A Thought Experiment on Muscles

It is, thank you. I think I understand the key metabolic ideas more clearly. Though presumably the central question for any theory to answer is, “how does this cause ME?“ And as you say, this is where you rely on speculation to bridge the gap.

I will bow out at this point, but thanks for taking the time to explain some of the basics to these of us struggling with brain fog.

 

No problem, thanks for engaging! Always happy to break things down for anyone that needs it.

I suspect more of the “how does this lead to ME” puzzle will have to be filled in by non-ME/CFS-specific research.

For example, fatigue in anemia is thought to be caused by insufficient distribution of oxygen for oxidative phosphorylation, which means it has some overlap with the malate NAD/NADH mechanism (with important differences).

but we don’t actually know for sure, at least on a detailed neurobiological level, how that manifests as the feeling of fatigue in anemia. Brain fog and muscle pain are similar question marks.

in the mean time, we can make guesses based on where mechanisms overlap with similar symptoms in other illnesses, and my theory has some decent evidence on that point.

 

@Jonathan Edwards Have you seen this thread about an Oxford study monitoring muscle with MR Spectroscopy. In the thread there are links to other papers that might have info. Karl Morten posted a link to the paper recently.

1H and 31P MR Spectroscopy to Assess Muscle Mitochondrial Dysfunction in Long COVID, 2024, Finnigan et al

This was another tweet from Karl Morten from 4/4/2025
"Great meeting yesterday! Sheeza Mughal's talk showing serum from severe ME/CFS & Long Covid patients impacts 3D muscle function, induces mitochondrial stress and eventual failure was one of the highlights. A bigger study is desperately needed."
https://twitter.com/user/status/1908207441231122600


EDIT : According to this post by @V.R.T. the Sheeza Mughal 3D Muscle study paper was submitted last autumn

 

To clarify I was referring to this post, in which Murph had been in contact with the author by email

 

Also I just want to say that to my layman's eye this 3d muscle stuff looks very impressive.

If as @wigglethemouse quotes Morten here, the follow up needs a large grant, is there any way we can aid them in this funding process?

Would be interested to hear any criticism of the study/methods. I watched the talk but was very brainfoggy and don't remember a lot unfortunately!

 

Oh and very impressed that the samples were from severe patients, very sensible!

 

I'm sorry i am too ill to read past page 1 so this might be redundant or repetetive. I trust it be ignored if so

This is my experience exactly.

Could there not be something in the way oxygen & glucose are converted into 'useable' stuff? or does the body run on unconverted glucose?

Please forgive my ignorance & feel free to ignore me. I was only wondering because I always wondered why reading or watching tv while lying down makes me feel weak all over, how can reading for too long make me struggle to get to the loo...
but its the same effect as having the flu/tonsilitis. I remember being a teenager with a throat infection, feeling bored & thinking i was better enough to watch some tv, and then it just being too much for me & feeling much weaker all over again. The experience is the same for me.

I hope all you scientific minds come up with something. Thanks so much for continuing to think & discuss Jonathan

 

That is the sort of thing people make theories about -in terms of mitochondria not being able to access the fuel this or that way.

But to me there are puzzles with any theory like this. In very severe ME/CFS people find it hard to tolerate shifting a muscle from baseline metabolism, which for muscle is pretty minimal, to just a bit more for some simple non-strenuous task. So the muscle had just about enough mitochondrialpower to chug along doing nothing but no more.

Yet the heart has to work all the time, pumping away. And the brain has to use up glucose simply to stay alive. No oxygen for five minutes causes permanent brain damage. Muscle can manage without oxygen for a hour or more at least during surgery. If energy supply is so critically low why don't we see anyone with ME/CFS get heart failure, or slip into coma? It never happens.

 

Indeed.
I think this is what drives the ideas of conversion disorder (psych) or unconscious secondary gain causing a behavioural & then deconditioning-led disability.

 

You are absolutely right that there are many many possible points of "failure" within the multiple overlapping systems that go from glucose molecules to ATP ("usable energy").

It would be too simplistic to talk about a critical lack of "energy supply" (i.e. ATP). No one taken seriously in ME/CFS cell metabolism research is trying to claim this.

Failure at the vast majority of these points will probably not leave you with "insufficient" ATP--that would just result in widespread cell death, which we don't see. There's backup measures upon backup measures that try to prevent that from happening.

But there absolutely are "warning signals" that go up when a cell type is forced to rely on one of those backups more than it would in healthy conditions. A bit like a siren going off at the same time as the backup generator goes on.

In my view, the trick is to figure out which of these warning signals (or, possibly, just a side effect of running the backup system for an extended time) mediates ME/CFS symptoms.

 

Can you give examples of this idea?
Wha would force cells to rely on backups in ME/CFS?

 

Sure, feel free to look through my previous comments on this thread. I've discussed possible answers to those two questions several times, as well as the parts that have not been directly addressed yet in ME/CFS research (or research more broadly).

 

Can you not give a couple of quick examples again?
I spend hours each day trying to keep with all the discussions here and I am not immediately clear how what has gone before relates to my question here.

I guess the question is that if some signal tells the cells they have to use other pathways might that not be the 'warning signal' that tells the neuromuscular apparatus to reduce activity? Rather than an effect of the cells being forced by something else to shift pathways.

 

Wow I’ve never thought of it like this, such a good point!

One thing I notice is that if I’ve crashed or over-exerted too much then I will sometimes get laboured breathing for a few days. I’ll also be far less able to do cognitive tasks or handle as much sensory input for a similar amount of time so perhaps more extreme over-exertion affects the vital systems a bit. But as you say, if someone is very severe and unable to move, it is odd that their heart muscle still keeps going.

I thought your comment about viral myalgia was interesting. When I looked it up it seemed to cross over with myositis, which seems very similar to my experience (especially as I’ve had significant muscle wasting for the past year).

 

There are some brilliant descriptions of what it feel like before and after exertion!

To add my own experience to what’s already been said, I’ve noted some things that may/may not be useful. Not sure if they’re just ‘me’ things or actual ‘ME things’!:

• I noticed that my general strength has massively deteriorated as I’ve worsened (I’m severe, mostly bedbound now) and I believe my hand grip strength has too

• My arms seem much weaker than my legs despite using them far more. My upper body strength was poor as a kid too (long before the onset of ME) eg. I could never do the monkey bars at the park, always slithered off after one rung, whereas my half-sibling quickly completed them

• I can do small short movements a fair bit without issue eg. typing on phone, but larger movements are immediately fatiguing and I need to rest directly after then eg. lifting my arms behind my head to adjust a pillow

• Similarly, if I’m able to talk (generally better later in the day), I can talk for longer if I’m a) having a better energy day or b) if it’s about things that are in my head already or easy to chat about. My brain tires much more quickly with higher levels things eg. planning. In fact talking is one of the most exhausting things for me (but I am severe so don’t so much physically to compare I guess). The same sudden exhaustion as happens in my muscles can occur and the same ‘recovery’ strategy applies ie. rest as quick as possible when I feel I’m starting to over-exert and I’ll be able to carry on relatively soon again – push past and regret it!

• Being upright too long will cause over-exertion too (I have severe POTS)

• Timing is crucial - generally as the day goes on I’m more able in every way so I can do things much more easily later that I couldn’t have done/safely done earlier. On a bad day I may not be able to do something at all that I could’ve done the previous day

• When I’ve over-exerted, immediately after I usually need to lie still and wait until I’m able to function again – the degree to which I’ve over-exerted coupled with my baseline that day seems to determine how long I’ll take to ‘recover’ function again and move around/talk/think more clearly again

• If I’ve over-exerted quite a lot, I can get sore throat, achy sore joints, cramps, dizziness, mild nausea – a bit flu-like. Makes me wonder if there’s viral involvement somehow when that happens.

• I need to eat regularly and will feel when my body needs more food as I become less able. Soon after eating I feel more energetic though maybe an hour after a larger meal will make me lethargic. I have low ketones (occasionally moderate) show up on pee sticks if I go a long time without eating and had short chain fatty acids show up in both stool and organic acid tests.

• I noticed that at my current level, on an average day I can hold something or use my arms to eg. hug my partner and the strength will persist for around 10 secs and then it’s like the energy suddenly bottoms out and I can’t keep my arms in use and need to rest them. The ‘strength’ will come back quite quickly but if I were to push through I’d experience significant aching and weakness. I think the length of time I can use the muscles is often around the same – I don’t know if this corresponds to some process in the body generally or if that’s just me having a consistent limit

• I think the sudden exhaustion described above relates to some things that happened at the onset of my ME and when I was mild (perhaps it just happens a lot more easily and frequently now?), which I’ve detailed below. They feel very similar and I think there’s something about the mechanism of them that’s important in the pathology of ME given it seemed to literally be the onset of ME for me as well as occur when mild and progressively as I’ve worsened:
  
  
  • My ME ‘onset’ happened suddenly at the end of a physically and mentally taxing house move. I was packing a box when my energy suddenly vanished and I became immediately very physically slow and weak, so my partner had to slowly lead me to bed as I couldn’t do so myself. This had resolved by the next day but I was never the same following that and after 5 or so years mild, have progressively deteriorated. I wonder if this ‘event’ in my body set off a loop I couldn’t get out of (especially as I wasn’t aware I needed to pace myself for a long time)

• A year or two following ME onset, I experienced something similar two or three times – this was when I consider myself to have had mild ME (I was still working part-time and socialising out of the house though in hindsight, unknowingly pushing too much). I was walking quickly down the street when – perhaps 15-20 mins into 45 min walk – my body suddenly and involuntarily slowed as if wading through treacle. I couldn’t move any more quickly or forcefully and I may have felt a bit weak too. This lasted a few mins and then resolved as if it never happened – I walked slowly out of caution immediately after but my movement was ‘voluntary’ again.

​

 

Yes, I think would expect that.
But I don't know of good evidence of mitochondrial abnormality in muscle in very severe ME/CFS and people with severe ME/CFS not infrequently improve to a stable state of more moderate illness. Some have more than one bout severe illness too.

If ME/CFS was an intrinsic degenerative process in muscle (like a mitochondrial myopathy) then we would expect progressive deterioration without improvement. My picture of the time course I ME/CFS tells me that it must be due to a regulatory disturbance in a system that can shift either up or down through positive or negative feedback. The two systems that are complex enough for that are the central nervous system and the immune system. The relation to infection strongly suggests the immune system is involved.

As analogy, we see a fairly similar situation in RA, which is due to dysregulated antibody production. Many patients gradually deteriorate but remission is not rare and many stabilise even if they have damage.

If an immune reaction was occurring within muscle itself we would expect to get a raised CK and histopathology. Myasthenia is more subtle but even there, EM shows complement mediated changes at end plates.

Which makes me consider the likelihood that nothing much is going on at all in muscle other than that soluble immune signals or perhaps neural signals are inhibiting muscle function either by sensitising to pain and fatigue sensations or by shifting metabolic pathways in a way that prevents very vigorous use. I would like to know what happens in flu myalgia and I cannot find any useful data on PubMed.

Clearly if immune cytokines were adapted to suppressing skeletal muscle use - which would make sense to limit activity and spreading disease - they would be adapted to sparing heart tissue. So muscle mitochondria might be sensitive to certain cytokines and not heart.

So if the immune cytokines are the alarm signals we use in flu and which are being used without good reason in ME/CFS, do we need to invoke more alarm signals from altered metabolism in muscle? Why not just the cytokines that sensitise to pain and fatigue?

But PEM does need a bit more explanation here. If nothing much is going on in muscles why does use produce PEM? The puzzle for me in invoking the metabolic shift is that one would expect that to produce signals immediately. If you run 800 metres your muscles start to burn during the race. People with ME/CFS do describe being unable to continue doing things but time and again I hear the reason people give for the disability in severe ME/CFS as the increased occurrence of delayed PEM.

One possibility is that muscle use normally generates cytokine signals that encourage a period of macrophage and CD8 T cell surveillance in the next 48 hours - and we know that is likely to be the case from studying normal muscle training. Those cytokines may amplify the ones coming from the immune system.

Another possibility is that the danger/illness signalling response involves autonomic neural circuitry and the hypothalamus and is quite sophisticated in the way it allows muscle usage over time. It might well be designed to inhibit activity but in a flexible 'trade-off' way that allows one to struggle home to the cave from one's day tracking animals to eat and then collapse in a heap. A bit like your hypothalamus will allow you to overeat if the food is really tasty (that chocolate mousse) but will then tell you you shouldn't eat anything for 8 hours. Maybe muscle usage in the face of inhibitory signals racks up adrenaline and that allows inhibition to be overcome briefly but also feeds back on to the immune signals to ramp up further?

 

Just to let you know many things you mentioned not for the last two points is my experience too. Arms much weaker than legs, POTS, timing, need for carbs, etc. Although I'm mild.

I will say that I can transition carefully off carbs and onto keto if I don't exert in the transiton phase, and then on keto I seem to get pem less. I have seen the idea that 'backup' energy systems may be in play, including perhaps systems that are activated in innate immunity, many times, e. the idea we are burning amino acids as a priority.

And maybe overusing some of those backup systems creates strange metabolites in excess or depletes certain cofactors triggering downstream effects?

 

From experience I know I can always make it home. No matter how exhausted I am, or how much my muscles hurt.
And I have done weird things to build up that experience.
That could support the last paragraph you wrote @Jonathan Edwards.
The "punishment" is always worse after overdoing it too much.