Review Key Pathophysiological Role of Skeletal Muscle Disturbance in Post COVID and ME/CFS: Accumulated Evidence, Scheibenbogen et al, 2024

ABSTRACT

Background
Recent studies provide strong evidence for a key role of skeletal muscle pathophysiology in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). In a 2021 review article on the pathophysiology of ME/CFS, we postulated that hypoperfusion and ischemia can result in excessive sodium and calcium overload in skeletal muscles of ME/CFS patients to cause mitochondrial damage. Since then, experimental evidence has been provided that supports this concept.

Methods
We collect, summarize and discuss the current state of knowledge for the key role of skeletal muscle pathophysiology. We try to explain which risk factors and mechanisms are responsible for a subgroup of patients with post COVID syndrome (PCS) to develop ME/CFS (PC-ME/CFS).

Results
Mitochondrial dysfunction is a long-held assumption to explain cardinal symptoms of ME/CFS. However, mitochondrial dysfunction could not be convincingly shown in leukocytes. By contrast, recent studies provide strong evidence for mitochondrial dysfunction in skeletal muscle tissue in ME/CFS. An electron microscopy study could directly show damage of mitochondria in skeletal muscle of ME/CFS patients with a preferential subsarcolemmal localization but not in PCS. Another study shows signs of skeletal muscle damage and regeneration in biopsies taken one day after exercise in PC-ME/CFS. The simultaneous presence of necroses and signs of regeneration supports the concept of repeated damage. Other studies correlated diminished hand grip strength (HGS) with symptom severity and prognosis. A MRI study showed that intracellular sodium in muscles of ME/CFS patients is elevated and that levels correlate inversely with HGS. This finding corroborates our concept of sodium and consecutive calcium overload as cause of muscular and mitochondrial damage caused by enhanced proton-sodium exchange due to anaerobic metabolism and diminished activity of the sodium-potassium-ATPase. The histological investigations in ME/CFS exclude ischemia by microvascular obstruction, viral presence or immune myositis. The only known exercise-induced mechanism of damage left is sodium induced calcium overload. If ionic disturbance and mitochondrial dysfunction is severe enough the patient may be captured in a vicious circle. This energy deficit is the most likely cause of exertional intolerance and post exertional malaise and is further aggravated by exertion.

Conclusion
Based on this pathomechanism, future treatment approaches should focus on normalizing the cause of ionic disbalance. Current treatment strategies targeting hypoperfusion have the potential to improve the dysfunction of ion transporters.


https://onlinelibrary.wiley.com/doi/10.1002/jcsm.13669

 

Co-author Klaus Wirth is Chief Scientific Officer and Co-Founder of Mitodicure who wants to develop oral treatment for "chronic fatigue", MDC002.

The drug is discussed in this thread:
https://www.s4me.info/threads/mitodicure-gmbh-applies-for-3-patents-for-me-cfs-drugs.37970/

Website:
https://mitodicure.com/

 

Their conclusions don't match my experiences with ME. My "fatigue-like" symptom doesn't lessen my ability to use my muscles; it just makes me feel worse while I do that.

 

They are looking for funding.

 

They say "The histological investigations in ME/CFS exclude ischemia by microvascular obstruction" but this is not true, those were longcovid studies and they were just looking at microclots. Other causes of reduced microcirculation are discussed in the text.

The claim that "The only known exercise-induced mechanism of damage left is sodium induced calcium overload." is a non-sequitur.

 

This feels like a gigantic pivot from Scheibenbogen away from autoantibodies. Maybe overdue!?

But the hypothesis is far too strong given the state of the data.

Based on our current knowledge on the known causes of muscle damage related to exercise and malperfusion, diminished function of ion transporters and consecutive calcium overload-induced toxicity is the only explanation for tissue necroses and particularly mitochondrial damage in ME/CFS.

Rob Wust's necrotic findings in muscle could be caused by many things, my own bugbear is that it could be an out-of-control Unfolded Protein Response(UPR).

Exercise stresses the cell so it needs more proteins, and so requires the endoplasmic reticulum (ER) to fire up the unfolded protein response (UPR) which increases protein folding capacity. But Hwang 2023 found the UPR markers were all out of whack in me/cfs, despite apparent ER stress. Suggesting UPR doesn't work right. A failed UPR resolves via apoptosis or necrosis (i.e controlled or unconrolled cell death) after a number of hours. It's certainly possible that a dodgy UPR creates a big wave of cell death a while after exercise. (Which could also explain why PEM can arrive on a delay).

Anyway Klaus Wirth is smart but he's just got too many theories and not enough data; he is all hypothesis papers and reviews and not enough experiments.

 

So, I’ve been thinking a lot about LC’s relationship to ME/CFS. I have long covid, but not PEM. My guess is they are not the same disease, but LC is good at triggering ME/CFS. So, after COVID infection, one could have LC, LC and ME/CFS, or resolved LC with ongoing ME/CFS. If we assume this is correct, the question is why does LC trigger ME/CFS so often? It sure feels like there is a lot of smoke around hypoxia in both. Along those lines, I think the below article regarding impaired gas exchange (no paper yet) could fit nicely with the Scheilbenbogen paper.

https://www.cidrap.umn.edu/covid-19/sluggish-gas-exchange-lungs-may-be-involved-long-covid-brain-fog

It would go something like this:

Covid Infection > Lung Damage and Impaired Gas Exchange > Intermittent Hypoxia > Unfolded Protein Response > Yet to be determined feedback loop > ME/CFS

or

Covid Infection > Lung Damage and Impaired Gas Exchange > Intermittent Hypoxia > Lung injury recover > Resolution of LL

The big fork in the road would be whether LC hypoxia triggers whatever goes wrong in or around the unfolded protein response, which leads to ME/CFS.

 

I would also think that if Lung damage was an important part of the picture as hypothesised above you'd be more likely to see people which required ventilation and actually had severe lung damage to be more likely to develop ME/CFS. If anything it looks more like the LC-lung damage/PICS cohort/severe acute infection cohort is almost the opposite from the LC-ME/CFS like cohort (which would appear to be younger and more female dominated). Of course the data on this subject has been of poor standard, but that's the (possibly biased) picture I have sort of seen.

As @Trish mentions if we ignore Covid, it would appear that the most common viral trigger for ME/CFS would be EBV. That has nothing to do with lung-damage and I also don't think there have been any meaningful links to hypoxia. On the other hand in the above hypothesis one could actually ignore the initial infection and jump straight to lung damage which is presented as an intermediate step. In that case you'd also be likely to see a higher percentage of a certain population (for instance smokers) amongst ME/CFS patients than in the general population, which I don't think there is any evidence for.

So I would be inclined to guess that those that develop ME/CFS after Covid are more likely to be those people where lung damage plays no role rather than the opposite.