Is PEM related to exerkines?

[Hoopoe]

Exercise leads to the release of a wide variety of substances, in the category of exerkines.

Exerkines are defined as signalling moieties released in response to acute and/or chronic exercise, which exert their effects through endocrine, paracrine and/or autocrine pathways. A multitude of organs, cells and tissues release these factors, including skeletal muscle (myokines), the heart (cardiokines), liver (hepatokines), white adipose tissue (adipokines), brown adipose tissue (baptokines) and neurons (neurokines).

https://www.nature.com/articles/s41574-022-00641-2

What if one or several of these exerkines were blunted in ME/CFS or, for some obscure reason, had a damaging effect instead of a health-promoting effect?

Is this something that might explain PEM?

A small proteomics study by Hanseon et al. found a pattern of markedly blunted response to exercise in ME/CFS.

Thoughts?

 

[Kitty]

What if one or several of these exerkines were blunted in ME/CFS or, for some obscure reason, had a damaging effect instead of a health-promoting effect?

Is this something that might explain PEM?

I don't know, but to me the striking thing is that most PEM isn't caused by exercise, or anything resembling it.

It can be triggered that way, of course, but the overwhelming majority is caused by routine day to day activity, some of it very trivial. The lack of a link with significant exertion is almost part of the definition.

 

[hotblack]

I suppose you could say it’s caused by exertion more than exercise? But even that isn’t telling the whole story and it’s certainly not a 1-1 relationship.

But there could be something whereby some of the things produced by activity are sometimes involved in something going awry.

From the article:

Although the terms ‘exercise’ and ‘physical activity’ are commonly used interchangeably, exercise is typically regarded as intentional physical activity, such as aerobic training1, resistance training or high-intensity interval training. By contrast, physical activity encompasses exercise as well as usual occupational and/or domestic activity

Irrefutable evidence supports the importance of physical activity, exercise and cardiorespiratory fitness in the prevention and treatment of chronic diseases, such as

Is it irrefutable? Anyway, let’s assume that activity may have a damaging effect, but exerkines are released which make it positive. Then I suppose it would make sense if there is a blunted response the damaging effect would prevail?

Just some thoughts.

 

[Kitty]

Anyway, let’s assume that activity may have a damaging effect, but exerkines are released which make it positive. Then I suppose it would make sense if there is a blunted response the damaging effect would prevail?

I wonder how many of the molecules they class as exerkines could be released by reading a web page or having a light on in a room, though?

That's enough to trigger PEM in some people with ME/CFS, and we've no reason to think it's different to the PEM triggered by a visit to a supermarket in a less severely affected person.

Obviously I don't know, and PEM might well be a response to signalling. The molecules involved probably need to have a broader range of triggers than skeletal muscle activity, but it's theoretically possible these exerkines do.

 

[hotblack]

Absolutely agree @Kitty

I’ve been reading (listening to) the paper some more and made some notes…

On the one hand I’m not sure this can be related to PEM because of their definition of exercise and exerkines. I can get PEM from minimal activity which certainly does not meet their definition.

For the purposes of this Review, we define an exerkine as a signalling moiety released in response to acute exercise and/or chronic exercise, exerting its effects through endocrine, paracrine and/or autocrine pathways.

On the other they also acknowledge we don’t have a good understanding of a lot of signalling chemicals resulting from exercise or activity in general.

The variable effects and number of factors they mention, from diet and fasting status to circadian timing and genetic effects all lead me to think much of this is very speculative. But that so much is unknown also means there’s possibilities here.

Although exercise exerts many beneficial effects across multiple organ systems, our understanding of the mechanisms driving the benefits of exercise and the variability in these benefits remains rudimentary.

Exerkines are increasingly recognized to include a broad range of signalling moieties, including cytokines, nucleic acids (microRNA, mRNA and mitochondrial DNA), lipids and metabolites, which are frequently driven by cell-specific extracellular vesicle secretion

The extent to which exerkines cross the blood–brain barrier to exert their effects remains unknown,

With so many possible chemicals, receptors and downstream interactions possible. If not a problem with the signalling chemicals themselves then perhaps their interactions with say the hypothalamus? Or something else?

 

[Hoopoe]

I wonder how many of the molecules they class as exerkines could be released by reading a web page or having a light on in a room, though?

These responses occur immediately though, right? That doesn't fit with PEM. I always thought that what happens in these examples is a sensitized CNS that cannot handle any further sensory stimulation.

I conceptualize PEM as a delayed response.

 

[Kitty]

But that so much is unknown also means there’s possibilities here.

100%.

If not a problem with the signalling chemicals themselves then perhaps their interactions with say the hypothalamus? Or something else?

It's possible it's due to the release of something that shouldn't be there, but is in ME/CFS.

But maybe it could also be due to something that should be there, and isn't in ME/CFS?

These responses occur immediately though, right? That doesn't fit with PEM.

I'm not severely affected, so I'm not speaking from experience—but those who are severely ill describe activities such as reading, talking, sitting up, and sensory stimulation causing delayed PEM, as well as being extremely challenging at the time.

 

[hotblack]

I conceptualize PEM as a delayed response.

I can get a delayed PEM response from sitting at a sink and washing my face. Or raising my hands and using clippers to cut my hair (even if lying down). Or having a conversation. Or… you get the idea.

Sometimes there’s immediate effects too. Sometimes not. But none of these are ‘exercise’ and may not even feel like exertion or effort at the time.

The sensitised CNS one I think I may be a bit fuzzier on explaining but will have a ponder.

All really interesting. But time for a rest!

 

[Creekside]

I think PEM is triggered by some kinds of signals, and exerkines are just one of many. I don't think the signals created by cognitive exertion count as exerkines. So, while PEM might be triggered by exerkines, or by the absence of certain exerkines, I don't think that knowledge is significantly useful for solving the problem of PEM.

 

[poetinsf]

I think PEM is hypersensitivity to the process of repairing the damage from exertion. Some exerkines/myokines may be relevant in that they are involved in the repair process. Mental exertion is also an exercise in my opinion, that causes damages that need to be repaired. Thinking is pretty exhausting even for the healthy.

 

[bobbler]

100%.



It's possible it's due to the release of something that shouldn't be there, but is in ME/CFS.

But maybe it could also be due to something that should be there, and isn't in ME/CFS?



I'm not severely affected, so I'm not speaking from experience—but those who are severely ill describe activities such as reading, talking, sitting up, and sensory stimulation causing delayed PEM, as well as being extremely challenging at the time.

Yes - I’m severe and it’s far more obvious with all of these that it’s a case of finding a window when I can do these and that I accumulate symptoms whilst doing these that cause me to struggle as it goes on as well as it being eventually time limited .

Those 3 aspects I’ve mentioned of course interact because the window is about it being possible and worth sitting up because I’ll be able to stay there long enough if feeling better at that point. We all push through and I hate how that gets used against us because we probably all feel it even if that’s in the form of ‘get up and go’ of adrenaline and mind over matter.

at least these days I know I’ll have to crumble back into lying flat in bed after x time and that feeling awful time with correspond to how far over exerted (it’s the sensory accumulating with other stuff that’s hard too) but I do remember when I was moderate I’d have to literally collapse into bed hoping I can get my work clothes off somehow whilst I could still move.

so those ‘pushes through’ are only shortish lived in the sense that if only these clinicians who see what they want to could actually watch the aftermath whenever it happens- because whenever that is the ‘amount’ is very logical to the ‘amount accumulated without resting it off’…. IF they see the WHOLE thing (which they generally won’t because what will shock them will be how long it lasts and they won’t see the delayed but which shocks even me that it’s worse than the ‘at the time’)

which is why I wonder whether it’s something either accumulating or - if these are ‘needed’ - becoming more and more depleted vs ‘needs’ , that makes sense

and yes when more severe that extra fragility means these things ‘show’ quickly (as well as if they hit later too)

 

[bobbler]

I think PEM is triggered by some kinds of signals, and exerkines are just one of many. I don't think the signals created by cognitive exertion count as exerkines. So, while PEM might be triggered by exerkines, or by the absence of certain exerkines, I don't think that knowledge is significantly useful for solving the problem of PEM.

When you are severe talking feels like a very physical activity - you certainly notice and can almost separate the cognitive element and physical of getting sound out etc, strain on body of moving mouth and the air etc

it’s really obvious when you compare pace of talking and ‘type’ of topic ie shooting the breeze vs direct questions and the complexity of those how ‘conversation’ itself is quite a generic term for something that could be more predominantly leaving you physically exhausted vs cognitive etc depending on what type it turns out to be (and of course other factors like if it’s a dodgy phone line you are trying to enunciate on or there is hold music etc)