A Thought Experiment on Muscles

[jnmaciuch]

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?

How would you use NMR to answer this question? I’ve been looking at ways to answer this question because it’s quite tricky to differentiate cytosolic vs mitochondrial NADH, and sticking an arm in an NMR machine never came up. Are you aware of an NMR technique that I haven’t found yet?

 

[Jonathan Edwards]

If that person is having PEM triggered by small amounts of activity regularly, how can you say it’s trivial for them?

The idea would be that it is a trivial metabolic demand. And if the problem is getting PEM later rather than not actually being able to do it at the time then it doesn't seem that there is actually a metabolic block, just a later signalling response.

 

[Jonathan Edwards]

if it’s not post-exertional,

I am assuming we are trying to understand a genuine post-exertional problem. Otherwise we have even less motivation to look for signals arising in muscles.

 

[Eddie]

I am assuming we are trying to understand a genuine post-exertional problem. Otherwise we have even less motivation to look for signals arising in muscles.

What's the rational for looking at muscles again? Presumably exertion impacts all sorts of biological systems including non muscular ones.

 

[Jonathan Edwards]

I’ve been looking at ways to answer this question because it’s quite tricky, and sticking an arm in an NMR machine never came up.

I think the DE Jones and Newton paper used MR spectroscopy - sticking the arm or leg in an NMR tube.

That is what the other David (A) Jones and Joan Round did in the 1980s. Whether they published much I don't know because they didn't find anything. You can pick up all sorts of peaks for metabolites from the spectrum without needing to do any imaging (you need to calibrate the region of interest of course).

The point being that if the metabolism is something to do with the disability in the severe at least one of the standard markers should show something, even if it is hard to measure NAD/NADH ratios directly.

 

[jnmaciuch]

I think the DE Jones and Newton paper used MR spectroscopy - sticking the arm or leg in an NMR tube.

That is what the other David (A) Jones and Joan Round did in the 1980s. Whether they published much I don't know because they didn't find anything. You can pick up all sorts of peaks for metabolites from the spectrum without needing to do any imaging (you need to calibrate the region of interest of course).

The point being that if the metabolism is something to do with the disability in the severe at least one of the standard markers should show something, even if it is hard to measure NAD/NADH ratios directly.

I am aware of how NMR works. If it was possible to answer my specific questions using NMR alone, then one of the many other researchers I've consulted with would probably have brought it up by now.

I can understand your dismissal, I agree that the link to immune signaling is a weak point that would need to be sorted out. However, in my view, the weakness are on par with other existing theories at this point. My hope is to refine my theory based on data, using what I have already put together as a promising starting point.

 

[Jonathan Edwards]

What's the rational for looking at muscles again? Presumably exertion impacts all sorts of biological systems including non muscular ones.

Well that is the question. The rationale for looking at muscles is that people associate 'fatigue' with energy and muscles. But the question that is begged is what is 'exertion'. Maybe it has much more todo with neural signalling and maybe feedback comes from all sorts of other tissues like proprioceptors or blood vessels or whatever.

My memory is that an important reason why we get short of breath when we run is that our proprioceptors notice legs going back and forward and tell the hindbrain to speed up signals to the phrenic nerve and so on. The hypothalamus does all sorts of extraordinary accounting procedures without our knowing. It tells you that another chocolate would make you feel overfull because it has predicted the glucose load from past experience.

 

[Jonathan Edwards]

one of the many other researchers I've consulted with would probably have brought it up by now.

Not so sure about that. It is a niche technology doing arm and leg MR spectroscopy and those who did it years ago probably don't do it much now because other diseases don't raise relevant questions. There probably aren't many machines around. People get very compartmentalised.

 

[Creekside]

In swimming you use a lot of muscles so I think the muscles are somehow involved in all of this.

I think muscles aren't directly involved in the mechanism of ME, but rather that signals from them can affect the ME mechanism. By this I mean that you can have the flu-like symptoms without muscle signals causing them. Likewise, you can get worse symptoms from signals due to a viral infection, but eliminating those signals only moves you back to baseline ME severity. I think ME has a variety of signals that can influence ME severity, but aren't part of the core ME mechanism.

 

[Creekside]

But we don't have any account of why 'really severe' people should have such a reduced metabolic capacity.

I must have missed those studies. What metabolic measures are abnormal? ATP production? Blood oxygen levels? Metabolic waste products?

 

[Jonathan Edwards]

I must have missed those studies.

No, or at least no more than I. I was referring to an assumed reduced metabolic capacity in the context of a constructed argument. I don't know of any evidence that there is such a reduction. We have no account of why they should have - if it is being proposed that they do.

 

[Sasha]

Those MRI scans with blobs show tiny fractional differences and all the rest is shown very misleadingly blank.

I haven't been entirely following this but would it be helpful to have MRI scans of brains or other bits of PwME? Many of us will have had them for various reasons and would be willing to provide them for a study.

 

[Sasha]

I haven't been entirely following this but would it be helpful to have MRI scans of brains or other bits of PwME? Many of us will have had them for various reasons and would be willing to provide them for a study.

By the time we've got to the MRI department, a lot of us will have been pretty PEM-ed up, or well on the way there.

 

[jnmaciuch]

Not so sure about that. It is a niche technology doing arm and leg MR spectroscopy and those who did it years ago probably don't do it much now because other diseases don't raise relevant questions. There probably aren't many machines around. People get very compartmentalised.

The point is that NMR alone, even done on an arm or leg, would not have the capability to answer my question.

It would likely not be enough to look at the absolute abundance of certain TCA cycle metabolites either. Even if you wanted to, you’d need to be able to target specific ones ahead of time, meaning you’d need to know where to look.

To answer my specific question, you’d need to specifically measure mitochondrial vs. cytosolic NADH ratios preferably in conditions of exertion, which you simply cannot distinguish via NMR.

 

[Eddie]

Well that is the question. The rationale for looking at muscles is that people associate 'fatigue' with energy and muscles. But the question that is begged is what is 'exertion'. Maybe it has much more todo with neural signalling and maybe feedback comes from all sorts of other tissues like proprioceptors or blood vessels or whatever.

Makes sense. I doubt exertion can result from a breakdown in muscle in a simple sense. When healthy I could go to the gym and work a specific muscle to the point of failure without feeling overly fatigued. Muscle breakdown is more closely related to soreness in my experience.

I would also guess that fatigue isn't necessarily tied to the amount of energy expended. I could feel much more tired following a shorter more intense exercise than a longer less intense exercise during which I would have burned many more calories. I'm not sure personal experience is good enough here though. It could be the case that longer exercise left me more 'fatigued' but lactic acid buildup made the shorter intense exercise more uncomfortable overall.

Either way, I think it would make sense for there to be some signaling path that limits unnecessary energy expenditure by causing an uncomfortable fatigue feeling. From an evolutionary perspective, humans with the ability to feel 'fatigue' might be more selective in what energetic tasks they pursue and thus are less wasteful in their use of energy. I don't think it even has to be tied that closely to actual energy use. If you only felt bad after using up the majority of your energy, then you might waste some of it and not have enough energy to secure your next meal.

 

[Kitty]

I doubt exertion can result from a breakdown in muscle in a simple sense.

No, me neither. It doesn't even make sense of the experience of it.

Go way over your activity threshold, then retire to bed exhausted to rest your muscles: so far, so sensible.

But then fail to get to sleep, and spend the whole night tossing and turning, fidgeting, trooping back and forth to the bathroom because your bladder's as hyperactive as your brain, then get up to read a book or use the computer because you're bored?

That doesn't happen when you're really exhausted. The muscles go heavy, then they go stiff, and when you lie down it's as if somebody's turned gravity up five notches. You're almost pinned to the bed. I remember this really clearly after the annual 25-mile night hike, which I did every year from starting secondary school. ME/CFS has never felt even vaguely like it.

Yet with PEM I can do so much less the next day. There were few after-effects from the hike other than waking with sore legs and a stiff back and shoulders, which needed a hot shower to persuade into action.

I think it would make sense for there to be some signaling path

Yup. I can't think of anything else that seems plausible.

 

[AliceLily]

Yes, I think a signaling problem too. I don't think there is any damage it's just that the use of the muscles triggers symptoms that make you feel very unwell and have to stop.

Before ME I use to go to the gym to tone up. With ME I can't get past the beginning of trying to tone.

It feels like there is some alarm system at play not allowing you to exert.

 

[Ravn]

I have always been a bit puzzled as to what people think might explain the change in results on the second day CPET in ME/CFS.

Grip strength, 10 repeats, wait an hour and have another go with 10 repeats. People with ME / PEM(?) will not be able to reach the same grip strength the second time around as they had an hour prior.

The CPET effect is a next day one. The handgrip effect is a next hour one. Question is are they the same, different, linked but different (e.g. early direct effect vs later downstream effect)?

I've never done CPET or any other repeat testing. For what it's worth, my n=1

The next-hour effect from physical exertion feels like it originates from muscle. It's limited to the muscles used, walking gives wobbly legs, using arms gives shaky arms. The affected muscles get the "lactic acid" burn and need more and more effort to move, like what happens when a healthy person really pushes themselves beyond their fitness level except at much lower levels of exertion. This already happened when I was very mild and very far from deconditioned. There's overall exhaustion but no feeling ill. This lasts a couple of hours so I would suspect, but haven't tested, that if you asked me to repeat the performance after 1 hour I wouldn't be able to. Possibly I would be able to again after 3 hours or any time before next day PEM hits but not sure on that one

The next-day effect is totally different, whole of body flu-like malaise with all manner of interesting add-on symptoms. All muscles, not just the ones used, feel heavy and hard to move but now without the "lactic acid" burn, and I don't get any other type of muscle pain either. In that state I assume I would not be able to repeat my day 1 performance but haven't tested. I would also assume an otherwise healthy person who actually had the flu would not be able to repeat their healthy day performance

Interestingly there's a difference between using legs and using arms

When I push my legs to short-term exhaustion I always also get next day PEM, no exception. Using my legs only a little too much, well short of going into "lactic acid" burn territory, also results in next day PEM. I think the same may also apply when using my core muscles

But I can use my arms to exhaustion without getting next day PEM (not sure about using arms to exhaustion repeatedly without adequate recovery between activities). Large muscle vs small muscle?

The straight lack of ATP explanation doesn't seem to fit my experience. Though it does feel like muscles could be directly involved in some other way in the 1 hour effect but not in the next day PEM, at least not directly. Maybe they're two totally separate processes. Maybe there is some sort of muscle damage, whatever that may be, which in turn causes abnormal reactions via two independent pathways. And the pathway that leads to next day PEM can also be fed into from OI issues or other types of exertion

I better stop, I'm really confusing myself now

 

[Jonathan Edwards]

To answer my specific question, you’d need to specifically measure mitochondrial vs. cytosolic NADH ratios preferably in conditions of exertion, which you simply cannot distinguish via NMR.

But if a shift of NADH ratio is having some relevant impact on symptoms either through weakness or unpleasant symptoms how is it doing that without at least some knock on effect on things at a larger scale within muscle?

 

[MSEsperanza]

Well that is the question. The rationale for looking at muscles is that people associate 'fatigue' with energy and muscles. But the question that is begged is what is 'exertion'

Would it be relevant to know whether people experience their muscle symptoms differently if their muscles are being moved passively, while they are lying down?

I can get shaking muscles and cramps, stiff limbs/ funny gait etc. e.g. both from doing stretching exercises/ repeated movements/ walking/ using my hands to prepare food, brush my teeth, typing on a keyboard etc and also remember to have got similar symptoms after a physiotherapist moved joints/stretched legs and arms (edit: mine not his) .

These are short-term symptoms though that usually go away within an hour rest and don't necessarily trigger PEM. It's more the other way round, that those symptoms will occur much sooner/ be heavier if I'm already having an PEM episode.

Edit: Not sure though whether these symptoms are due to another medical condition -- my doctors still suggest diverse potential suspects, while physiotherapists said it's a completely normal reaction (but the latter never saw my reactions because symptoms were there only shortly after I left their clinic -- so perhaps my account just didn't describe it well enough.).