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

Pyrrhus

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Pathophysiology of skeletal muscle disturbances in ME/CFS (Wirth and Scheibenbogen, 2021)
Klaus J. Wirth & Carmen Scheibenbogen
https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-021-02833-2

A paper describing how their previous hypothesis has now been augmented with an additional hypothesis.

Excerpt:
Wirth and Scheibenbogen 2021 said:
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.
(spacing added for readability)
 
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msf

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"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."

Weren't these autoantibodies only found in about 20-30% of patients?
 

Revel

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Weren't these autoantibodies only found in about 20-30% of patients?
Study subjects may all identify as having ME/CFS but, without an accurate, universally accepted diagnostic test, nobody can be certain that they share exactly the same illness.

We only have to look at the diverse experiences of PR members to realize that "ME/CFS" is, to quote my GP, a bit of an "umbrella diagnosis" at present.

Then we have folks like Prof. Paul Garner, who went public with his diagnosis of ME/CFS following a bout of COVID-19, and has subsequently been even more vocal about his "cure" after embracing the power of GET and positive thinking. :cautious:

Diagnosis of ME/CFS is a minefield . . . and a mess.

Perhaps the 20-30% represented a particular ME/CFS subset?
 

Pearshaped

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@Revel you mean his selfdiagnosis..😆
I think this is a subset and not a reliable biomarker but I could be wrong of course.
Im not positive for B2adrenergic Receptor antibodies, but Alpha1 and others.. so Im confused now😳🧐
But anyway interesting.
 
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This is good, in the absence of very obvious clues as to whats happening it seems very important to generate such speculative hypothesis, then they can set to work on disproving it, then generate a wholly different one and try again, have many groups doing this around the world. Would be interesting to know how commonly tested for is this ß2AdR, how many users here know whether they have the autoantibody or not. ME/CFS is confirmed to be umbrella disease I would say, due to the emergence of the CCI patients being indistinguishable in symptom presentation yet fully treatable. For all we know it could be 20% this thing, 20% HHV-6 mito fragmentation / CDR, 40% CCI or other as yet unknown explanation/s. The CCI thing really bears further investigation as to how the PEM etc is being generated in that scenario, it could give clues, but that form is so hard to discover and it seems unethical to experiment on them rather than just do the corrective surgery asap, maybe they could induce CCI in animals ? do animals even get me/cfs ? if not why not ? maybe they could also expose animals to ß2AdR AA and see if that is sufficient to induce full on me/cfs ?
 

Learner1

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Would be interesting to know how commonly tested for is this ß2AdR, how many users here know whether they have the autoantibody or not.
Of the people I am aware of who have done the CellTrend test, pretty much everyone has had positive results to at least one or two antibodies. Several of us have A1 and M4 which have been related to POTS, buy not the beta antibodies.
ME/CFS is confirmed to be umbrella disease I would say, due to the emergence of the CCI patients being indistinguishable in symptom presentation yet fully treatable. For all we know it could be 20% this thing, 20% HHV-6 mito fragmentation / CDR, 40% CCI or other as yet unknown explanation/s. The CCI thing really bears further investigation as to how the PEM etc is being generated in that scenario, it could give clues,
They're definitely seem to be subsets. Seems like a mix and match thing where given a list of maybe 15 common problems, we each have a unique grouping of 3 to 6 of them. This is made the research extremely difficult, and why we are reporting so many different reactions to some of the same treatments.
 

Lisa108

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Of the people I am aware of who have done the CellTrend test, pretty much everyone has had positive results to at least one or two antibodies.
I recently had the CellTrend panel done (11 auto-antibodies) and I am negative to all of them.
 

nerd

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This is the first time I heard of the NHE1 upregulation possibility. Interestingly, they link it with MIAT upregulation. But what is the cause of this? Viral cardiomyopathy and/or hyperreactive lymphocytes?

ß2AdR antibodies can be a physiological or a pathological response, after all. It's possible that there is just a hyperexcitability of these receptors due to Na+ overload and this causes the neuropathy at these receptors. Hence, NHE1 could still be the causal player (and MIAT respectively). Following this theory, adrenergic and cholinergic antibodies would only be found in patients who have PEM often and who push themselves too much without pacing.

After all, there is still an immunological link that doesn't necessarily involve active autoreactivity. It's also associated with CD4+ CD8+ double positive T cells (10.1371/journal.pntd.0001294).
 

Hip

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I posted the following elsewhere, but it may be relevant here:



The older Wirth and Scheibenbogen 2020 paper is here.

In this paper these researchers are hypothesizing that ME/CFS begins with two factors that both constrict the blood vessels:
  • Too much sympathetic nervous system activity, which is the "fight or flight" response, and is known to constrict blood vessels.
  • Autoantibodies which disable the beta-2 adrenergic receptor (ß2AdR) and/or the muscarinic M3 acetylcholine receptor (M3). Both these receptors are involved in blood vessel dilation, so disabling them leads to constricted blood vessels.
In order to compensate for the vasoconstriction caused by these two factors, they theorize that the body releases several vasodilators, including bradykinin and prostaglandins. So those dilators help to fix the issue of vasoconstriction.

But high levels of bradykinin, prostaglandins etc then bring on their own problems, and according to their theory, lead to the symptoms of ME/CFS.


In terms of treatment possibilities:

There used to be a ME/CFS treatment available that reduces bradykinin, namely the injectable drug Kutapressin (other brands include: 4ME, Nexavir and Hepapressin), but these are no longer available. I tried 4ME myself when it was available, but without noticing any benefits. Some info on Kutapressin in my post here.


If under-activated ß2AdR or M3 receptors are part of the problem, then maybe drugs which stimulate these receptors could help.

There are lots of ß2AdR agonists, but most appear to be inhaled drugs for asthma or COPD. There can be adverse effects with these drugs though.

And there are some M3 agonists too.


Note that Scheibenbogen et al found only around 30% of ME/CFS patients have elevated antibodies to one or more M acetylcholine or β adrenergic receptors (see this study), so these autoantibodies are only found in a subset.
 
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I posted the following elsewhere, but it may be relevant here:



The older Wirth and Scheibenbogen 2020 paper is here.

In this paper these researchers are hypothesizing that ME/CFS begins with two factors that both constrict the blood vessels:
  • Too much sympathetic nervous system activity, which is the "fight or flight" response, and is known to constrict blood vessels.
  • Autoantibodies which disable the beta-2 adrenergic receptor (ß2AdR) and/or the muscarinic M3 acetylcholine receptor (M3). Both these receptors are involved in blood vessel dilation, so disabling them leads to constricted blood vessels.
In order to compensate for the vasoconstriction caused by these two factors, they theorize that the body releases several vasodilators, including bradykinin and prostaglandins. So those dilators help to fix the issue of vasoconstriction.

But high levels of bradykinin, prostaglandins etc then bring on their own problems, and according to their theory, lead to the symptoms of ME/CFS.


In terms of treatment possibilities:

There used to be a ME/CFS treatment available that reduces bradykinin, namely the injectable drug Kutapressin (other brands include: 4ME, Nexavir and Hepapressin), but these are no longer available. I tried 4ME myself when it was available, but without noticing any benefits. Some info on Kutapressin in my post here.


If under-activated ß2AdR or M3 receptors are part of the problem, then maybe drugs which stimulate these receptors could help.

There are lots of ß2AdR agonists, but most appear to be inhaled drugs for asthma or COPD. There can be adverse effects with these drugs though.

And there are some M3 agonists too.


Note that Scheibenbogen et al found only around 30% of ME/CFS patients have elevated antibodies to one or more M acetylcholine or β adrenergic receptors (see this study), so these autoantibodies are only found in a subset.
Yes but they say it doesn’t need to be antibodies but also desensitised receptors or polymorphism. I’m also negative for these AAB but maybe they are deformed or desensitised
 
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I understood disc arches as follows: They are natural autoantibodies. Everyone has it. In some they are increased. However, it is due to the impaired function of the autoantibodies and not necessarily to the altitude.

At Berlin Cures everyone is positive. At CellTrend 30%. I think they are using a different limit.
 
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I understood disc arches as follows: They are natural autoantibodies. Everyone has it. In some they are increased. However, it is due to the impaired function of the autoantibodies and not necessarily to the altitude.

At Berlin Cures everyone is positive. At CellTrend 30%. I think they are using a different limit.
Cell Trend uses Elisa and Berlin Cures Bio Assay