A reader asked for my thoughts on “Pathophysiology of skeletal muscle disturbances in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)” 21 Apr 2021. With over 20 years of reading many many hypothesis of ME/CFS, I have learnt to look for earlier indicators that it will be unlikely.
First, “skeletal muscle disturbances” applies to a subset of ME/CFS only. The second item is simple – is this a new hypothesis or an old one-recycled? What I found was:
- Symptoms, signs and laboratory findings in patients with chronic fatigue syndrome 
“The characteristic abnormality in CFS patients is the low values of 17-Ketosteroid-Sulfates/creatinine in morning urine and the acylcarnitine deficiency. It seems likely that this deficiency of acylcarnitine induces an energy deficit in the skeletal muscle, “
- Long-chain acylcarnitine deficiency in patients with chronic fatigue syndrome. Potential involvement of altered carnitine palmitoyltransferase-I activity 
- Low levels of serum acylcarnitine in chronic fatigue syndrome and chronic hepatitis type C, but not seen in other diseases 
- Acylcarnitine deficiency in chronic fatigue syndrome 
- Serum carnitine and disabling fatigue in multiple sclerosis 
- Normal carnitine levels in patients with chronic fatigue syndrome “ The previously reported decreased level of acylcarnitine in CFS patients was not confirmed.“
- Specific correlations between muscle oxidative stress and chronic fatigue syndrome: a working hypothesis 
What is the new hypothesis?
The author’s earlier title was “A Unifying Hypothesis of the Pathophysiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Recognitions from the finding of autoantibodies against ß2-adrenergic receptors”  There is no reference to acylcarnitine in the document – this is a red flag for an under-researched paper. You want to cite and discuss prior papers on the same topic.
“sympathetic overactivity in the presence of vascular dysregulation by ß2AdR dysfunction causes predominance of vasoconstrictor influences in brain and skeletal muscles,”
The conclusion is below and amounts (IMHO) to a bunch of hand-waving. The key factor is that the hypothesis is really not testable (hence authors get credit for a publication, suffers of ME/CFS gets nothing).
Considering all the potential predisposing factors we think that in the presence of a high sympathetic tone dysfunction of the ß2AdR could play an essential role (conditio sine qua non) in the etiology of ME/CFS although secondary and rather complex mechanisms have to get involved and to interact, particularly in the chronification of the disease (Figs. 4 and 5). Dysfunction of the ß2AdR by autoantibodies, mutations and desensitization by chronic stress would favor vascular dysfunction and cause insufficient stimulation of the Na+/K+-ATPase at least as a risk factor together with other precipitating factors. There may be numbers of different, still unknown predispositions.
According to our hypothesis dysfunctions of the ß2AdR or post-receptor mechanisms, of the NHE1, the Na+/K+ATPase, the NCX, the RAAS and the KKS could be causally involved in ME/CFS and should therefore be further investigated. This concept offers potential novel strategies for the treatment of this debilitating disease.
The only use of the word “treatment” is in the last sentence.
Going to the earlier study by the same author, I read “Metabolic changes in ME/CFS are also in line with a concept of hypoxia and ischemia.” — that echoes the old hypercoagulation hypothesis from Dave Berg [1999, 2000]. The key difference is that Berg’s hypothesis was testable (via the ISAC Panel) and a variety of treatments (depending on the results). For myself, it worked and I went into full remission. This was confirmed in a trial but then a series of poorly done studies faded away. I recall one study that tested using baby-aspirin on ME/CFS patients and reported no results, thus dismissing the coagulation hypothesis.
A major factor in Berg’s hypothesis fading was the complexity of multiple treatment plans was more than most ME/CFS physicians wanted to deal with (give me one magic bullet please!) , patients referred to hematologists were tossed back because low grade chronic coagulation was not of interest to them.
How well studied is ß2-adrenergic receptors?
I checked PubMed and found there is only 16 results. Several deal with asthma, and thus I would expect an association to asthma to be in the ME/CFS literature – which I was unable to find
I would drop this concept into the circular filing cabinet. It lacks any direct test results on ME/CFS patients to support it, offers no treatments. It is full of speculation and “reasoning”, i.e. “Therefore, QTc shortening can be explained only by ß2AdR dysfunction in the presence of intact ß1-adrenergic receptors and a high sympathetic tone.” The use of the phrase “can be explained only” instead of ” could be explained” signals spin-doctoring and salesmanship to me, not careful science.