcap for when I really need it (such as before exercise) and use ALA the rest of the time. Another reason to do this is that Chinese skullcap is a rare but likely cause of acute liver damage, according to an article I read summarizing this effect, whereas ALA seems not to have any very deleterious effects. The liver damage thing is reversible if it is caught early enough and the use of skullcap is discontinued, so this is something that anyone taking Chinese skullcap should keep in mind. I really don't want to not be able to take the single most effective treatment I have found for the lactic acid problem because I have overdone it and harmed my liver.

I have taken skullcap for over a month so far, and this has pretty much made me functionally normal, which has always been my goal in terms of pursuing treatment; I like to think that I am the normal person version of Henry Slade, the diabetic in the England rugby team who is able to play one of the most physical sports at an elite level, as long as he takes his insulin before the game. As a 35-year old with ME though, I am just happy if I can stay in shape and enjoy exercise again.

NB// I have posted some studies in the thread I started on Chinese skullcap.. If anyone has any questions about anything relating to this, please just ask. I hope some of the long hours I have spent reading medical articles will prove helpful to others as well.

3rd update:

As I mentioned in the thread I started on the subject, Chinese skullcap seems to be a very effective PEM blocker, but does not seem to get rid of the problem at source. This time I went to the boxing class on Saturday like last time, but decided to stay out until the early morning and have a few drinks. The next day I felt pretty tired and rested, but the next day I decided to see if the skullcap would allow me to exercise while I was suffering from PEM. It actually did allow me to get through the work out, but I still crashed to a certain degree afterwards (although not as bad as I have done previously without skullcap, even when I wasn't suffering from PEM to begin with). My sleep and gut were disrupted to a degree that I won't try this again, but I still managed to get through the work day pretty normally, when in the past it would be a write-off.

My conclusion, based on the theory I pulled together in my blog: the skullcap prevents the immune response to bacterial endotoxin derived from increased gut permeability after exercise, and subsequent impairment of Complex V. It either does this by acting on the immune cells directly or possibly by acting on the muscles themselves, or on both. If the gut permeability is not increased to begin with (at least not over the baseline ME state) then a traditional dose of skullcap is sufficient in some individuals to prevent PEM despite rigorous exercise. If, however, the gut permeability is already increased, or increases during the period of recovery, whether from eating the wrong foods or drinking alcohol, a traditional dose of skullcap is not sufficient to entirely prevent PEM, although it may reduce its severity.

Given this, I would not expect skullcap to entirely prevent PEM in ME patients who still have severe gut problems, although it is likely to reduce the severity of PEM to a certain degree. For those patients, it is likely that they would need to address the gut permeability first before they would be able to avoid PEM entirely with a traditional dose of skullcap. I would suggest that those patients try the FODMAP diet first, or a similar kind of elimination diet, as this was the most effective intervention I have tried for the gut, and only then look at more complicated ways to treat the gut such as taking probiotics and antibiotics. I also think that sleep issues would need to be addressed by something like Trazodone before the body will be able to recover from exercise in a normal way.

Comments

Here is the thread for the blog - any feedback would be much appreciated!

http://forums.phoenixrising.me/index.php?threads/my-current-understanding-of-me.51319/
 
Surprised you didn't get a lot of comments. I pictured a scenario very much like this (didn't bother to research in depth for a few reasons, including that ME/CFS just cannot back this up yet, which is maybe why no one is commenting), such that I have little to add.
 
Thanks for the feedback Tunguska. Yes, I did expect a few more comments, at least on the thread, but I think you are right, it probably falls in the category ´interesting but unproven´ at the moment.
 
Thank you very much. This is clearly written and makes sense of several loose ends of research I have been reading. I look forward to going back and reading your other posts.
 
Just thought I would mention here that ALA (as a subsitute for DCA) has pretty much got rid of my lactic acid problems. I have written more about this in the DCA thread.
 
Also, I found myself a little thrown by Hanson's recent finding that glycolysis in immune cells in ME is downregulated, but then I realized that this does not necessarily mean that the hypothesis I outlined above is incorrect, since while it may be true that, individually, glycolysis in each immune cell is downregulated, the immune system as a whole may still be producing too much lactic acid due to being more activated than a healthy person's (even though a healthy person's would be producing even more with the same stressor). The fact that glycolysis is downregulated might even suggest chronic exposure to such a stressor, i.e. this finding may be a type of immune exhaustion.

Edit: just had a read through of Hanson's article, seems like they are thinking along similar lines (i.e. immune exhaustion):

"Other cytokines of interest had unique relationships with ME/ CFS and healthy control T cell metabolism. IL-10, which was also negatively correlated with ME/CFS CD8+ T cell glycolysis, is an immunosuppressive cytokine that has previously been linked to chronic infection, immune cell exhaustion, and inhibition of T cell activation (46, 63, 67). In these examples, diminished T cell metabolism would be predicted so that the negative correlation with glycolysis in ME/CFS CD8+ T cells is expected. Nonetheless, the absence of this correlation in healthy controls is notable."

"It is clear that the immune system plays a role in ME/CFS. Our data indicate that there are existing reductions in resting T cell metabolism in patients. In particular, CD8+ T cells had altered mitochondrial membrane potential and an impaired metabolic response to activation. Both CD4+ and CD8+ T cells had significant reductions in glycolysis. This hypometabolism in T cells aligns with other findings of hypometabolism in ME/CFS cells (50, 51, 59). Furthermore, patients with ME/CFS appeared to have altered relationships between plasma cytokine abundance and T cell metabolism, in which proinflammatory cytokines unexpectedly correlated with hypometabolism. Such a dysregulation may indicate that ME/CFS T cells have lost responsiveness to some proinflammatory cytokines. Along with hypometabolism in immune cells, this is consistent with a possible ongoing infection (42), though such an infectious agent has not yet been identified. A high priority moving forward will be to determine the mechanism behind hypometabolism in ME/CFS T cells as well as how altered metabolism affects the function of these cells. "

https://dm5migu4zj3pb.cloudfront.ne...-covered-253bed37ca4c1ab43d105aefdf7b5536.pdf

Interestingly, only CD8, not CD4 cells had downregulated glycolysis upon activation. So the CD4 cells would react to the proposed stressor just as strongly as a healthy person's cells, and it seems that both types of cells actually produce more extracellular acidity (ECAR) than healthy control's cells. So I would say the hypothesis summarized in this blog is still a viable one.
 
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Hello MSF......How are you doing presently (Dec. 3l/20)? Also, and with having read the link you sent, I didn't see any mention about how much chinese skullcap is to be taken.

It makes sense...the build-up of lactic acid, I mean. Just think of the feeling we have after doing anything?....it's as if we had expended great amounts of energy. That heavy feeling, mixed in with pain.

It was kind of you to read ( & it makes me understand how at almost 74 yrs. of age, I finally gave that up giving the info to others) and then report to us what was contained in the article(s). But the only questions I have are these: 1. How are are you now? and 2. How much skullcap do you use? Personally, I don't plan on returning to what I did before, I think that's too much for anyone with buME, but I would like to move more and take part in a new exercise program...and walk of course. Thanks for all your help. It's greatly appreciated. Yours, Lenora.
 
Hi Lenora,

I am doing really well still - I do serious exercise 3-5 times a week, plus a good amount of walking. I take anything from 9 to 15 g of Chinese skullcap root each day, divided into 3 doses and infused in hot water for 15 minutes, I have added a fuller update in the thread I started about using skullcap. If you have any other questions please just ask.
 
Really interesting if a bit over my head in scientific terms though. Im nearly 50 and prob mild conditions mixed with fibro/sjorgens. I need to get confidence back in fitness as my children and husband are superfit and this gets me down plus doesnt help with my core Im just so flabby. Im also in UK. Can you tell me what brands and amounts please. In my instance ALA or scullcap be best. Regards
 
How much ALA do you take? I’ve tried it a few times but it hasn’t done anything for me. But I was taking very low doses, like 100-200mg I think. I’m also about to try skullcap, hopeful about that. But I’m very severe so I don’t know if it will be enough to make much of an impact.
 
Hey, I take large amounts of ALA on days I work out, approx 3000mg in three doses. The Chinese skullcap is just pieces of the root, bought from a Chinese medicine store, the brand doesn't matter as much as the kind of skullcap, you should go for 条芩 (see the thread I started on skullcap for more details).
 
Oh wow, that’s probably the highest dose I’ve ever heard of. I really wish I could take more though, I take 600mg and it does help. You take 3000mg every day? Do you have side effects/did you slowly work your way up? Yeah I really want to give skullcap another try, but I don’t think it did anything for me when I tried it. I only took it for a couple days, but usually things start to help me within 24-48 hours.
 

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