Preprint Indistinguishable mitochondrial phenotypes after exposure of healthy myoblasts to myalgic encephalomyelitis or control serum, 2025, Ryback et al

[Jonathan Edwards]

'Neural inhibitory signals’ could be, at least in part, downstream of respiratory metabolic failure in neural tissue?

I am afraid I think that is totally implausible. Metabolic failure in neural tissue leads to confusion, coma, stroke and death.

I have said it before but maybe need to keep saying it. Coming to ME/CFS after having been a physician all my life it was clear to me that the symptoms members describe in great detail and very eloquently sound absolutely nothing like the effects of respiratory metabolic failure we see in all sorts of illnesses - whether general failure in terminal heart failure or local failure in end stage muscle disease.

I know that it feels like 'energy failure' and a whole culture has grown up around that, but I am not alone in my view. When I talked to mitochondrial or muscle experts who have wide experience and then encounter ME/CFS they say exactly the same.

 

[hotblack]

I'm concerned some are interpreting this study to say that there is nothing wrong with mitochondria of PwME, or there is nothing in patient serum affecting patient cells. That is not what this study shows.

Most people here probably have a good idea of the bigger research picture and I know I’ve been keenly following the work in Surrey you mention (recent discussion in this thread ).

@Simon M did a good overview of the other studies a while back too.

I don’t think people are misunderstanding more showing trust in a study that is clear, concise and focussed, without some of the fuzziness or fishing we sometimes see. Hopefully that allays some of your concerns.

 

[DMissa]

How much would the specifics of the target muscle cells change things? There seem to be differences in absolute values compared to Fluge, presumably different people’s myoblasts perform a bit differently?

The absolute OCR are higher in Fluge but this varies with the seahorse model used so I wouldn’t worry about it too much. I’ve worked with multiple models and the absolute values definitely do vary even with the same samples in side by side comparison and cell numbers adjusted to well area.

As a general thing, it’s the bottom end of a seahorse output that is more of a thing to keep an eye out for. I’ve seen uncontaminated background wells (no cells) on different models of seahorse machine go to potentially +\- ~10-15pmol/min from 0. Some cell types produce readings smaller than this range depending on the stage of the assay. Something like max OCR is “safer” because as you can see in Audrey’s work here it’s way above this background noise danger zone (ie 25-100 ish vs 0-10 ish). And it is just as well that max OCR is the variable of interest here (and I am sure these factors will have informed the reasoning of both the original study and this one). Other parameters in low oxidative cell types, like post-oligomycin, I would generally be more cautious about interpreting due to where the numbers typically sit, but it’s not important to the interpretation or point of this particular study (and the authors here astutely didn’t stray into this).

^(These are general comments to help people make sense of seahorse data when they see it pop up)

 

[hotblack]

The absolute OCR are higher in Fluge but this varies with the seahorse model used so I wouldn’t worry about it too much.

Really useful insights, thanks @DMissa

 

[jnmaciuch]

edit: removed and sent in email, the extreme volume of highly technical questions is probably not appropriate to put you through answering on a forum (lol!! )

I’ll second @hotblack’s post and say that if you and @chillier feel comfortable sharing, I’d love to read the back and forth. I have general familiarity with Seahorse but have not been able to perform it myself so far due to physical limitations. Would greatly appreciate the opportunity to be exposed to more technical details!

 

[Creekside]

I know that it feels like 'energy failure'

I wonder just how few brain cells functioning improperly could produce that feeling, even to making a person bed-bound. I know the brain has specific variants of cells in specific locations, so it would be easy for such cell dysfunction (transport tubes blocked by molecules, or whatever) to not be noticed by examinations so far.

 

[Sean]

I know that it feels like 'energy failure' and a whole culture has grown up around that, but I am not alone in my view.

Feels to me more like a problem with trying to use energy.

The difference between a battery not being charged, and it being charged but there being a break in the cable connecting it to the rest of the circuit.

 

[Jonathan Edwards]

I wonder just how few brain cells functioning improperly could produce that feeling, even to making a person bed-bound.

The brain stem and hypothalamic nuclei that deal with this sort of thing (sleep, hunger etc.) are no more than a few millimetres across. If just a hundred cells shifted their synaptic weightings - which would be completely invisible - you might be bed bound. But I doubt that the problem is just in the brain. Some seriously inappropriate signals must be coming in from somewhere.

 

[jnmaciuch]

To me it feels like I'm just getting way less miles per gallon out of my energy, and at a certain point I have to tap into "emergency reserves", which corresponds to that "push of adrenaline" feeling that so many describe. The battery starts out charged, but everything seems more costly for me than it did before I got sick. That felt to be the biggest difference when I tried my malic acid--it was like for the first time I was getting proper mileage, and things were "costing" the amount of energy that they actually should

[Edit: actually one of the most consistent findings for me was that I could get much more "mileage" by eating a high fat high calorie meal before activity. There's something about fat being a preferred fuel source, at least for me]

 

[Simon M]

These are just 4 examples of promising work that still needs to be replicated in larger sample sizes and by independant groups.

I think that's the key point: we need replication.

These are all interesting findings. But there are hundreds, if not thousands, of interesting findings out there. Almost none of them have been replicated, so we can't rely on them.

What we need are more independent replications, like this one. If something replicates, that's great. If not, I don't think we can rely it.

Until we have replication, the findings are interesting and promising. But we need more.

Hopefully, DecodeME results will provide some solid findings. That has the advantage of being a very thorough and rigourous study. But ultimately, any findings it makes also need to be replicated.

 

[Hoopoe]

I know that it feels like 'energy failure' and a whole culture has grown up around that, but I am not alone in my view. When I talked to mitochondrial or muscle experts who have wide experience and then encounter ME/CFS they say exactly the same.

An alternative to energy failure might be:

I feel exhausted and doing activity becomes uncomfortable due a specific sensation that is very hard to overcome for long. That sensation feels like I'm causing or risk causing harm to myself if I continue. It is effective at limiting activity.

This sort of description is probably how the CBT/GET people decided that the problem was fear-avoidance.

But this is not a fear or anxiety. It's a physical sensation, not the emotion of panic, worry that something might happen. I suspect we patients are all used to ignoring this sensation as much we can.

 

[TamaraRC]

Sad that that this paper couldn't find the same result of 'something in the blood' but good that they checked anyway.

Not at all sad, I would say. It is part of making sense of things - some of which were not making a lot of sense previously.

Since this study used serum rather than plasma, could it be that certain factors potentially involved in earlier ‘something in the blood’ findings were lost or altered during clotting? I’m wondering if a plasma-based assay might still reveal effects that serum can’t capture.

 

[Jonathan Edwards]

I’m wondering if a plasma-based assay might still reveal effects that serum can’t capture.

It is conceivable but it is has never seemed very likely to me that the assays that claimed to find 'something in the blood' were telling us anything reliable or useful. There may well be something in ME/CFS blood involved in generating symptoms but I think it highly unlikely that that would be through altering muscle cell metabolism.

 

[wigglethemouse]

I’m wondering if a plasma-based assay might still reveal effects that serum can’t capture.

Comment on previous work on muscle cells + plasma at Oxford. They felt complement in plasma had a masking effect.

 

[Jonathan Edwards]

I was not aware that complement was lost when plasma is converted to serum. Maybe it is but I am a bit surprised if so.

 

[Hutan]

I'd suggest using ME/CFS throughout, though, not ME or myalgic encephalomyelitis (except when mentioning the ME Association, of course).

Why use ME/CFS? I think we have to stop the fatigue from being used in any form as it confuses the symptoms and the issue which is PEM.

Because PEM is the defining feature of ME/CFS, as established by CCC in 2003, and ME was a name for a neurological syndrome we now know never existed (or at least has not been seen for seventy years). Unless we move on from past mistakes we will never develop a scientific basis that can provide treatments.

Quoting these posts from elsewhere, in defence of a suggestion to use ME/CFS throughout the paper and the title. Currently, ME/CFS is only used once in the abstract of this paper, elsewhere the disease is referred to as ME. It's a minor point and I certainly don't want to resurrect a naming debate. But I would have thought ME/CFS papers these days would use ME/CFS. A recent paper also from the Ponting team used ME/CFS throughout.

 

[Jonathan Edwards]

A recent paper also from the Ponting team used ME/CFS throughout.

That is because I told Chris to change it at the preprint stage! And he saw the point.

Audrey was criticised for using ME at her presentation at UCL in January. The critic was a physician who treats ME/CFS who made the point that nobody would take her seriously unless she used ME/CFS, because of all the mess created by Simon Wessely around ME.

So this is a preprint too, @chillier !

 

[chillier]

That is because I told Chris to change it at the preprint stage! And he saw the point.

Audrey was criticised for using ME at her presentation at UCL in January. The critic was a physician who treats ME/CFS who made the point that nobody would take her seriously unless she used ME/CFS, because of all the mess created by Simon Wessely around ME.

So this is a preprint too, @chillier !

@Jonathan Edwards I want to push back on that point about the critic at UCL. I wasn't at the UCL meeting of course but I don't get the impression this person was acting in good faith. The tone was aggressive to the point that people came up to Audrey after her talk to apologise for his behaviour. We are never going to convince people like this to take us seriously. All we can do is do our work earnestly and transparently and make it clear that we are definitely referring to the same clinical syndrome whatever you want to call it.

We introduce the disease as Myalgic Encephalomyelitis (ME) / Chronic Fatigue syndrome at the beginning and subsequently use ME as an acronym. I think we make it pretty clear that we're referring to the same thing, but we can change this as it goes through review if there is a strong feeling about this. The main thing is to make sure as much as possible that people are thinking about the science rather than the name.