A Thought Experiment on Muscles

[jnmaciuch]

A curious question for others:

if you’ve experienced PEM triggered by some trivial amount of activity, did it follow periods of more activity than usual even if that prior activity didn’t trigger PEM?

As a mild formerly moderate person, I’ve never experienced trivial activity triggering PEM if I had not already been active or at least under a huge amount of stress.

In my theory, I would assume it’s a different case for very severe people, who may be primarily reliant on non-mitochondrial ATP generation and therefore might get PEM triggered very easily.

 

[MelbME]

Does anyone feel like they experienced PEM without exertion?


Have you had a flare of symptoms with no exertion you'd point to?

 

[Utsikt]

if you’ve experienced PEM triggered by some trivial amount of activity, did it follow periods of more activity than usual even if that prior activity didn’t trigger PEM?

No it did not always as far as I can tell.

Although I would probably not use the word trivial, very small amounts of exertion is probably a more neutral description.

 

[jnmaciuch]

Actually now that I think about it, I did once experience PEM triggered by just brushing my teeth. It happened when I was forced to be on a strict elimination diet for 6 weeks because my doctor wouldn’t consider stimulants before I ruled out “food sensitivities.” So I was already in a pretty severe calorie deficit since I couldn’t have most carbs, proteins, or fats.

 

[jnmaciuch]

No it did not always as far as I can tell.

Although I would probably not use the word trivial, very small amounts of exertion is probably a more neutral description.

If you don’t mind me asking, how severe is your ME? I think it would be good to see if there’s a correlation between general severity and whether you’ve experienced PEM from very small amounts of exertion without prior activity.

 

[Utsikt]

Does anyone feel like they experienced PEM without exertion?


Have you had a flare of symptoms with no exertion you'd point to?

I’ve had unexplainable flares while I’m still in PEM and complete bedrest except for toileting. E.g. back up to 8/10 on an arbitrary symptom scale on day 6, instead of declining from 5 to 4.

 

[Utsikt]

If you don’t mind me asking, how severe is your ME? I think it would be good to see if there’s a correlation between general severity and whether you’ve experienced PEM from very small amounts of exertion without prior activity.

Bedridden. I can use the toilet on my own and eat. Walk 50-100 meters a day at most. My parents do everything for me. M29.

 

[Jonathan Edwards]

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?

It is challenging to solve. I have no doubt that the account is real.

 

[Utsikt]

It is challenging to solve. I have no doubt that the account is real.

That’s what I assumed, but it’s always good to ask when English is my second language. Thanks!

 

[Eddie]

Does anyone feel like they experienced PEM without exertion?


Have you had a flare of symptoms with no exertion you'd point to?

I think we have to define what exertion is in this context. If PEM is delayed, it could always be the case that it is caused by some exertion at some time father back in the past. At what point do we say the events are connected? And do we have to notice the exertion to connect it to the PEM?

Also if we think that increased severity lowers the threshold for PEM than there is a point at which any possible activity would be considered exertion and could hypothetically cause PEM. How could we ever differentiate if the PEM was caused by the exertion or something else?

 

[Jonathan Edwards]

Only one part of the brain would need to “overexert” itself to start a signaling cascade,

Yes but even the bits most active are only marginally different. Those MRI scans with blobs show tiny fractional differences and all the rest is shown very misleadingly blank.

If you’re really severe,

But we don't have any account of why 'really severe' people should have such a reduced metabolic capacity. To go back to a term used elsewhere, where is the disease memory for this severe metabolic defect. I don't see the big picture dynamics.

Redox mostly gets invoked as a reason for 'damage' and 'inflammation' which we don't see in ME/CFS. So I am still unclear what it would mediate. You might like a Phair-type metabolic trap state but it is hard to see where that comes from. If PEM myalgia is like flu myalgia it is entirely dependent on immune signals at the time and will resolve without them. So all we really need is immune signals. And we know that immune signals can continue because of disease memory in the adaptive arm of the system.

 

[Jonathan Edwards]

How could we ever differentiate if the PEM was caused by the exertion or something else?

A very important point I think.

 

[AliceLily]

Some of my worst PEM triggers were anything to do with squatting (out in the garden for 10 minutes). Carrying something heavy, or even holding onto a light book in bed reading in my very severe years. Travelling also.

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 spent the week in bed at the bach with sore throat also. No sightseeing was done. This was all a hint of how much worse it would eventually get.

 

[jnmaciuch]

Redox mostly gets invoked as a reason for 'damage' and 'inflammation' which we don't see in ME/CFS

I don’t see any reason to inherently link redox to damage and inflammation? That’s a false conflation. What I’m specifically referring to is NAD/NADH ratios in cytosol and mitochondria.

But we don't have any account of why 'really severe' people should have such a reduced metabolic capacity. To go back to a term used elsewhere, where is the disease memory for this severe metabolic defect. I don't see the big picture dynamics.

I don’t understand the question here. If it is mediated by repression of succinate dehydrogenase or another TCA enzyme, then severity would correlate with degree of repression. I don't have an answer for how that happens yet, thats the golden ticket overall. 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.

 

[Jonathan Edwards]

then severity would correlate with degree of repression.

So if it is so severe these people cannot eat why has nobody been able to demonstrate it using MR spectroscopy or whatever. We have some stuff on changes in lactate but not consistent. There seems to be a gap in the correspondence between disability and postulated metabolic derangement. Postulating something nobody can find is not so helpful.

What I’m specifically referring to is NAD/NADH ratios in cytosol and mitochondria.

So I am not clear how that helps us understand PEM - the symptoms we are trying to explain.

 

[jnmaciuch]

How could we ever differentiate if the PEM was caused by the exertion or something else?

That’s a great question! I honestly don’t think it would be possible without some kind of biomarker for exertion-induced PEM. Which is kind of a shot in the dark at this point.

I think it’s much easier to see an immediate connection to exertion in mild ME/CFS folks.

I’ve known people where the PEM was quite delayed but when they plotted it out in a calendar journal, it could consistently be linked back to exertion within the past 2-3 days. There was never an instance where this pattern didn’t hold true. Though of course that may be difficult to gauge for others—this friend had a pretty clear picture of what counted as “exertion” for them.

 

[EndME]

A curious question for others:

if you’ve experienced PEM triggered by some trivial amount of activity, did it follow periods of more activity than usual even if that prior activity didn’t trigger PEM?

As a mild formerly moderate person, I’ve never experienced trivial activity triggering PEM if I had not already been active or at least under a huge amount of stress.

In my theory, I would assume it’s a different case for very severe people, who may be primarily reliant on non-mitochondrial ATP generation and therefore might get PEM triggered very easily.

What do you mean by trivial activity? Aren't all cognitive activities trivial when it comes to ATP consumption?

 

[jnmaciuch]

So if it is so severe these people cannot eat why has nobody been able to demonstrate it using MR spectroscopy or whatever.

How many samples have we been collecting from really severe people? Even in the few that have been collected, measuring this phenomenon would require specialized techniques. You’d have to know where you’re looking.

What do you mean by trivial activity? Aren't all cognitive activities trivial when it comes to ATP consumption?

That’s a great question, I’m not actually sure what @Jonathan Edwards meant with this. I assumed it would mean very small amount—but it would have to be defined relative to what normally triggers PEM for that person. If that person is having PEM triggered by small amounts of activity regularly, how can you say it’s trivial for them?

 

[Jonathan Edwards]

How many samples have we been collecting from really severe people? Even in the few that have been collected, measuring this phenomenon would require specialized techniques. You’d have to know where you’re looking.

Why not just put an arm in an MR spectroscopy machine? Surely something would show? When arms or legs of people with ME/CFS were put in such machines in the 1980s nothing showed up. They weren't so severe maybe but the people who understood the technique were pretty sure there was little point in pushing the approach. If the problem isn't damage or inflammation presumably the idea is that it would explain weakness, but with the level of disability seen in very severe ME/CFS a metabolic shift ought to show up like a sore thumb - and at least like a slightly sore thumb in the moderate cases looked at.

And as far as I know nobody has shown any such metabolic effects in simple viral myalgia which can be bad enough that you cannot sit up or feed. Do we think that is a redox problem?

 

[jnmaciuch]

So I am not clear how that helps us understand PEM - the symptoms we are trying to explain.

As it happens, a supplement with the primary effect of enabling H- shuttling to shift NAD/NADH ratios eliminates PEM for me and a handful of others who have tried it. Is there some other secondary effect it might have on immune signaling? Possibly.

I know that this theory relies on [some signaling that is triggered by going beyond mitochondrial capacity in the moment]. That requires more research.

I’m interested in the theory because, as it stands, it explains many parts of my personal experience plus several semi-consistent metabolomics and other findings in the literature, as I’ve explained elsewhere. It paints a clear picture of activity leading to PEM, which I see as a weakness of solely immune-based theories.

if it’s not post-exertional, why are we calling it PEM and not just a flare of malaise? Can the folks who have experienced PEM that wasn’t preceded by any activity share if there’s a qualitative difference with PEM triggered by activity?