A Thought Experiment on Muscles

[Utsikt]

I understand that to mean "Will yu gi us an 'and" and we have farmers in the area by names such as Lund

It says ‘will you give us a hand?’.

That’s cool! Lund and Lunde are common Norwegian surnames.

 

[tuha]

I dont know if it´s interesting but I found this observation. I can do 6000 steps a day and I get only occasionally PEM. My muscles are weak so that´s why I was thinking to try to swim. I tried to do several times around 10 minutes of swimming. I did it very slow, I kept my heart beat around 80 times/minutes. I did several breaks. I felt less tired than after 6000 m walk but I got PEM. In swimming you use a lot of muscles so I think the muscles are somehow involved in all of this. Or the question is. Why I get PEM after small swimming and not after walking even if I feel more tired after walking?

 

[jnmaciuch]

I’ve shared bits of this elsewhere, but my stubbornness on the role of redox balance (rather than specific mitochondrial damage) comes from my personal experience. I’ve never done a 2-day CPET, but I think the time-dependent changes of what I experience when I commute to a doctors appointment will be applicable here.

If I was able to avoid overexerting myself in the days before, then I’d be able to handle a 10 minute walk to the train, probably getting out of breath by the time I got there with my heart racing by the end of it. I’ll probably feel winded but otherwise fine for the train ride to the doctor’s appointment. I’ll probably even make it through the doctor’s appointment and appear like a completely healthy 26 year old to the doctor.

The walk back to the train will be tougher. I’m starting to feel pain in the soles of my feet, my back, and my legs. My body begins to radiate heat in some places, most notably the base of my skull. At this point, it feels like my tank is empty, but I have to force myself to keep going. Even if I close my eyes on the train, it’s hardly restful—the noise and sensory stimulation around me tires me even further.

I get back home around 3-4 hours after I set out (the commute to my doctors office is unfortunately not easy in my city). I’m absolutely wiped at this point. I’ll usually just collapse onto the couch and stay there for the rest of the day. By the time my heart rate finally gets back to normal that evening, it’s like the floodgates open and my entire body is in pain.

The residual pain I was feeling on the way back home intensifies exponentially, like it was being suppressed while I was forcing myself to make it home, but now that suppression is gone. It hurts just to stand up and use the bathroom, everything is stiff. I’m out of it, extremely irritable, can’t pay attention.

Usually that night I will get some pretty bad insomnia. Once I wake up, the pain is still there, usually with even worse stiffness. I know I’ll have to really limit being on my feet for the next few days.

If an emergency arose, and I absolutely had to get up and do something, then I might be able to force myself by leaning into the momentum of a sustained “panic” mode—the few times I’ve had to do this, I paid dearly for it with days or weeks of PEM once I finally was able to relax.

I’ll tie this into a speculative explanation with redox imbalance in another message to avoid making this one too long.

 

[jnmaciuch]

I’ll tie this into a speculative explanation with redox imbalance in another message to avoid making this one too long.

I should note, the timeline for PEM changed for me when I started taking a stimulant. Pre-stimulant, the pain was less sharp and tended to occur much later. I’d get soreness and weak muscles on the way back home, but the PEM mostly consisted of a prolonged flat-out exhaustion that usually started the next day rather than a few hours after the activity.

Now for my “redox” theorizing, which I acknowledge is probably amateur as I am only just recently learning about cellular metabolism in depth. I independently came to some conclusions about insufficient activity of the malate-aspartate shuttle from trying to explain other semi-consistent findings in the literature. As it happens, my theory here actually meshes pretty well with the itaconate-shunt hypothesis from Phair and Armstrong.

If succinate dehydrogenase activity is repressed, not completely but enough to reduce levels of downstream TCA cycle metabolites, then you might end up with a limited amount of malate available in the cytosol.

The role of that malate is to shuttle H- from NADH in the cytosol and pass it off to NAD+ in the mitochondria. The ATP production of the mitochondria are going to be limited by the pumping of H- into the inner mitochondrial membrane to generate proton motor force that is then utilized by complex V. That gradient is primarily going to be limited by the availability of mitochondrial NADH that can pass the H- at complex I.

Assume that a person with ME/CFS has spent the last few days doing very little activity. Even if SDH activity, and therefore malate availability, is at (choosing a random number) 50%, they might be able to generate sufficient ATP to have generally normal bodily function.
Over time, even a sub-optimal level of malate will be able to shuttle enough H- to be stored by mitochondria NADH.

The issue comes when your activity level requires faster replenishment of that mitochondrial NADH. Going back to my doctor’s appointment example, the residual store of mitochondrial NADH may be enough to last me for 10 minutes of walking and an hour of train riding.

Fortunately, once that runs out, there are backup mechanisms to generate more TCA cycle metabolites to compensate—the GABA shunt, as mentioned in the itaconate shunt hypothesis. There’s also beta oxidation that can be relied on (I think it’s interesting to note that I tend to have the most endurance right after I eat a bagel sandwich with bacon, two eggs, and cheese).

Once those backup substrates can’t be relied upon anymore, you could also continue to generate ATP by substantially upregulating glycolysis, which can be mediated through the HPA axis stress response.

Here is where I think immune signaling plays a role, since it’s already known that shifting macrophages towards glycolysis is enough to trigger cytokine release. Furthermore, insufficient mitochondrial NADPH prevents cortisol production from being ramped up beyond a certain point.

Now as we’ve already discussed elsewhere, it’s not known for sure whether or what combination of cytokines are mediating muscle pain in e.g. viral myalgia. I’m only trying to speculate based on what little is known—this part might have to be reworked as new information comes to light.

Crucially all those backups are not as efficient towards restoring redox balance, and will only last a finite amount of time. When I finally crash, I’d be left with a massively skewed redox balance, and my mechanism for recovering that balance through malate shuttling is already being suppressed.

Couple that with macrophage (or other immune cell) activation with insufficient circulating cortisol levels to counteract it (not pathologically insufficient at steady state, just unable to be ramped up to counteract cytokine signaling) and you might have some runaway cytokine signaling explaining days-long muscle pain and stiffness.

Some additional evidence I have in favor of this comes from my experiences with a malic acid (dietary form of malate) supplement, which immediately gave me the ability to walk nearly 2 hours with only the mild soreness and tiredness that can be expected from limited physical activity up to this point.

The only time ive experienced PEM since starting that supplement has been when I let it wear off after 8 hours and I was still in the middle of activity. Even in that case when i started to feel the muscle pain and weakness characteristic of PEM, it was actually completely reversed when i took another malic acid once i got home

 

[Mij]

Why I get PEM after small swimming and not after walking even if I feel more tired after walking?

Maybe because you are also using your arms when swimming and using up more energy?

I find that I'm ok if I only use specific muscles groups at a time. I can power walk, but can't take a shower afterwards because of the warm water, and it would require using my arms. I can lift light weight afterwards as long as I dont' raise my arms above my shoulders.

I don't feel tired after walking though, but I did years ago after walking in the pool.

 

[jnmaciuch]

Some additional evidence I have in favor of this comes from my experiences with a malic acid

As has been noted in other threads, there are still some outstanding questions about the malic acid. Notably, not everyone with ME/CFS who has tried it feels an effect, so this might mean that a malate “insufficiency” might only be the pathological mechanism for a subset of people.

Also, since malic acid is plentiful in fruits, why has no one cured themselves with apple juice? I don’t have a definitive answer for this, but I did notice that my malic acid supplement is less effective if I take it alongside fruit juice, so my guess is that it has something to do with sucrose or fructose interference.

So, to recap, I don’t necessarily think mitochondrial damage is the Cause of ME/CFS, or if it exists it might be due to some downstream effect of insufficient electron shuttling. From personal experience that I’ve detailed elsewhere, I also think that FAD/FADH2 is implicated, since the malate alone doesn’t really fix my brain fog but coq10 + super B complex really did.

furthermore, I think this theory provides some hints for why I and others with no viral trigger but pre-existing thyroid issues might end up with ME/CFS, since thyroxine directly acts on SDH in a concentration-dependent manner and there might be some effect that occurs when you have a period of chronic glucocorticoid signaling but no concomitant increase in thyroxine. That’s more firmly in the realm of pure guesses, though.

 

[jnmaciuch]

Maybe because you are also using your arms when swimming and using up more energy?

I find that I'm ok if I only use specific muscles groups at a time. I can power walk, but can't take a shower afterwards because of the warm water, and it would require using my arms. I can lift light weight afterwards as long as I dont' raise my arms above my shoulders.

I don't feel tired after walking though, but I did years ago after walking in the pool.

I’m the same way. My worst PEM episodes were actually triggered by going on vacation with my family and forcing myself to go swimming with them. I think swimming tends to utilize nearly all your muscle groups at once.

 

[tuha]

@Mij @jnmaciuch
but is it not bizarre that we get PEM with activities where you are less tired after but you use more your muscles? Why is it like this?
Maybe there is not enough oxygen? Many patients also feel like they dont have enough oxygen when they breath. just guessing with no scientific background

 

[jnmaciuch]

@Mij @jnmaciuch
but is it not bizarre that we get PEM with activities where you are less tired after but you use more your muscles? Why is it like this?
Maybe there is not enough oxygen? Many patients also feel like they dont have enough oxygen when they breath. just guessing with no scientific background

It’s just speculating since we don’t know if PEM symptoms can be triggered by innate immune signaling via cytokines, but going with my redox imbalance theory, the only thing that matters is that the immune cells specifically in the muscle are forced into a “backup” energy generation mode.

Once they are, this could trigger a self-perpetuating signaling cascade that leads to PEM. Since the muscles are such a big organ system, it’s possible to imagine that some rampant signaling just in the muscles can have knock on effects in other systems.

I think this could potentially explain PEM in response to only mental exertion too to some extent. What matters is whether the local innate immune cells in the brain, where the activity is happening, are being activated and whether this activation is actually correlated with PEM.

 

[Mij]

@tuha it could also be a combination of autonomic fatigue.

 

[Utsikt]

@tuha it could also be a combination of autonomic fatigue.

What’s that?

 

[Mij]

Fatigue related to dysfunction of the ANS which can also bring on cognitive fatigue.

Physical and cognitive exhaustion are interchangeable in ME.

 

[jnmaciuch]

Similar to others earlier in the thread, I notice that the muscles I was using in the activity that triggered PEM tend to be the worst the next day. But on top of that there is a general global pain and exhaustion.

so if I triggered PEM by walking, my feet back and legs are the most wobbly and painful the next day, but I still probably couldn’t use my arms to the same extent as I could after a few days of rest and minimal activity.

which makes me think it’s a “starts in whatever is being used” -> “spreads everywhere” kind of effect.

 

[MelbME]

This is a good paper on the subject, even though it's long COVID patients that experience PEM.

https://www.nature.com/articles/s41467-023-44432-3


Muscle structure changes at baseline were similar to what occurs in deconditioning.
However the level of necrosis of muscle after exercise was far greater than expected by deconditioning, the level of lactate rise after exercise was more than expected too.

Also features like amyloid in muscle are unique and not part of deconditioning.

It's like deconditioning with added inflammation and altered mitochondrial metabolism (beyond expected deconditioning)

 

[Jonathan Edwards]

I think this could potentially explain PEM in response to only mental exertion too to some extent. What matters is whether the local innate immune cells in the brain, where the activity is happening, are being activated and whether this activation is actually correlated with PEM.

I am sceptical that using brains cells and using muscle cells are likely to have similar activating effects on any 'innate immune cells' present. The changes in metabolic rate in brain during mental activity are pretty marginal. The whole brain is using oxygen the whole time, even during sleep.

I am unclear why innate cell activation needs to be in muscle during physical activity either, even if it is an option that comes first to mind. What worries me is that the accepted idea that PEM can be triggered by trivial exertion (as I think will go into the Fact Sheet) means that we need another explanation at least some of the time. And if we need another explanation some of the time why not make us eo fit all of the time?

 

[Jonathan Edwards]

I still probably couldn’t use my arms to the same extent as I could after a few days of rest and minimal activity.

which makes me think it’s a “starts in whatever is being used” -> “spreads everywhere” kind of effect.

But that means that we do need to invoke signals from somewhere else from some muscles affected by PEM, so why not all? As I said before, the situation may be quite similar to viral myalgia and I don't think anybody has a good grasp of that either - it is about time they did.

 

[jnmaciuch]

What worries me is that the accepted idea that PEM can be triggered by trivial exertion (as I think will go into the Fact Sheet) means that we need another explanation at least some of the time.

I don’t think it requires another explanation. Like I mentioned before, my capacity for an activity is highly dependent on how much activity I’ve been doing in previous days. Even if previous activity isn’t enough to trigger PEM, I still need to take it easy later on or it becomes easier to trigger PEM with less activity.

That fits very well with the redox imbalance explanation. The capacity at the moment, which can trigger PEM when it is surpassed, is dependent on a finite tank that is refilled by a substantially slowed mechanism in ME/CFS.

So if you’ve allowed time for it to be “refilled” (for mitochondrial NADH to re-accumulate), then you can go at full capacity for a brief amount of time without overdoing it.

If it hasn’t refilled yet, you’re gonna reach that limit sooner where you need to switch over to alternative methods.

If you’re really severe, you may already be primarily relying on the backup methods, and it takes very little to go past their capacity and trigger whatever happens at that point leading to PEM.

 

[Utsikt]

What worries me is that the accepted idea that PEM can be triggered by trivial exertion (as I think will go into the Fact Sheet) means that we need another explanation at least some of the time. And if we need another explanation some of the time why not make us eo fit all of the time?

By ‘worry’, do you mean that it’s a challenging issue to solve or that it’s wrong to include trivial exertion as a cause of PEM?

 

[jnmaciuch]

I am sceptical that using brains cells and using muscle cells are likely to have similar activating effects on any 'innate immune cells' present. The changes in metabolic rate in brain during mental activity are pretty marginal. The whole brain is using oxygen the whole time, even during sleep.

Only one part of the brain would need to “overexert” itself to start a signaling cascade, if there is one that can be triggered by this mechanism. In the times I have had triggered PEM from mental effort before, it has come from trying to troubleshoot some code for several hours. Those will be neural circuits that are not nearly as active while sleeping.

even in that case, if my PEM was triggered cognitively, the next day it is cognitive issues that are the most stark, even with general fatigue and other PEM symptoms in other parts of the body.

Either way, metabolic regulation of the brain is a complete black box at this point. The little we know suggests that there absolutely is short term fluctuation that occurs because of the preferential utilization of FADH2 as an electron shuttling mechanism, which is less efficient but can be upregulated in the short term faster than the malate-aspartate shuttle. There’s also probably differential reliance on glycolysis vs. Oxphos for different neural circuits.

I agree that the “signaling” cascade is a weak point in this theory just because science at large doesn’t have enough information to fill that part in. It may not be mediated by innate immune cells at all. But from my experience I’m seeing good evidence that it starts with one or multiple parts of the body being overtaxed, and then spirals from there. Innate immune cells are a good potential candidate since they’d be present everywhere that PEM might be triggered, and their signaling is known to function in time scales that correspond with PEM.

 

[richie]

It says ‘will you give is a hand?’.

That’s cool! Lund and Lunde are common Norwegian surnames.

Some of the best such names are the Norse Gaelic/Irish ones. (Mc)Sweeney is ,for example, Svenson.
Apologies to others for off topic.