A Thought Experiment on Muscles

[SNT Gatchaman]

This has been a busy thread so some points I'm responding to were made a few pages back.

I will never forget my first severe bout of PEM in my early years of ME when I didn't know I had ME. My mother and I had booked a bach for a week on a nearby island. I felt quite unwell the day before leaving. We arrived and I immediately headed out for a swim. I felt exhausted and walked slowly to the beach. Once in the waves I was shocked at how utterly exhausted I was trying to swim with the waves.

I'm pretty certain that this is the explanation for some drownings. Otherwise fit and healthy people who were confident in their water abilities but not realising those abilities were suddenly very vulnerable. And once they've declared it's too late.

I've already speculated on how it could happen in someone like me with no viral trigger but pre-existing thyroid issues + a period of intense stress.

I don't think we can be at all certain to say that people had no viral trigger, when so many infections are asymptomatic (~40% with SARS2).

mental exertion uses little extra energy, so it probably doesn't fit with thinking triggering PEM through simple energy demand

Maybe there are some clues in MS?

I keep coming back to my uncle with severe MS, he’s the only one that understands PEM. And he seemingly has many of the same cognitive difficulties that I experience in PEM.

Could it be the increased neural activity having effects on adjacent cells (eg astrocytes, microglia, oligodendrocytes, endothelial, mast) rather than simply the use of energy?

EndME is thinking along similar lines and perhaps neither of are using too much more ATP in the process

But do we have any indication that "cognitive fatigue" would arise from a lack of local ATP? Does it not seem more likely that it would be consequence of other neurological processes?

 

[jnmaciuch]

Could it be the increased neural activity having effects on adjacent cells (eg astrocytes, microglia, oligodendrocytes, endothelial, mast) rather than simply the use of energy?

EndME is thinking along similar lines and perhaps neither of are using too much more ATP in the process

That’s exactly what I was thinking! I don’t think it’s a full stop lack of ATP—that’s most likely to just kill neurons.

But there definitely could be signaling arising from having to resort to ‘backup’ mechanisms to keep up with ATP demand, for example. We see that in isolated macrophages already. Not a lack of ATP per se, but something that happens when the preferred, easiest method of ATP generation is no longer available

 

[Turtle]

Has brainfog made me dumber?
Before I got ME/CFS I was a final year uni student. I had to stop and work as a telefonist because of brainfog.
I was tested some years ago on 2-back 3-back, not once in a clinic, but over a period of three weeks, online, on good and bad moments.
On good moments mistakes on 2-back were 20 % reaction time 665 msec.
On bad moments 60% 932 msec.
On good moments 3-back 33% 786 msec.
On bad moments 67% 1167 msec.

I needed more time and made way more mistakes on bad moments.
What about oxygen and OI playing a role?

 

[Simon M]

I don't think we can be at all certain to say that people had no viral trigger, when so many infections are asymptomatic (~40% with SARS2).

I'm not sure we have robust data on asymptomatic infections causing LC, given the very broad definition of LC and whether asymptomatic infections lead to LC that is ME/CFS. There is quite a bit of evidence that people with no serological sign of Covid later developed LC-like symptoms, though as many of those are generic, it's hard to figure out quite what is happening. It's a bit of a mess.

 

[hotblack]

I'd previoiusly liked the idea that simple energy demand - mental or physical - triggers PEM. But I hadn't done the maths.

Really interesting data. I’ve always seen the brain and heart as high energy so it’s sort of made sense I have problems with them. But now I’m also less sure.

I wonder then if it’s related less to the amount of energy used and more how it is used, perhaps focus or context switching? So again some sort of signalling or maybe efficiency of cell/membrane factors. Stuff does work but works less efficiently, given the ‘clock-speed’ or ‘update frequency’ for want of a better word of our brain and body, a slight shift could be very noticeable to finely tuned systems.

Signalling could explain why I have coordination problems and get clumsy much better than energy deficits alone too. It certainly feels when foggy and having other issues that my brain is misfiring.

I’m not sure how heat fits into it but it triggers these problems and I can feel ‘sharper’ when cool. It may be a separate process though. But the description of Trolls brains by Terry Pratchett covers it well for me.

 

[MeSci]

Probably a semantic point, but even if it were the over-consumption of energy there would have to be some signal for that to be perceived as fatigue by the brain.

Apologies if this has been mentioned/discussed before, but I wonder whether amphetamines have any relevance here?

I used to use amphetamines (I got addicted), and when I used them (prior to addiction) I had no fatigue at all, cognitive or physical. Amphetamines also speed up bladder activity and therefore thirst.

Ignore this if it doesn't appear to have any relevance.

 

[jnmaciuch]

As a clarification, I don’t see evidence for a substantial lack of or insufficient ATP—my NAD/NADH theory doesn’t try to claim that. ATP production is extremely vital to a cell and if it is substantially reduced, you’re going to see either outright cell death or at least extremely serious heart issues.

Since ATP production is so vital, cells have evolved several methods of getting to that end product, some of which are much more efficient than others. These other methods can step in when one fails.

What the evidence does indicate to me, in layman’s terms, is an impairment in the method of generation that is most efficient and preferred by most cells in the body. That results in increased reliance on those ‘backup’ methods.

Particularly, it means that the preferred method can’t ’turn over’ as fast in ME/CFS than in a healthy person. Think of it like a fire where someone is available to throw logs into it multiple times an hour vs. one where logs can only be added every several hours.

If you need more of a blaze in the moment, you can start supplementing with small sticks and paper etc. It won’t be as efficient fuel, but it’ll get the job done for a bit. No (substantial, at least) lack of ATP.

In this theory, the more severe you are, the longer it takes to throw logs into the fire (if at all).

We already know that some innate immune cells start signaling if you force them to upregulate one of those ‘backup’ methods. Furthermore, one of the main system for shutting down that signal (steroid hormones) is also dependent on the amount of logs in the fire.

Maybe this is not the actual ‘signal’ that many of us have been discussing, but it is a plausible candidate.

this is an oversimplified explanation, but I’m hoping to make it accessible for anyone that might have trouble following along with detailed discussion of NAD/NADH and redox balance.

 

[Simon M]

this is an oversimplified explanation, but I’m hoping to make it accessible for anyone that might have trouble following along with detailed discussion of NAD/NADH and redox balance.

Thanks.
Presumably, there are vast numbers of possibilities as to what has gone wrong in ME/CFS (I've been reading research papers for 30 years and have come across more than a few). What makes you think this is the answer, and what evidence is there currently? And how would you test your theory?

 

[Jonathan Edwards]

What the evidence does indicate to me, in layman’s terms, is an impairment in the method of generation that is most efficient and preferred by most cells in the body.

Yes, can we recap on the evidence for this? Maybe from Chris Armstrong or Fluge's group?
If redox imbalance were to jigger up oligodendrocytes to signal their unhappiness, what would be driving the redox imbalance in the brain in the first place?

 

[jnmaciuch]

Thanks.
Presumably, there are vast numbers of possibilities as to what has gone wrong in ME/CFS (I've been reading research papers for 30 years and have come across more than a few). What makes you think this is the answer, and what evidence is there currently? And how would you test your theory?

Thanks for your questions! I currently have all my thoughts for this outlined in a messy multi-page Word doc, so can’t succinctly go over all of it here. But I’ve put some of the highlights re: evidence in this post: https://www.s4me.info/threads/malic-acid-supplement-sumac.42716/
In addition to what’s listed there, the biggest pieces of evidence are pretty consistent metabolomics findings pointing to differential utilization of beta oxidation and glutamine metabolism (some of the ‘backups’ referenced in my previous post). (Added: shown by work from Missailidis/Fisher, Hanson lab, and Armstrong lab off the top of my head, these are only some of the publications that mention it). Some of the referenced evidence for the itaconate shunt hypothesis would be applicable.

There’s also inconsistent but repeated findings of lactate differences which also show up in other studies linked here, which could correspond to glycolysis upregulation as an additional backup. Booth et al. showed differences in various measures of OxPhos capacity. There’s Missailidis et al’s finding of Complex V inefficiency.

Potentially sphingolipid level differences (naviaux et al. and germain et al. as well as others I'm not remembering) can be explained by the same mechanism listed for alcohol intolerance in my linked post via decreased serime metabolism or by the fact that the serine-formate shuttle can be used to regenerate mitochondrial NADH (review). I believe Naviaux explicitly mentioned that all their findings can be linked to mitochondrial NAD(P)H as well

Kynurenine pathway differences could be explained by this since NAD+ production may be ramped up as a compensation mechanism. And there’s already evidence that macrophages (the link is just one example of many), T-cells, and other immune cell types are highly sensitive to multiple regulatory points in cellular metabolism in a bi-directional manner, which provides a link to immune signaling as I’ve discussed before.

granted, all of these are various puzzle pieces which don’t individually prove my theory, especially considering different cell types. However, I think there is merit in the fact that so many various findings can be easily traced back to the same mechanism.

 

[jnmaciuch]

Thanks for your questions! I currently have all my thoughts for this outlined in a messy multi-page Word doc, so can’t succinctly go over all of it here. But I’ve put some of the highlights re: evidence in this post: https://www.s4me.info/threads/malic-acid-supplement-sumac.42716/
In addition to what’s listed there, the biggest pieces of evidence are semi-consistent metabolomics findings pointing to differential utilization of beta oxidation and glutamine metabolism (some of the ‘backups’ referenced in my previous post). Some of the referenced evidence for the itaconate shunt hypothesis would be applicable.

There’s also inconsistent but repeated findings of lactate differences, which could correspond to glycolysis upregulation as an additional backup. Booth et al. showed differences in various measures of OxPhos capacity. There’s Missailidis et al’s finding of Complex V inefficiency.

Potentially sphingolipid level differences (naviaux et al. and germain et al.) can be explained by the same mechanism listed for alcohol intolerance in my linked post or by the fact that the serine-formate shuttle can be used to regenerate mitochondrial NADH.

Kynurenine pathway differences could be explained by this since NAD+ production may be ramped up as a compensation mechanism. And there’s already evidence that macrophages, T-cells, and other immune cell types are highly sensitive to multiple regulatory points in cellular metabolism in a bi-directional manner, which provides a link to immune signaling as I’ve discussed before.

granted, all of these are various puzzle pieces which don’t individually prove my theory, especially considering different cell types. However, I think there is merit in the fact that so many various findings can be easily traced back to the same mechanism.

as for how to prove it, I’ve been working pretty hard on figuring that out. I’m only a first year grad student and my background is entirely computational (since ME/CFS makes it hard to be in the lab), so I’m having to learn a lot of very technical and niche information all at once.

from consulting with other researchers, the first step would be measuring mitochondrial vs. cytosolic NADH ratios, which as far as I could tell, has not been done in ME/CFS. That can be done biochemically or via a specific microscopy method. There’s also the possibility of 13C glucose tracing experiments, which might be able to show whether a specific TCA cycle enzyme is operating insufficiently in ME/CFS. Phair and Armstrong have publicly announced interest in doing that for the itaconate shunt hypothesis, but nothing is published yet.

for each of those options, there’s limitations on how many cells are needed to even get a reading, and if the cell types that can feasibly be obtained at that abundance (PBMCs most likely) would provide generalizable results.

I’m trying to determine if the 13C experiment can be done on muscle biopsies as a more representative cell type than circulating immune cells. It might also be possible to measure labeled TCA metabolites in the blood to avoid getting a cell type-specific result, but I don’t know yet if blood plasma levels are good correlates of cellular levels. If not, it’ll have to be done on immortalized primary cells, which potentially adds more confounding effects.

since this mechanism is so tricky to prove, I suppose that answers why we haven’t found it already.

And as I’ve discussed in my linked post, there’s definitely a possibility of subsets in ME/CFS defined by slightly different upstream mechanisms to the same downstream manifestation. This may just be one of those upstream mechanisms.

I’m trying to figure out how that can be determined in a meaningful way—I’m as annoyed as anyone by clinical trials that claim “subset-specific responses” without anything further to back that up.

There would also need to be further experiments confirming if innate immune cells in the tissue are being activated by local shifts in cellular metabolism method, and if this signaling can explain PEM and/or brain fog. That’ll take even more time to sort out experimentally, so it would be next on my list. Though others may already be ahead of me on many of these fronts

 

[Simon M]

Thanks for your questions! I currently have all my thoughts for this outlined in a messy multi-page Word doc, so can’t succinctly go over all of it here. But I’ve put some of the highlights re: evidence in this post: https://www.s4me.info/threads/malic-acid-supplement-sumac.42716/
In addition to what’s listed there, the biggest pieces of evidence are pretty consistent metabolomics findings pointing to differential utilization of beta oxidation and glutamine metabolism (some of the ‘backups’ referenced in my previous post). (Added: shown by work from Missailidis/Fisher, Hanson lab, and Armstrong lab off the top of my head, these are only some of the publications that mention it). Some of the referenced evidence for the itaconate shunt hypothesis would be applicable.

There’s also inconsistent but repeated findings of lactate differences which also show up in other studies linked here, which could correspond to glycolysis upregulation as an additional backup. Booth et al. showed differences in various measures of OxPhos capacity. There’s Missailidis et al’s finding of Complex V inefficiency.

Potentially sphingolipid level differences (naviaux et al. and germain et al. as well as others I'm not remembering) can be explained by the same mechanism listed for alcohol intolerance in my linked post via decreased serime metabolism or by the fact that the serine-formate shuttle can be used to regenerate mitochondrial NADH (review). I believe Naviaux explicitly mentioned that all their findings can be linked to mitochondrial NAD(P)H as well

Kynurenine pathway differences could be explained by this since NAD+ production may be ramped up as a compensation mechanism. And there’s already evidence that macrophages (the link is just one example of many), T-cells, and other immune cell types are highly sensitive to multiple regulatory points in cellular metabolism in a bi-directional manner, which provides a link to immune signaling as I’ve discussed before.

granted, all of these are various puzzle pieces which don’t individually prove my theory, especially considering different cell types. However, I think there is merit in the fact that so many various findings can be easily traced back to the same mechanism.

Thanks. I was hoping for something more succinct because of my brain fog. From a quick scan of your other post, malate seems to play a central role, but I wasn’t sure if the underlying issue was presumed reduced Mitochondrial reduction of NAD(P).

Can you sum it up in a couple of sentences?

 

[Evergreen]

Stumbled on this review by Newton's group in a folder on my computer:

Rutherford G, Manning P, Newton JL. Understanding Muscle Dysfunction in Chronic Fatigue Syndrome. J Aging Res. 2016;2016:2497348. doi: 10.1155/2016/2497348. Epub 2016 Feb 22. PMID: 26998359; PMCID: PMC4779819.

https://pmc.ncbi.nlm.nih.gov/articles/PMC4779819/

 

[jnmaciuch]

Can you sum it up in a couple of sentences?

Sure! Sorry, hard to find the right balance between “simple enough to understand with brain fog” and “so simplified that the idea is getting misunderstood/misinterpreted”

main point in more detailed terms:

Mitochondria use controlled release of electrons (H-) to make ATP (oxidative phosphorylation)

Two pools of NAD(P)—inside and outside of the mitochondria—serve as storage for those electrons, becoming NAD(P)H.

Malate is the main “shuttle” taking H- from NADH outside and bringing it inside the mitochondria. Think of it like charging a battery.

If less Malate is available (from impairment in TCA cycle or another mechanism), shuttling of H- is a lot slower.

Added: It takes longer for the battery to recharge. If not enough time has passed to fully recharge or if the rate of battery usage exceeds the rate of recharge during an activity, it will "run out" after only a little activity.

Other “shuttles” AND other ways of generating ATP exist that can step in, but they are less efficient than above. Added: Much more fuel required to get the same output. We have evidence of those other methods being relied on more in pwME.

Speculation: being forced to fire up those backup mechanisms during activity results in a potentially uncontrolled signaling process leading to PEM and/or other symptoms.

@Simon M hope this is easier to follow, I think this is the most simplified it can get without pure analogy. Happy to answer more questions!

 

[forestglip]

Other “shuttles” AND other ways of generating ATP exist, but are less efficient than above. We have evidence of those other methods being relied on more in pwME.

Could you say more about the evidence for this?

 

[jnmaciuch]

Could you say more about the evidence for this?

Yes, unfortunately it requires a lot of text as in my comment above:

Thanks for your questions! I currently have all my thoughts for this outlined in a messy multi-page Word doc, so can’t succinctly go over all of it here. But I’ve put some of the highlights re: evidence in this post: https://www.s4me.info/threads/malic-acid-supplement-sumac.42716/
In addition to what’s listed there, the biggest pieces of evidence are pretty consistent metabolomics findings pointing to differential utilization of beta oxidation and glutamine metabolism (some of the ‘backups’ referenced in my previous post). (Added: shown by work from Missailidis/Fisher, Hanson lab, and Armstrong lab off the top of my head, these are only some of the publications that mention it). Some of the referenced evidence for the itaconate shunt hypothesis would be applicable.

There’s also inconsistent but repeated findings of lactate differences which also show up in other studies linked here, which could correspond to glycolysis upregulation as an additional backup. Booth et al. showed differences in various measures of OxPhos capacity. There’s Missailidis et al’s finding of Complex V inefficiency.

Potentially sphingolipid level differences (naviaux et al. and germain et al. as well as others I'm not remembering) can be explained by the same mechanism listed for alcohol intolerance in my linked post via decreased serime metabolism or by the fact that the serine-formate shuttle can be used to regenerate mitochondrial NADH (review). I believe Naviaux explicitly mentioned that all their findings can be linked to mitochondrial NAD(P)H as well

Kynurenine pathway differences could be explained by this since NAD+ production may be ramped up as a compensation mechanism. And there’s already evidence that macrophages (the link is just one example of many), T-cells, and other immune cell types are highly sensitive to multiple regulatory points in cellular metabolism in a bi-directional manner, which provides a link to immune signaling as I’ve discussed before.

granted, all of these are various puzzle pieces which don’t individually prove my theory, especially considering different cell types. However, I think there is merit in the fact that so many various findings can be easily traced back to the same mechanism.

To try to summarize, there’s repeated metabolomic evidence from multiple labs of increased beta-oxidation (one of the main backups).

Added: also repeated but inconsistent evidence of glycolysis being upregulated (another way to compensate)

There’s repeated evidence of reduced metabolites that are reliant on NADPH in the mitochondria to be produced.

There’s also other findings that may point to reduced cytosolic NAD+. If Malate is not available, most NAD outside the mitochondria stays as NADH.

There are multiple mitochondrial studies showing slightly reduced ATP production and less efficiency overall. This is what you would expect to see if the most efficient malate mechanism is impaired.

it’s not always consistent across studies, and others have pointed out potential methodological reasons for that.

but to me, it seems to overwhelmingly point to the same place despite inconsistencies.

 

[V.R.T.]

Yes, unfortunately it requires a lot of text as in my comment above:



To try to summarize, there’s repeated metabolomic evidence from multiple labs of increased beta-oxidation (one of the main backups).

There’s repeated evidence of reduced metabolites that are reliant on NADPH in the mitochondria to be produced.

There’s also other findings that may point to reduced cytosolic NAD+. If Malate is not available, most NAD outside the mitochondria stays as NADH.

There are multiple mitochondrial studies showing slightly reduced ATP production and less efficiency overall. This is what you would expect to see if the most efficient malate mechanism is impaired.

it’s not always consistent across studies, and others have pointed out potential methodological reasons for that.

but to me, it seems to overwhelmingly point to the same place despite inconsistencies.

If your theory is correct, what kind of treatments would we be looking at?

 

[Utsikt]

Speculation: being forced to fire up those backup mechanisms during activity results in a potentially uncontrolled signaling process leading to PEM and/or other symptoms.

I guess the key question to answer is how you go from backup mechanism to PEM?

 

[jnmaciuch]

If your theory is correct, what kind of treatments would we be looking at?

I've outlined some things that have worked really well for me here:
https://www.s4me.info/threads/malic-acid-supplement-sumac.42716/

To summarize, I'm taking a malic acid (different form of malate) supplement. It has pushed me into near-remission, though I am already at mild from a stimulant.

I'm also taking coQ10 and super B-complex to specifically address brain cellular metabolism which has slightly different preferences than the rest of the body. I should note: I've tried coq10 and B-complex before with no effect, but suddenly noticed a huge difference when taken with the malic acid.

So far, 50% of people who reported to me (4/8 including me) said they got a noticeable boost from the malic acid alone with no stimulant or other supplements. Of course there might be bias in reporting, and it's a small sample size.

Overall, I'm interested in the question of why malic acid seems to help some but not others. As I've written before, it's possible that there are multiple upstream issues that can lead to the same downstream problem in ME/CFS. Malate might just be one of those upstream things, so malic acid supplementation wouldn't be fixing the problem for all pwME.

I'm trying to figure out how to address that robustly. If it turns out to just be a fluke or very powerful placebo effect, I'll use my newfound energy to look into other explanations.

Supplementation would be a bit of a duct tape fix. If research could pinpoint an exact point of impairment in the TCA cycle, more specific treatments might be possible to address the impairment itself.

For example, the itaconate shunt hypothesis proposes a "stuck" feedback loop that results in the SDH enzyme being inhibited, which could lead to all these malate problems. Breaking the loop might be the answer, though I personally don't like to get my hopes up prematurely without evidence.

 

[jnmaciuch]

I guess the key question to answer is how you go from backup mechanism to PEM?

Exactly right. As I've acknowledged before, this is the part of my theory that cannot be easily filled in with existing research.

Fortunately, from cellular metabolism research in other contexts, we have a couple possibilities.

I suspect that the actual signal would be similar to what triggers viral myalgia (i.e. muscle pain and stiffness from a virus or vaccine without vascular inflammation), which is unknown.

Right now my best educated guess is macrophage-mediated cytokine signaling, since we already know that macrophages can become "hypersensitive" to stimuli just by shifting their method of ATP production.