Do ME symptoms fit with the faulty energy metabolism hypothesis?

unicorn7 said:
I do agree with this as a possibilty, but there is one thing that also doesn’t correspond with this: the peripheral effects on the muscles that you used. The muscle weakness is specific to the muscles that were used.
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This is not the case for me. When in PEM all my muscles are affected, I can hardly raise my arms when overdoing walking or thinking.
 
unicorn7 said:
I do agree with this as a possibilty, but there is one thing that also doesn’t correspond with this: the peripheral effects on the muscles that you used. The muscle weakness is specific to the muscles that were used.
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I actually think this may be consistent. It is purely anecdotal but if I am brewing on infection I may find that when I go to bed I am sore and stiff specifically in the muscles I used that day - maybe to cut a hedge or something. The cytokines that go around with febrile episodes seem to be able to potentiate signals that have been generated locally in peripheral tissues of a sort that normally you are unaware of. This would make biological sense in that the cytokines are there to tell the immune system to go out and look for tissues that might be harbouring damaging processes.
 
Mij said:
This is not the case for me. When in PEM all my muscles are affected, I can hardly raise my arms when overdoing walking or thinking.
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Yes, I agree, when in PEM, all muscles are affected. For me this does feel like a flu-like state which Jonathan Edwards describes. Full body burning, pain and illness.

During and right after after exertion, the muscles that I use are specifically affected with musculair fatigue and pain.

I’m mild now, pacing very well and get a lot of medication that has stopped most of the flu-like illness, but I still get the specific effect on the peripheral muscles. So, in my case, I see it as two separate problems.
 
My experience fits with @Trish ‘s description. (3 types).

One other thing that doesn’t seem to have been mentioned yet is the variation in stamina and the loading effect of multiple days worth of activity that triggers PEM.

Some days I have much more stamina than others. Now this could be an accumulation of things I’m not aware of. However I do keep a daily activity and symptom diary and it’s clear that one week I may be able to do 5 times the activity of a similar week previously. This occurs randomly outside of the PEM event.

I’m just wondering if this is a regulatory/signalling issue then why isn’t it a more consistent one?
 
arewenearlythereyet said:
One other thing that doesn’t seem to have been mentioned yet is the variation in stamina and the loading effect of multiple days worth of activity that triggers PEM.
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My energy expenditure is so well controlled at this point that I haven't had PEM for 3 years. It takes a lot discipline, and because I don't have responsibilities (family to take care of etc) in turn gives me the luxury to do pre emptive resting.
Man it's boring but it's the only thing that works!
 
Jonathan Edwards said:
So the problem is that a defect in ATP generation does not explain the triple problem. It might explain the first but not the others. That means we need another explanation as well and one always likes to minimise the number of explanations needed.
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Is defect really the right framing? It seems to be doing what it is programmed to do and that the problem is upstream. Same with the similar crushing fatigue from the flu, it's not a bug, it's a feature. It's part of a larger process that serves a purpose. Energy metabolism rather seems to be purposefully impaired, not defective, doing what it's supposed to be doing, just for the wrong reasons.
 
arewenearlythereyet said:
I’m just wondering if this is a regulatory/signalling issue then why isn’t it a more consistent one?
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This is a key point. If this was all hypothalamic/neural then I don't know of any superimposed cycles of sensitivity of the signalling system that would give the inconsistency - not that that means there aren't any. One thing about immune regulatory signals is that they have set time frames that can extend into a week or two at least. Maybe fluctuations are due to immune signal cycles weighing in and weighing out in a haphazard way.

I remember a patient with Reiter's syndrome whose inflammatory symptoms consisted of swelling of one knee every eight days. Some feedback cycle seemed to be stuck going round and round. Perhaps it's TGF beta or something.
 
I also find that I get cramp in the muscles I am trying to use - this happens much more quickly when I am more exhausted. I can get cramp in my abdominal muscles from a shortish car journey for example. I would have said a few years ago that my strength for a short-term effort was unaffected but that’s no longer true. It could be just ageing I suppose, or the inevitable result of loss of fitness over the years.
 
Jonathan Edwards said:
This is a key point. If this was all hypothalamic/neural then I don't know of any superimposed cycles of sensitivity of the signalling system that would give the inconsistency - not that that means there aren't any. One thing about immune regulatory signals is that they have set time frames that can extend into a week or two at least. Maybe fluctuations are due to immune signal cycles weighing in and weighing out in a haphazard way.

I remember a patient with Reiter's syndrome whose inflammatory symptoms consisted of swelling of one knee every eight days. Some feedback cycle seemed to be stuck going round and round. Perhaps it's TGF beta or something.
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Yes ..it feels like there is almost 2 signals conflicting with each other ....Or maybe there is a signal that is wanting some feedback to turn itself off..and it keeps on coming back because it hasn’t received the signal. So you are left with feeling better followed by feeling worse like an alarm that’s constantly in snooze mode. The fact that it’s so unpredictable though is odd.
 
Interesting thread. I think there are two good arguments raised against the hypothesis that PEM is due to a signaling issue such as when you have the flu. I would like to elaborate on them using my personal experience:
  • In my case, there seems to be a red line, an amount of activity or energy expenditure, that if exceeded, causes PEM. If I stay just below that level (or within the energy envelop if you will) there's virtually no PEM. In the case of the flu however, there seems to be no safe space, no energy envelope: you just feel a bit worse each time you try to do something. In my experience, PEM isn't just feeling worse after an activity but a relapse if you exceed a certain activity limit. To me, that suggests that something goes awry if and only if we try to spend that amount of energy or that amount of activity. It seems that some mechanism is set in motion when we try to do that.
  • When I have the flu, everything aches and I can't really exercise at all. With ME/CFS it's a bit different. The strange thing is that I can "exercise" for a very short time at almost full strength, but there is a very notable muscle fatiguability. So I still have strength and speed but my muscles tire extraordinary fast and I get muscle soreness like I had just finished the Tour de France. (I had this at the beginning of my illness when I was still quite fit so I'm confident it's not related to deconditioning). This may be true for only a subgroup of ME/CFS patients but I have heard that others have this as well and have seen it mentioned in the literature. So I can sprint 10-20 meters without a problem or help with lifting a heavy object, but I can't help with something like attaching ME-ribbons to leaflets because my muscles do not have the endurance. I think this phenomenon (do not know how common it is) is related to PEM and also difficult to explain with the hypothesis of central fatigue and signaling issues.
 
Michiel Tack said:
Interesting thread. I think there are two good arguments raised against the hypothesis that PEM is due to a signaling issue such as when you have the flu. I would like to elaborate on them using my personal experience:
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Yes but I am not suggesting that ME is having the flu. I am simply saying that the sort of signalling that occurs, probably with a different kinetic pattern, with flu, might explain PEM or feeling exhausted immediately after exertion, in a way that a simple failure to generate ATP would not. If you have no ATP you have no ATP now. Period. Symptoms later need to be explained through a mechanism that takes time to express itself.
 
Jonathan Edwards said:
Symptoms later need to be explained through a mechanism that takes time to express itself.
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It reminds me of the first time I went to the gym to do power training and I did a bit too much. The exercises were hard and difficult but at the time you don't feel like you're overexerting yourself. It's only the day after that your muscles are sore and you can't move like a normal person would. So that muscle soreness also comes afterward. (It's a bit of a misleading example because the muscle soreness I described above comes on during or immediately after exercise, it's the PEM that's delayed, at least in my case).

One other example I can think of is sunburn: you only feel it afterward, the next day for example.

That would be my immediate thought: that something goes wrong or is damaged when we exceed our activity limit and that this causes the body to respond with delayed symptom exacerbation. So a bit like what strategist suggested with having too much oxidative stress.
 
Just thinking off the top of my head here, I have no references for what I'm suggesting, and I may be suggesting something that doesn't make sense biologically.

What if the "something in the blood" is an attempt by an infection to hinder the immune system in its attempts to clear the infection? So the mitochondria, in response, get as efficient as possible in producing ATP, however for some people the immune system hinderance is still so strong that they are left bedbound, while for others there is sufficient energy for more functionality, but when there are higher energy demands on the body, this is the equivalent, on this already stressed energy production system, of very strenuous exercise, which, I believe, has a suppressive effect on the immune system. The immune system, being hindered further, is unable to keep the "something in the blood" under as much relative control as it had previously, and therefore there is even less energy available than previously and we have PEM? Perhaps the delay to PEM is because it takes time for the "something in the blood" to build up?

One issue with this idea - we don't have any evidence of ongoing infection (as far as I can recall). I'm sure there are others, so feel free to find the flaws in this idea. :)
 
Jonathan Edwards said:
In ME I am sceptical about any hypotheses that try to explain symptoms on the basis of impaired energy metabolism. The symptoms don't fit with that because they occur after the exertion more than during it.
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I understand what you mean here, and am sure you are right regarding the delay between cause and effect, a notion I am very familiar with in engineering. But I do wonder if it is a multi-faceted problem, because for my wife, her energy depletion pattern is has at least two apparent modes:
  1. As you say, PEM, that hits her some time after her exertion has finished.
  2. But also her energy availability depletes during her exercise, and there comes a point she simply cannot continue.
1 and 2 may of course be differing presentations of the same underlying mechanism ... or they may not. No idea.

It's as if whatever the exercise is messing up, the damage continues for some time even after she stops exercising; or maybe her body's recovery mechanisms are such as to make her feel completely cr*p whilst it does whatever it needs to. I'm not saying I think this is what is happening, just trying to give some insight into what it seems like.

As a very crude analogy, it is as my wife were powered by a battery with several major faults:
  1. It can only hold a fraction of its normal charge, no matter how long you charge it for.
  2. Its ability to source current is way less than it should be; as if its internal resistance is too high. Energy release is much too slow.
  3. It's charging capability is abysmal. Even though its maximum charge level is way too low, it still takes ages to get it even to there.
  4. As if the very act of recharging completely dominates and swamps everything else.
Again I emphasise I'm not trying to suggest this is how it is, it's just the best way I can get across what I observe.
 
My experience is similar to @Trish's except that phase 3 is divided into two: a first wave of symptoms at 4 hours post-overexertion followed by a second and more severe wave starting about 20 hours post-overexertion.

Also, again like @Trish, if I stop activity early enough I get away with only phases 1 & 2.

Symptoms in phases 1&2 for me are closely linked to the activity: walking causes leg & cardiopulmonary symptoms.

But symptoms in phase 3 are the whole random laundry list of everything: walking causes sore throat, insomnia, brain fog, etc etc

Based on those observations, I provisionally view phases 1&2 as "exercise intolerance" similar to what's found in many other illnesses. Whereas phase 3 is what I consider ME-specific PEM.

Speculatively seen through the lens of energy metabolism problems, could this be explained like this?

Phases 1 & 2 could be the direct result of an ATP-generation problem (possibly as a result of upstream blocks or signalling faults).

This ATP-generation problem also causes the cells to pump out some 'danger' signal (cytokines, miRNA, ATP fragments, exosomes, or another "factorX").

Once the cumulative amount of 'danger' signal reaches a certain level it triggers another, slower process that eventually leads to phase 3 PEM. So phase 3 could be an indirect result of the same ATP-generation problem.
 
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