Do ME symptoms fit with the faulty energy metabolism hypothesis?

[Perrier]

This might be too long for some to read. Sorry for this.

Yes, there are similarities to having a flu and overdoing and the flu worsens severely. Except that the ME PEM has many more symptoms,

The problem with very severe and severe ME is that you can do very little without triggering PEM and so you are on a rollercoaster of PEM on top of PEM. This level of ME is not a comfortable one, there's a lot of desperation and trying to hang in there. You are mostly suffering day in and day out with symptoms that are very loud and never-ending and from hour to hour you don't know what you are going to experience next symptom-wise because there are so many coming and going and some stay longer than others, symptoms added on top of other ones.

I agree with others about the 3 different PEMs. I experience the instant, delayed and the accumulation PEM.

Thank you Rosie for an excellent description. I would have to say that the last paragraph, where you describe severe ME is what I am watching daily here at home. There is no remitting of symptoms whatsoever, ever. Upon lying still like a statue the symptoms may go down, but they never abate. Then when standing up is attempted, or bathing, the horror of high PEM just reemerges. It is very hard to go on living with this level of symptoms. It leads to awful spiritual distress.

 

[Jaybee00]

@Jonathan Edwards

As mentioned above, these mitochondria data come from a presentation by Prof. Paul Fisher, https://scholars.latrobe.edu.au/display/prfisher, the video of which can be found here https://mecfsconference.org.au/videos/paulfisher/ If I may, I would like to encourage you to watch this video, so that we can obtain your opinion/feedback on his research. Unfortunately, he asked the camera-person, not to video some of his data slides, because he felt that showing video of his slides might jeopardize his chances of having his publication accepted. I don't think that this belief is in fact correct. Most journals will let you prepublish your data on the web, and this will not jeopardize the formal publication of your article. Some exceptions are JAMA and NEJM see here

https://en.wikipedia.org/wiki/List_of_academic_journals_by_preprint_policy

 

[Jonathan Edwards]

I think I need to see actual data to be able to make anything of this. Fisher seems to be studying cultured lymphoblasts. I am puzzled as to why these should show any stable mitochondrial abnormality away from plasma factors. ME/C~FS is not congenital so any abnormal activity would need to reflect some sort of stable acquired transcriptional shift. I am interested to see what gets published from this but so far I don't get a clear idea of what is being proposed.

 

[AliceLily]

Thank you Rosie for an excellent description. I would have to say that the last paragraph, where you describe severe ME is what I am watching daily here at home. There is no remitting of symptoms whatsoever, ever. Upon lying still like a statue the symptoms may go down, but they never abate. Then when standing up is attempted, or bathing, the horror of high PEM just reemerges. It is very hard to go on living with this level of symptoms. It leads to awful spiritual distress.

@Perrier Thanks for being a wonderful Mum. I have my wonderful Mum with me too. I didn't think I would ever come out of those severe years because it just went on and on, year after year without any seeming improvement. But after many years I started to notice some change.

Hugs to you and your daughter.

 

[Hip]

This paper says that type I interferons both down-regulate mitochondrial gene expression, as well as inhibiting mitochondrial functioning.

Thus if ME/CFS patients have elevated levels of interferon due to chronic low-level intracellular infection or due to dysfunctional immune activation, then you might expect an energy depletion.

This paper perhaps suggests that the fatigue experienced during infections such as the flu, as well as ME/CFS, may be a direct result of a physical energy shortage in the cells, due to the interferon-induced mitochondrial inhibition.



One could speculate that PEM may then be a secondary phenomenon that arises (perhaps via the ATP-destruction mechanism proposed by Myhill et al) once mitochondria are down-regulated by interferon.

In other words, because energy resources are already stretched due to mitochondrial down-regulation, perhaps during times of major exertion this leads to the Myhill et al emergency cannibalization of ATP molecules, in order to extract every last ounce of energy from them to supply the exertion, which then results in an ATP shortage as well as mitochondrial inhibition, leading to PEM.

 

[Barry]

The symptom pattern sounds to me much more like what happens when developing a viral infection like flu. You find you cannot do a normal task, feel worse after and then worse still later and cannot begin to try again. You end up lying in bed not wanting to see or hear anything. And none of that is due to faulty energy metabolism. As far as we know it is due to signals like interferons blocking the ability to use muscles.

Is this saying that, if correct, the energy conversion and transport mechanisms could all be intact and OK, but that regulatory control of them could be screwed up?

 

[Jonathan Edwards]

Is this saying that, if correct, the energy conversion and transport mechanisms could all be intact and OK, but that regulatory control of them could be screwed up?

I think it is more likely that regulatory control of voluntary muscle use is screwed up. If you twist your knee you cannot voluntarily contract muscles because the nervous system prevents it in advance. So the problem is not about energy production. It might be that energy production is also blocked by cytokine driven signals but if there was a genuine lack of ATP I am surprised nobody has picked it up on MR spectroscopy of muscle in the past.

 

[obeat]

@Jonathan Edwards so what sort of research would need to be done in ME to show this signal blocking?

 

[Barry]

A question @Jonathan Edwards please. When you have flu, am I right in thinking that much of the fatigue experience is because the body's defences are diverting urgently needed to energy away from normal use, to "combat duties"; and that there would be deliberate control signalling needed to implement this energy diversion? Are you thinking this sort of thing might be happening to pwME - the energy is there but cannot be utilised properly? Either because the body mistakenly thinks there is a bug it needs to fight off? Or just possibly that maybe there really is something it does have to fight off, but no one has yet found?

 

[Jonathan Edwards]

@Jonathan Edwards so what sort of research would need to be done in ME to show this signal blocking?

A simple thing to do is to stimulate the muscle directly with electricity, which will overcome neural inhibitory signals. It is that sort of experiment that led people to think the problem is central some time back. The experiments may not have been done well though.

The other thing is to look with MR spectroscopy during activity to see whether limits of activity are related to specific biochemical changes. There may be difficulties with this but it seems to me a much more sensible approach to trying to understand muscle fatiguability than looking at blood cells, where there are all sorts of confounding factors involved.

 

[Jonathan Edwards]

When you have flu, am I right in thinking that much of the fatigue experience is because the body's defences are diverting urgently needed to energy away from normal use, to "combat duties"; and that there would be deliberate control signalling needed to implement this energy diversion?

Roughly yes. But I think it may be too simple to talk of energy as in ATP availability. During infection the body wastes vast amounts of energy raising the body temperature. The retiring to bed response ('illness behaviour') may be designed to prevent all sorts of situations that might distract from killing viruses. In order to kill viruses the body may have to switch off tissue regeneration mechanisms of the sort necessary every day after running after food across the savanna. An important part of blocking viruses is to block DNA replication of your own.

 

[Barry]

A simple thing to do is to stimulate the muscle directly with electricity, which will overcome neural inhibitory signals. It is that sort of experiment that led people to think the problem is central some time back. The experiments may not have been done well though.

If this is true then of course it would be good to establish. But then how do you go about clarifying that the neural inhibitory signals are not down to some mental condition that can be fixed by going round in circles and chanting stuff, but instead a real physical shortcoming, be it in the brain, body, whatever?

 

[Jonathan Edwards]

If this is true then of course it would be good to establish. But then how do you go about clarifying that the neural inhibitory signals are not down to some mental condition that can be fixed by going round in circles and chanting stuff, but instead a real physical shortcoming, be it in the brain, body, whatever?

Anything that alters our behaviour has to be a real physical shortcoming. All mental events are physically mediated as far as I am concerned. I know what you mean but I think it is a false way of categorising - the same mistake that the BPS people make, whilst denying that they do.

The key thing is whether or not it is a process amenable to going round in circles and chanting or listening to someone in a blue cardigan. So far we have no evidence that it is.

 

[Sasha]

A simple thing to do is to stimulate the muscle directly with electricity, which will overcome neural inhibitory signals. It is that sort of experiment that led people to think the problem is central some time back. The experiments may not have been done well though.

The other thing is to look with MR spectroscopy during activity to see whether limits of activity are related to specific biochemical changes. There may be difficulties with this but it seems to me a much more sensible approach to trying to understand muscle fatiguability than looking at blood cells, where there are all sorts of confounding factors involved.

Is anyone planning on doing any of this stuff?

 

[Amw66]

A simple thing to do is to stimulate the muscle directly with electricity, which will overcome neural inhibitory signals. It is that sort of experiment that led people to think the problem is central some time back. The experiments may not have been done well though.

The other thing is to look with MR spectroscopy during activity to see whether limits of activity are related to specific biochemical changes. There may be difficulties with this but it seems to me a much more sensible approach to trying to understand muscle fatiguability than looking at blood cells, where there are all sorts of confounding factors involved.

To be demonstrative should this not be done before and 24, 48 hours after exercise ?

 

[Amw66]

Roughly yes. But I think it may be too simple to talk of energy as in ATP availability. During infection the body wastes vast amounts of energy raising the body temperature. The retiring to bed response ('illness behaviour') may be designed to prevent all sorts of situations that might distract from killing viruses. In order to kill viruses the body may have to switch off tissue regeneration mechanisms of the sort necessary every day after running after food across the savanna. An important part of blocking viruses is to block DNA replication of your own.

Would signalling not be more to do with uncoupling the supply and demand side of ATP production ?

 

[obeat]

What are the muscle physiology boffins @Nottingham who are collaborating with Harvard going to do?

 

[Jonathan Edwards]

Is anyone planning on doing any of this stuff?

Not that I know of. The muscle MR spectroscopy group from UCL are all disbanded and retired now.

What are the muscle physiology boffins @Nottingham who are collaborating with Harvard going to do?

Maybe this sort of thing but I know very little about them.

To be demonstrative should this not be done before and 24, 48 hours after exercise ?

I guess one would want to do something like the 2 day CPET - to look at muscle biochemistry in vivo alongside the cardiorespiratory data.

Would signalling not be more to do with uncoupling the supply and demand side of ATP production ?

I think the signalling may control things at a much higher level - nothing to do with how much ATP you have. Just as the accelerator in your car operates irrespective of how full your petrol tank is.

 

[BruceInOz]

I think it is more likely that regulatory control of voluntary muscle use is screwed up.

How does this explain the cognitive symptoms? For example, if I'm doing basically ok but maybe a bit close to the top of the energy envelope and then encounter certain cognitive challenges (for example, searching for something in a cluttered drawer or trying to find the words to explain something) then my brain just wants to shut down and my legs get all achey like I've been on them rushed around all day.

 

[Jonathan Edwards]

How does this explain the cognitive symptoms? For example, if I'm doing basically ok but maybe a bit close to the top of the energy envelope and then encounter certain cognitive challenges (for example, searching for something in a cluttered drawer or trying to find the words to explain something) then my brain just wants to shut down and my legs get all achey like I've been on them rushed around all day.

It seems to me likely that the brain can orchestrate both a desire to stop having to think and aching in the muscles through efferent neural signals modulating afferent sensory signals. Maybe it is a bit like the opposite of the effect that allows soldiers who lose a limb to carry on home without bothering about it because they are so focused on other things. Except that the idea would be that in ME what is out of synch is not the psychological context but the way the regulatory signalling apparatus is functioning.

Maybe an analogy is cataplexy in narcolepsy subjects. A quite ordinary weak joke, if it is enough to make them laugh at the time, can produce complete paralysis.