Pathophysiology of skeletal muscle disturbances in (ME/CFS): 2021, Wirth, Scheibenbogen

Abstract
Chronic Fatigue Syndrome or Myalgic Encephaloymelitis (ME/CFS) is a frequent debilitating disease with an enigmatic etiology. The finding of autoantibodies against ß2-adrenergic receptors (ß2AdR) prompted us to hypothesize that ß2AdR dysfunction is of critical importance in the pathophysiology of ME/CFS.

Our hypothesis published previously considers ME/CFS as a disease caused by a dysfunctional autonomic nervous system (ANS) system: sympathetic overactivity in the presence of vascular dysregulation by ß2AdR dysfunction causes predominance of vasoconstrictor influences in brain and skeletal muscles, which in the latter is opposed by the metabolically stimulated release of endogenous vasodilators (functional sympatholysis). An enigmatic bioenergetic disturbance in skeletal muscle strongly contributes to this release.

Excessive generation of these vasodilators with algesic properties and spillover into the systemic circulation could explain hypovolemia, suppression of renin (paradoxon) and the enigmatic symptoms. In this hypothesis paper the mechanisms underlying the energetic disturbance in muscles will be explained and merged with the first hypothesis.

The key information is that ß2AdR also stimulates the Na+/K+-ATPase in skeletal muscles. Appropriate muscular perfusion as well as function of the Na+/K+-ATPase determine muscle fatigability. We presume that dysfunction of the ß2AdR also leads to an insufficient stimulation of the Na+/K+-ATPase causing sodium overload which reverses the transport direction of the sodium-calcium exchanger (NCX) to import calcium instead of exporting it as is also known from the ischemia–reperfusion paradigm. The ensuing calcium overload affects the mitochondria, cytoplasmatic metabolism and the endothelium which further worsens the energetic situation (vicious circle) to explain postexertional malaise, exercise intolerance and chronification.

Reduced Na+/K+-ATPase activity is not the only cause for cellular sodium loading. In poor energetic situations increased proton production raises intracellular sodium via sodium-proton-exchanger subtype-1 (NHE1), the most important proton-extruder in skeletal muscle. Finally, sodium overload is due to diminished sodium outward transport and enhanced cellular sodium loading. As soon as this disturbance would have occurred in a severe manner the threshold for re-induction would be strongly lowered, mainly due to an upregulated NHE1, so that it could repeat at low levels of exercise, even by activities of everyday life, re-inducing mitochondrial, metabolic and vascular dysfunction to perpetuate the disease.

https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-021-02833-2

 

The thread on their previous paper is here:

A Unifying Hypothesis of the Pathophysiology of (ME/CFS)

 

So glad they've found where it comes from.

 

At least they are looking at ME symptoms to try to find a cause, rarer than you would expect.

 

That's actually a technical term, I just looked it up thinking it must be a typo

Is this the longest ME hypothesis paper ever published? Especially since it looks to be only one half of the full hypothesis.

Anyway, the biochemistry is way above my head, so no idea how much sense it makes. If anybody can boil it down to simpleton level I'd be very grateful.

However, I'm pleased to see the authors have clearly thought uncommonly hard about factors other than fatigue, for example they try to explain how a PEM threshold "switch" might work, or how our weird temperature regulation problems could fit into the picture. Heck, they even distinguish between fatigue, fatiguability and PEM. The hypothesis may turn out to be wrong but the shift away from the default reflex thinking of ME as primarily fatigue - which way too many biomedical researchers are still prone to - is a necessary step towards developing a hypothesis that really explains what's going on with us.

Unfortunately the authors didn't outline how their hypothesis could be tested (unless I missed it, I got a bit lost in all those very many words). But as far as I can make out the hypothesis predicts altered levels of intracellular sodium, potassium and calcium in muscle cells. Can this sort of thing be reliably tested?

 

I think it can, having the periodic paralyses and e.g. mutations in other ion channels in mind. You can do cellphysiological experiments where you measure ion fluxes etc.

This is a bit what you find in periodic paralysis, only that the Na+/K+-ATPase works as it should; in hypocalemic PP certain triggers that activate Na/K-ATPase lead to a shift of too much sodium out of the cell and too much potassium into the cell. In recent times, RYR1 mutations have come into focus as possible causes for hypoPP - here, the detailed mechanism isn't clear yet, but RYR1 and Cav1.1 communicate with each other; so here, calcium seems to play a role. In order to verify if a leaking RYR1 leads to hypoPP, you would have to do cellphysiological experiments that look whether Cav1.1 produces so-called omega-fluxes (which you find in PP).

But this is a different mechanism than proposed in the paper. In PP sth. else is different: the threshold for getting weakness/paralysis is higher than in healthy people, e.g. a pwPP gets paralysed with 3.5mmol/l or 4,1mmol/l, while a healthy person maybe would get paralysed with 2.5mmol/l.

In the hypothesis, these ion fluxes seem to be a "downstream effect".

 

Thanks for that. They'd set me up with this passage:

But not a typo! "The term misery perfusion refers to a condition of the cerebral circulation in which regional blood flow is reduced relative to regional metabolic demand for oxygen."

And yes, it's fascinating stuff. Dense, dense, fascinating stuff.

I do appreciate it, really. They could just look a bit further to find a good, proof reader.

Edit: No, it does seem to have been a typo and the one I found, above, seems to be just another instance of it... Unless there are two terms, the correct one seems to be "miserly perfusion", which makes more sense. But the mistaken -- or different? -- term seems to occur quite a bit. Non-native writers must find technical English a real nightmare.

 

ME= Misery Exertion.

 

If this is the meaning:

"Cerebral misery perfusion (CMP) is a condition where cerebral autoregulatory capacity is exhausted, and cerebral blood supply in insufficient to meet metabolic demand."

...then misery makes more sense to me? At least inasmuch as miserly is behavioural, whereas misery is situational and reflects inadequate resources as opposed to an active choice.

It doesn't half sound weird in a sentence, though!

 

Just realised I've fallen prey to my own bias with this and also the preceding paper from this team . I saw the authors' names and together with the mention of autoantibodies I mentally filed the hypothesis as just another poorly supported claim of autoimmunity.

I completely missed that their approach is much more nuanced than that. Yes, they refer to their previous findings of somewhat elevated autoantibodies but here they treat this in a similar way to how a finding of somewhat elevated frequency of a particular snp in GWAS* would be treated, not as proof that all pwME have autoimmunity, though a few might, nor that all pwME have a genetic disease, though a few might, but as a signal that may point to an important mechanism.

Specifically they used their previous finding of somewhat elevated autoantibodies against ß2-adrenergic receptors (ß2AdR) to more generally look at ß2AdR dysfunction from two angles:

1) Can ß2AdR dysfunction cause the ME symptom picture?

2) Are there pathways other than the autoantibodies that can cause ß2AdR dysfunction (or equivalent effects of disturbed vasoconstriction/vasodilation)?

They hypothesise that the answer to both is yes. Does this make sense to those of you who actually understand the biochemistry of it all?

*One of the hypothesised alternatives to autoantibodies against ß2AdR is polymorphisms of ß2AdR - will be interesting to see if they turn up in the GWAS study.

 

I likely have a fault with sodium handling via slc13a3 and low blood potassium

 

https://www.healthrising.org/blog/2...chronic-fatigue-syndrome-wirth-scheibenbogen/

Cort interviews Klaus Wirth

I also asked about ways to validate the hypothesis. Wirth replied that “Such complex disease hypotheses are usually not proven or disproven by single findings”, and that he thinks that “the final answer would come from the efficacy or inefficacy of drugs that are derived from the disease hypothesis. Effective drug principles derived from the disease hypothesis would prove the hypothesis.”

When I asked Wirth, who spent much of his career at a pharmaceutical company, about the treatment implications of the hypothesis, he reported that “potential pharmacological strategies can be derived from the hypothesis, and that they’re making an attempt to elaborate potential therapeutic strategies”.

​

 

The issue with this paper is that you have to accept the premise that pts with ME/CFS have beta adrenergic autoantibodies. This is frequently asserted but as far as I can tell totally unproven. There are papers from German researchers claiming this as far back as 2013 or so. If it’s so straightforward it would have been replicated by now.

 

It is somewhat strange that Dr Scheibenbogen continues to view autoantibodies against B2-adrenergic receptors as key to the pathophysiology of ME/CFS, considering that she contributed to the validation study on cohorts from two Swedish ME/CFS clinics. The study failed to find a correlation between patients' symptoms and the presence of autoantibodies to beta-adrenergic and muscarinic receptors. Further, only the cohort from the Gottfries clinic, not the one from Stora Skondal, had autoantibodies against B2-adrenergic receptors.

If my memory serves right, I recall seeing studies in patients with POTS showing the presence of these autoantibodies. Unless it was omitted that they also had post-exertional malaise, this rather seems to be evidence against their uniqueness to ME/CFS.

It should also be noted that Celltrend, the laboratory that has developed the screening assay and whose employees have collaborated with Dr Scheibenbogen, market this assay for POTS too.

 

Pretty conclusive evidence of these antibodies not being the cause of our symptoms. The fact that this test is being sold to patients is a disgrace. (Btw I don’t know if others here experience this but sometimes I look at an old thread and am shocked to see a post I made that I don’t recall writing and only the vaguest memory pops up of ever having read the paper. )