A Hypothesis on Why Exercise Triggers PEM

[Wishful]

In another thread I reiterated how my physically-induced PEM was not triggered by overall exertion, but rather by activity that would damage muscle cells. A 40 km bike ride might not trigger my PEM, but less than a minute of washing a window would, since that was an activity my muscles weren't used to. Thus my hypothesis that my PEM was triggered by the immune response to damaged cells. This fits the well-known rise in IFN-g 24 hrs after exertion, which matched my PEM delay. Also, my physically-induced PEM seemed very similar to the symptoms I got from viral infections (although I only had a couple of viral infections in 20+ years of ME).

The new addition to the hypothesis is dysfunction of the immune system's response to damaged muscle cells (and connective tissue cells?). In some people, this might be a relatively extreme abnormal response, resulting in severe PEM, and possibly lasting a long time. For others, such as me, it's only mild PEM, typically lasting less than 24 hrs. It might not just be a simple case of one or more cytokines being elevated in ME, but some more subtle changes in the immune response.

I believe that the immune system response to cell damage triggers activation of glial cells, which in turn influence other brain cells which results in PEM. A good question is whether the problem in the body's immune response, the glial response, or both.

Lots of people, researchers included, seem to jump to the "exertion = elevated mitochondrial demands, therefore that's the cause of PEM" theories. However, that same exertion also typically results in immune system activation, so that's also a valid correlation and thus potentially valid theory. I think that perspective should be more widely spread to the research community, so they can consider that when thinking "Why is x happening in ME?", and also so they can think of ways of testing that hypothesis. Is the immune system response in/around the muscles different in PWME vs similarly physically limited people without ME? Is there an abnormal autoimmunity response to the debris from damaged cells?

This study ( https://www.mdpi.com/1422-0067/24/3/2698 ), posted in another thread, found significant transcriptomic changes in PWME following exertion, which caused "dysregulated immune signaling pathways". That supports the theory that PEM is triggered by immune response to exertion, rather than mitochondrial dysfunction. I would like to see that study improved by a larger group, longer times (at least 24 hrs), and taking samples from within the brain, rather than just CSF.

 

[hapl808]

My PEM is severe, but also triggered by cognitive exertion or allergic reactions. So I think some kind of immune connection or glial involvement does sound plausible. No idea really, but I don't think doctors are on the right path when they look solely at muscular triggers as many people seem to respond similarly to cognitive exertion, social interaction, etc. I don't think it's a 'mental' issue, as mild enjoyable activities can trigger me when other more tiring activities don't do so.

 

[Murph]

I like the observation that not all muscle groups cause PEM equally. I'm the same. washing windows or using arms above my head is a particular trigger. Whereas I can do some situps without much risk. my stomach muscles just don' seem to cause PEM as easily.

However, I can also get pem from staying up late working and from digestive distrubance so i feel that a muscle breakdown theory isn't great as an exclusive explanation for PEM in my case.

One theory I have is that muscles that are under regular use are regularly refreshed by the body, exercise breaks them down and we rebuild them during rest. What gets rebuilt is the vascular architecture and the cells themselves. so everything is fresh and new. they might not have exhauasted, diseased endotheliums, they may not have old busted mitochondria, they might not have virus living in them. so when we use those muscles, whatever is wrong in other cells is fine.

my theory implies that if you have muscle groups that don't give you pem, you should keep using them /. build them up as much as you safely can. It also implies that if you can build a muscle group up slowly you can get it to a point where using that muscle won't give you pem as easily. this is controversial obviously as it's what the GET people argue. I recently developed a theory of exercise as a sort of paradox in me/cfs. exercise will make you worse. but if you can do it, it can make some aspects improve. it implies that there's a subset of mild patients who can identify a muscle group they can work on fairly safely, and they should work on it, gently, on days they feel okay. I doubt there is any such muscle group for more moderate severe patients.

 

[hapl808]

my theory implies that if you have muscle groups that don't give you pem, you should keep using them /. build them up as much as you safely can. It also implies that if you can build a muscle group up slowly you can get it to a point where using that muscle won't give you pem as easily. this is controversial obviously as it's what the GET people argue. I recently developed a theory of exercise as a sort of paradox in me/cfs. exercise will make you worse. but if you can do it, it can make some aspects improve. it implies that there's a subset of mild patients who can identify a muscle group they can work on fairly safely, and they should work on it, gently, on days they feel okay. I doubt there is any such muscle group for more moderate severe patients.

This resonates with me a bit. When I kept in good shape, the PEM was much more mild. However, pushing myself to try to build a bit more muscle, do sets to failure, etc - led to some enormous crashes. Difficult line to walk (or not walk, as the case may be).

 

[Murph]

This resonates with me a bit. When I kept in good shape, the PEM was much more mild. However, pushing myself to try to build a bit more muscle, do sets to failure, etc - led to some enormous crashes. Difficult line to walk (or not walk, as the case may be).

yep. This disease is not just deconditioning. And rest helps enormously. But we are mammals and deconditioning is going to make vascular performance worse. For most mecfs patients they can't do exercise and so that performance decrement is something that is just part of the deal. But for anyone who can manage even a little, holding off deconditioning is a good idea (only never going so far as to get PEM).

 

[Wishful]

My PEM is severe, but also triggered by cognitive exertion

I was going to include a statement about cognitively-induced PEM, but forgot. For me the two triggers caused the same symptoms, but cognitive exertion had a much shorter (could be under 1 hr) and more variable delay. My theory is that physical triggers work via the immune system, which causes a delay (often very consistent) in triggering glial cells. Cognitive exertion triggers the glial cells directly, resulting in the same effects much sooner.

 

[Wishful]

One theory I have is that muscles that are under regular use are regularly refreshed by the body, exercise breaks them down and we rebuild them during rest. What gets rebuilt is the vascular architecture and the cells themselves. so everything is fresh and new. they might not have exhauasted, diseased endotheliums, they may not have old busted mitochondria, they might not have virus living in them. so when we use those muscles, whatever is wrong in other cells is fine.

That's plausible. Another explanation is simply that regular use means that they're able to withstand regular exertion without being damaged. Going past those limits causes microtears or other damage. My legs were accustomed to the strains of cycling, but climbing a ladder pushed them past the normal limits of movement, so that would be unaccustomed strain, and thus damage.

Another example: I could dig soil for hours using my regular movements (stomp blade in, pry, lift, throw) without triggering PEM. A few shovel load dug using a different movement pattern (stab forward, lift, throw) would trigger PEM. My guess is that the typical PWME will trigger PEM with even a short duration of unaccustomed movement. For example, if you walk up a normal flight of stairs, one step at a time, daily without triggering PEM, walking up it two steps at a time (strains muscles past normal limits) would trigger PEM. Anyone want to test that, or a similar experiment where the activity isn't particularly demanding of energy but is unaccustomed? PEM for science!

 

[Rufous McKinney]

But for anyone who can manage even a little, holding off deconditioning is a good idea (only never going so far as to get PEM).

My main activities are:

stand up from my chair.......against gravity.

Mostly I sit up most of the day and evening (evening is harder, and I wonder if I"m sitting up too long)

Try to stand up straight, use core muscles wash a few dishes. Kitchen and food prep are: the standing up and posture work out.

My neck is a problem all evening....ligament laxity.


I was getting a tad more stronger when another long term crash arrived. This seems to be the story.

My hip flexors seem to be the center of some problem outside all the spine problems.

When you have permanent spine problems, I think we can be inflamed there all the time.

 

[Rufous McKinney]

My legs were accustomed to the strains of cycling, but climbing a ladder pushed them past the normal limits of movement, so that would be unaccustomed strain, and thus damage.

I agree with some of what you describe muscle wise likely is happening.

Altho I"ve never been in particularly great shape aerobically speaking, I could hike in rugged terrain and used to do a lot of leaping on boulders. I was pretty strong in the legs etc dept.

Most of those muscles are ..gone. All my joints are super ligament weak.

 

[Mary]

For me PEM is triggered by any exertion or stress, whether physical, mental or emotional - e.g., watched a 3 hour lecture on DVD about cancer, it was fascinating and I used heavy concentration - result: crashed the next day. Doing any physical exertion, regardless of muscles involved, for more than 3-1/2 hours (and this is light exertion, not a 3 hour walk) - crashed the next day. And socializing, whether on the phone or in person, for too long, again I'll be crashed the next day. And the crashes are all the same involving muscle aches and extreme fatigue, unable to do anything until they pass. Fortunately BCAAs have cut my recovery time down to 1 day from 2 - 3 days.

 

[Wishful]

For me PEM is triggered by any exertion or stress, whether physical, mental or emotional

Are the delay times different for the three triggers? Durations or intensity of the PEM?

 

[Wishful]

Since the paper about transcriptomic changes said that PWME were lacking certain immune responses, I wonder whether those responses help turn off immune responses, especially glial ones. The 'off switch' might not be the reduction of a factor, or one specific factor, but rather a pattern of changes in non-glial cells that occurs when the body's immune cells finish up their work. Maybe the missing factors from muscles are supposed to signal "there's some damage here, but the cleanup crew has it under control", and if that's missing, the glial cells think there's a serious viral infection going on.

Instead of looking for an abnormally high factor, researchers might need to focus on the abnormally low ones, or the ones that simply don't show up when they are supposed to.

 

[Mary]

Are the delay times different for the three triggers? Durations or intensity of the PEM?

No - the PEM always hits the next day, like clockwork, and has the same duration and intensity.

 

[Wishful]

No - the PEM always hits the next day, like clockwork, and has the same duration and intensity.

The same time each day, or a consistent 24 hr delay from the start of the activity? To me, a consistent delay indicates one process responsible. If physical exertion has the same delay as cognitive exertion, maybe it's the cognitive exertion of doing the physical activity? Emotions involve nerve firing, so I think that would count as cognitive exertion too.

This nasty disease would be easier to figure out if we had common responses to various factors, but no, it wants to be difficult.

 

[hapl808]

No - the PEM always hits the next day, like clockwork, and has the same duration and intensity.

My cognitive PEM seems to hit the same way. If I exert myself at night, I have acid reflux the next morning. Then in the afternoon a migraine and that poisoned feeling starts and I end up in bed for the next 1-2 days at least.

I'm relatively severe, so I don't do much physical activity, so I think my PEM episodes are more likely to be from cognitive exertion. Cooking can exhaust me, but I don't think it causes crashes the same way as a doctor's appointment - but I don't know if that's from the cognitive or physical aspect?

Yeah, no idea overall.

 

[Mary]

The same time each day, or a consistent 24 hr delay from the start of the activity? To me, a consistent delay indicates one process responsible. If physical exertion has the same delay as cognitive exertion, maybe it's the cognitive exertion of doing the physical activity?

Well, the start of activity is when I get out of bed in the morning. If I'm up to it, I'll take a shower. And a day can be filled with lots of little things - breakfast, dishes, maybe laundry . . . or a big thing like grocery shopping, though now I order on-line and pick up curbside shopping, much easier. So it's not one 3-1/2 hour activity, it's the cumulative energy I expend throughout the day. Usually my days end by 1:00 p.m. And I'll rest fairly often during the morning too.

But one night I watched a 3-hour educational video and that did me in too. Several times I've taken a phone call late in the day (late for me would be after 4:00 p.m.) and if I talked for 45 minutes, that often is enough on top of other things to put me over the edge.

All I know is in the morning after such a day I'll feel extra tired, not quite sure if I'm crashed, but I usually am - and as the morning wears on I get more and more tired and often fall asleep midday which I never do when not crashed, and it feels horrible and then by late in the day I can feel it start to lift and by the time I go to bed I can tell it's over or just about over.

All I know is that enough exertion of any kind will make me crash. and there's very little cognitive exertion when doing laundry, etc. When I'm crashed, I am able to read, but only light reading - murder mysteries, etc. If I try for anything which requires mental stamina - e.g., doing ME/CFS research, I can't do it while crashed. I can feel my energy draining even further if I try to do that while crashed. Or if I talk to someone on the phone while crashed, I can only talk a few minutes - again, I can feel what little energy I have draining away. This doesn't happen when I'm not crashed. But I can read light mysteries for a few hours while crashed - it doesn't take much mental stamina to do that.

So I don't any cognitive exertion while doing physical exertion has any bearing on crashing. There just isn't much cognitive exertion when doing the dishes or taking a shower etc.

 

[Wishful]

There just isn't much cognitive exertion when doing the dishes or taking a shower etc.

Hard to know. Maybe it's which brain cells are used that matters. Even doing dishes probably involves millions of neurons firing, with their associated glial cells responding to those firings, and if even a few of those cells are extra sensitive or produce/consume abnormally large quantities of whatever, that could trigger PEM. Someone else might do significant cognitive exertion and not trigger PEM, because all those cells lack whatever abnormality in involved, but maybe they'd trigger on strong emotions, which involve other cells.

My PEM triggers never seemed to be cumulative. If climbing one ladder rung didn't trigger PEM, I expect that climbing that same rung once per hour wouldn't result in PEM. Can't test that theory anymore (cured of PEM), and darned happy about that.

 

[Wishful]

Huh, that's something else to include in this thread about PEM: it can be successfully blocked and cured. While I don't know why cuminaldehyde worked, or why it took two years of taking it every 3rd day to result in a permanent cure, that might make sense to a researcher.

Also, cumin blocked my physically-induced PEM 100%, but didn't block cognitively-induced PEM. Both triggers stopped at the same time though. At the same time, I lost the need to take T2 every 21 days to block worsening of symptoms. That's probably an important clue to what was going on, but there's probably not enough known about T2 and all the immune and neural functions involved to make sense of that single clue.

 

[Mary]

@Wishful - I can read a light book (mystery novel, etc.) for a couple of hours which does not require much mental exertion or brain power and it won't trigger PEM, plus it's something I can do when I'm crashed and it won't make it worse. However, 3 hours of intense concentration and which I have to work at is enough to trigger PEM and is something I would never attempt while crashed. So I don't think it's the minimal brain cells which are needed to do the dishes (maybe comparable to light reading?) which trigger PEM, for me at least.

Doing the dishes alone won't trigger PEM for me. It's the cumulative exertion - do the dishes, take a shower, do 2 loads of laundry - okay, that I should be okay with but no more. If I go over that limit, I'm doomed the next day. So I'm always calculating, always trying to add up what I've done and what I think I can get away with.

 

[hapl808]

So I don't think it's the minimal brain cells which are needed to do the dishes (maybe comparable to light reading?) which trigger PEM, for me at least.

Yep. I didn't even realize PEM triggers years ago, just crashing all the time. Now I realize that hours of concentration would crash me. Unfortunately now that I'm more severe, even 30 mins of certain kinds of concentration will crash me badly. Sometimes less. So I have to only barely engage in things to avoid constant crashes. Not an enjoyable way to live.