Muscle abnormalities worsen after post-exertional malaise in long COVID, 2023/4, Wüst, van Vugt, Appelman et al

[Simon M]

“This paper is being discussed on the Science for ME forum: https://s4me.info/threads/muscle-abnormalities-worsen-after-post-exertional-malaise-in-long-covid-2024-appelman-et-al.36769/“
>Rob Wüst: “Please remind me later. It’s a bit hectic today”
> can someone please remind him if I forget?]

Great result - don't know if you need a reminder still? I think RW would find the discussion interesting, particularly about creatine kinase and the recent post by @SNT Gatchaman

My understanding is that difference in energy consumption of a thinking brain and a resting brain is minimal – energy production alone does not explain cognitive impairment in ME/C

That's a good point about the modest impact of thinking on overall brain energy consumption. But maybe that's not quite the right way to look at it.

For muscles and exercise, especially for this study, the whole muscle is engaged. By contrast, the brain has a mass of functions: basic bodily control (brain stem), muscle motor control, vision, hearing etc. Plus 'awareness/consciousness circuits' and I'm not sure how much of the brain a thinking circuit would consume.

Perhaps with thinking it's a case of the weakest link in the chain breaking. If the network involved in thinking can't produce enough energy (i.e. the neurones involved can't) maybe particular thinking activity grinds to a halt while most of the brain sails on unperturbed.
@SNT Gatchaman (sorry to tag you twice in the same post) or others might know more about thining and energy use.

 

[Jonathan Edwards]

They did see the amyloid deposits (or whatever they might be staining with Thioflavin T) in LC before exercise. Not really a huge change after either (excepting those three outliers with very high densities).

The change looks pretty big to me - maybe a doubling in at least a good number of the higher scoring samples. This is new 'deposits' appearing within a day or so it seems.

This paper seems like it might be relevant to the amyloid in muscle question: TDP-43 and RNA form amyloid-like myo-granules in regenerating muscle

Except that that refers to aggregates in muscle cells and the staining in the current paper is nowhere near muscle cells - mostly in interstitial around vessels. Moreover it does not look much like polymerisation from solution. The structures are of a stereotyped conformation and size.

I think it would be worth trying to find out exactly where these are so that we can make some sort of sense of them.

 

[Simon M]

All of this, & indeed other recently published research, reminds me of why we need GWAS studies (like DecodeME) i.e. to focus research on the most promising areas. I think I recall Simon M posting that we've had decades of hypothesis drive research and it's got nowhere.

I'm still hoping that GWAS will provide powerful clues about what is causing ME/CFS (because genetics is ideally suited to identifying causation). That said, I think this study is very interesting: Ihad the impression that Wust and colleagues know what they are doing in this field (though I might be wrong).

it is crucially important that someone actually tries to replicate already existing research, which requires the research to be methodologically strong

Yes, poor replication attempts that fail further muddy the field. However. would still expect the original authors to follow up on their own work, and that we rarely see.

 

[Robert 1973]

Great result - don't know if you need a reminder still?

I’ll try to remember give Rob Wüst a nudge next week if he’s not joined by then.

 

[Kitty]

would still expect the original authors to follow up on their own work, and that we rarely see.

I wonder what the main reasons for that are? I suppose it might partly be because by the time a study has been completed or published, things have just moved on. But I also wonder about funding, where the results are interesting but not quite convincing enough to make a strong case for a larger grant.

 

[Sid]

I wonder what the main reasons for that are? I suppose it might partly be because by the time a study has been completed or published, things have just moved on. But I also wonder about funding, where the results are interesting but not quite convincing enough to make a strong case for a larger grant.

Funding is one factor. Another issue is staff moving on. A lot of small/exploratory studies in medicine aren't carried out by professional scientists but rather registrars (residents) who move from one post to the next every 6-12 months. There may be no one left with interest in the same topic in the next rotation. Another issue is perceived novelty. Everyone wants to publish something "novel". Replication studies are harder to publish in good journals.

 

[dave30th]

I would guess he is trying to lay the ground for the "of course there is something going on in the body but it's how the brain interprets it that is the problem" line of psychobabble hardware/software, 'definitely not cartesian dualism' waffle.

As, so the "inference" in that sense refers to the brain's "inference" or interpretation of these acknowledged post-exercise symptoms, which he considers to be DOMS, I guess.

 

[LarsSG]

The change looks pretty big to me - maybe a doubling in at least a good number of the higher scoring samples. This is new 'deposits' appearing within a day or so it seems.

Discussing this on Twitter so I made a plot showing the individual changes (I've removed one LC patient who didn't have both baseline and PEM data). Two figures here, same data as figure 4B for both, one separating controls and LC and one combining them.



This looks less meaningful to me than the figure in the paper suggests, as there are big increases for some in the LC group, but also significant decreases for others. Other than those three LC patients with huge increases, the main difference looks like a higher baseline in LC to me.

I think it would be worth trying to find out exactly where these are so that we can make some sort of sense of them.

Definitely.

 

[SNT Gatchaman]

Perhaps with thinking it's a case of the weakest link in the chain breaking. If the network involved in thinking can't produce enough energy (i.e. the neurones involved can't) maybe particular thinking activity grinds to a halt while most of the brain sails on unperturbed. [...] others might know more about thining and energy use.

From personal experience, I haven't had cognitive dysfunction (at least recognised). The closest is getting much less chatty, with loss of "resting everything's ok face". I definitely have the baseline exertion intolerance, rapid fatiguability and PEM with neurosensitive symptoms; along with POTS / OI / dysautonomia that worsens with (all too modest) over-exertion. In most modern ME criteria, cognitive dysfunction is not mandatory. This suggests to me that problems occurring at the interface between blood/microcirculation and muscle cells/mitochondria may be quite different from those affecting the brain.

Obviously the brain also has the blood-brain barrier to consider as well and it could be that the problem is opposite. While the muscles might be suffering from fuel starvation with evidence focal necrosis and regeneration, the brain might be allowing too much in through a dysfunctional BBB leading to neuroinflammation. The brain can't regenerate like muscles do and we've never seen evidence of hypoxic/ischaemic/metabolic damage on imaging, or indeed clinically. What little we do commonly see on current imaging (non-specifically) is increased numbers of and enlarged perivascular spaces (or white matter hyperintensities) which might suggest abnormality at the interface of brain parenchyma and its microcirculation.

From COVID-19 and Long COVID: Disruption of the Neurovascular Unit, Blood-Brain Barrier, and Tight Junctions (2023, The Neuroscientist) —

Transporting through the BBB is tightly controlled by barrier components not only physical (intercellular tight and adherens junctions) but metabolic (enzymes, transporters). Thus, the BBB acts as a gatekeeper and allows the passage of required substances only. Specifically, the BBB regulates brain nutrition, neurotransmitter levels, and macromolecule entry but also protects the brain from the entry of neurotoxins. The BBB further regulates ion homeostasis via ion channels and transporters that control the ionic levels for neuronal synaptic transmission activities. Thus, BBB dysfunction leads to several brain pathologies.

See also —

Recapitulation of pathophysiological features of AD in SARS-CoV-2 infected subjects (2023, eLife)

Blood-brain barrier disruption in Long COVID-associated cognitive impairment (2023, Preprint: Research Square)

Markers of blood-brain barrier disruption increase early and persistently in COVID-19 patients with neurological manifestations (2022, Frontiers in Immunology)

 

[Jonathan Edwards]

This looks less meaningful to me than the figure in the paper suggests, as there are big increases for some in the LC group, but also significant decreases for others.

Useful to see that.
I think more than anything it emphasises the sampling problems likely to play a big part in the results. Measures that jump about all over the place like that when the literature suggests they usually occur very gradually over months are worrying.

 

[Mij]

Wouldn't amyloid deposits found in heart and brain tissues make it harder for these organs to function properly? Are there different types of amyloids?

We can't obtain biopsies but it might also explain/contribute to delayed PEM, cognitive impairment/function, heart failure/dysfunction et

 

[Simon M]

From personal experience, I haven't had cognitive dysfunction (at least recognised). ...In most modern ME criteria, cognitive dysfunction is not mandatory. This suggests to me that problems occurring at the interface between blood/microcirculation and muscle cells/mitochondria may be quite different from those affecting the brain.

I'm very interested in the similarities or not between brain and body PEM triggers.

But I'm not sure your point necessarily follows given that ME is such a heterogenous illness and many researchers it's more than one illness. Neurocognitive issues are incredibly common, typically over 90%, including 93% in the initial data (fig 3) coming out of DecodeME. (I'd also be surprised if all pwme with neurocognitive symptoms have the same illness).

I think it's also worth noting that at least one survey has found that PEM is triggered for many patients by both physical and mental (cognitive/emotional) exertion. As someone in this group, PEM (and relapses) feel exactly the same whether it's due to a brain or body trigger. So instinctively I like the idea of an explanation that works equally in the brain and the body.

That said, I take your points and I'm interested in the evidence you posted about BBB issues in long Covid patients with neurocognitive issues (the only data I've seen on this suggested they are in a minority). BBB has been suggested numerous times as an issue in ME, but I think the data on it is thin.

Sorry not to provide any links, my health is rubbish and I'm not up to retrieving information. I do not have the best memory but am fairly confident about the findings I mentioned…

 

[Sean]

As someone in this group, PEM (and relapses) feel exactly the same whether it's a brain or body trigger. So instinctively I like the idea of an explanation that works equally in the brain and the body.

+1

 

[ahimsa]

Article from NPR:
A discovery in the muscles of long COVID patients may explain exercise troubles

https://www.npr.org/sections/health...exercise-post-exertional-malaise-mitochondria

Hit the gym. Get back in shape.

That's what many patients with long COVID are told when they talk of the crushing fatigue that envelops them after even a light bout of physical activity.

These symptoms of exhaustion, or post-exertional malaise as it's called, are a hallmark of long COVID and similar complex illnesses like chronic fatigue syndrome or ME/CFS.

The idea that exercise can help patients has proven difficult to shake — despite evidence suggesting this isn't merely a case of deconditioning that patients can overcome by pushing through the pain.

"I don't think the messaging has been strong enough," says David Putrino, the director of rehabilitation innovation for Mount Sinai Health System. "It is very clear that this is not a typical response to exercise."

Now research published this month in Nature Communications gives new weight to this assessment.

 

[rvallee]

The idea that exercise can help patients has proven difficult to shake — despite evidence suggesting this isn't merely a case of deconditioning that patients can overcome by pushing through the pain.

Even though it has failed miserably despite being used, without evidence, for 4 years, and even though this is obviously not deconditioning, if only for the simple fact that deconditioning does not fluctuate, and that most pwME or pwLC have never been extensively bed-bound. We are in an absurd state where it's plainly acknowledged that there are no treatments for LC or ME, but also there are standard treatments that are 100% safe and effective. It's insane!

There is something very wrong with how medicine holds on to plainly debunked nonsense and how almost no one has the courage to even say it out loud, let alone do something about it. None of this is normal. A single plane suffers a single incident without any injuries and an entire industry turns on a dime to inspect the whole fleet and rage about a few untightened bolts. This is how a professional industry reacts. And yet there were zero victims to this incident.

(For those out of the loop, an airplane had one its doors blown off after lift-off, depressurizing the cabin, because of missing bolts. The plane quickly diverted and safely landed at another airport).

Meanwhile medicine is simply incapable of taking this seriously. It's beyond baffling, it's crossed well over unreasonable into I-don't-even-know-what-to-call-it territory. Insane barely covers it, because this is calculated and systematically applied with systems of rules.

 

[Andy]

Trial By Error: Dutch Study Links PEM in Long Covid to Biological Abnormalities

A new study in Nature Communications, called “Muscle abnormalities worsen after post-exertional malaise in long COVID,” caused a stir after it was published last week. The investigators identified significant biological differences after an exercise challenge between long Covid (LC) patients with post-exertional malaise (PEM) and matched healthy controls who had recovered from acute bouts of COVID-19.

The study, which was conducted by a team of Dutch investigators, has received lots of media attention as well as buzz among patients, physicians and other researchers. It has also gotten some polite pushback from Professor Alan Carson, a neurologist and a leader of the movement to increase awareness of functional neurological disorder (FND) as well as a long-time associate of Professor Michael Sharpe, a co-author of the discredited and arguably fraudulent PACE trial. Professor Carson weighed in on X—formerly known as Twitter—and raised two issues, both of which seemed to be irrelevant and non-responsive to the actual findings. As a result, his comments seemed like non-sequiturs and left the impression that he hadn’t read or understood the research in question.

https://virology.ws/2024/01/09/tria...em-in-long-covid-to-biological-abnormalities/

 

[poetinsf]

And what does this study say about PEM from mental exertion? The short answer is: it doesn't. Since PEM from mental exertion is the same, and nobody said they are different afaik, you have to wonder how a mental exertion could bring about muscle damage or amyloid deposit. I'll have to see a replication before I can get excited about it.

 

[Jonathan Edwards]

And what does this study say about PEM from mental exertion? The short answer is: it doesn't.

I agree. I don't see how these findings can be taken as 'accounting for PEM'.

 

[Hoopoe]

And what does this study say about PEM from mental exertion? The short answer is: it doesn't. Since PEM from mental exertion is the same, and nobody said they are different afaik

They feel different to me.

 

[Kitty]

They feel different to me.

And to me, I've never known cognitive exertion provoke the flu-type symptoms or muscle pain that physical exertion does. Might be slightly beside the point, though, as the study seems to have involved an exercise challenge.