Circadian rhythm disruption in [ME/CFS]: Implications for the post-acute sequelae of COVID-19, 2022, McCarthy

is that a good thing?

 

Potentially. If somebody can point the author to this thread so he can refine his ideas about ME and our actual sleep problems. Presupposes he's genuinely prepared to learn. I like to give newcomers to the field the benefit of the doubt.

 

No, my ability to fall asleep had switched off overnight like someone had flipped a switch. I had been sleeping like a baby with uninterrupted sleep for years before that. After 3 days from not sleeping I felt like was going to have a seizure so my doctor rx'd me trazodone. I went to a sleep lab but that experience didn't go well and my lab report was never sent to my doctor.

My sleep slowly came back on it's own after almost 2 years. It was a weird experience with no answers.

 

Let's face it, sleep is a dynamic process not rest so it is not wonder our ME bodies can't do it properly.

Maybe in the early days the body is trying to fix viral damage in the brain by having lots of sleep but eventually there is not enough energy produced so it can't be sustained.

We do not know how hard the body systems are is working to compensate for our low levels of energy. The brain, heart and lungs take what they need as a priority but there may come a time when the flow of oxygen does not leave enough for the extra effort of the brain to fix its damage so it stops trying and maybe does not have enough to spare to initiate proper sleep.

We may still feel we are doing OK but we are working to our limits without the spare energy available to healthy people.

 

The paper is longwinded but to me it is raises interesting possibilities.

A big question for me is whether the perpetuation of ME can be put down to some dysregulation of brain cell signalling - maybe brainstem - or whether we really have to propose that peripheral target tissues like lymph node and muscle are dysregulated as well.

What message get stored where during the triggering event? If it was autoantibody that would be easy. I can think of any number of variations on a theme. But the evidence for autoantibody driving ME looks to me weak.

It might be a shift in T cell populations - an acquired T cell response.

But there are other ways to leave a mark I tissues. One would be some persistent epigenetic shift that meant that peripheral tissue cells, such as muscle cells, remained programmed to say 'no thanks' to stimuli in the way they normally are just for a few days during a viral infection or maybe for a few weeks after a major road traffic accident.

The persistent signal could also be 'written on the wall' as for Nebuchadnezzar. This is where TGF beta might come in. TGF beta binding proteins form part of structural fibres in tissues. They get painted with TGF beta when the body wants to switch off local T cells. They also get painted with complement inhibitor proteins. Tissue passageways are a bit like town streets - with road signs everywhere saying how fast to go and when to stop and not to turn right and so on.

This guy is a psychiatrist but a molecular one. His primary interest seems to be sleep disturbance. I am a bit sceptical about sleep clinics for people who snore but sleep disturbance in a psychiatric context is worthy of a lot of attention. The misery of insomnia and early waking is at least as bad as crippling arthritis.

Having 'slightly longer Covid' so far (five weeks) I am getting to feel from inside what the answers to questions about mechanisms have to be. A purely brain problem is possible but it falls short on a number of things. And of course the brain has all these signposts too so it could all be part of a failure to repaint the TGF beta signposts after the roadworks have packed up and gone home.

 

Jo, I'm sure you've discussed this before but I can't remember where or when. Beyond the brain, what's your take on the idea of mitochondrial dysfunction/broken ATP-cycle/etc?

 

I follow the view of Mike Murphy, mitochondrial researcher at my Alma Mater, Cambridge. Failure of respiratory metabolism in terms of ATP production does not really make sense for ME. If you cannot make ATP you find you cannot lift an arm or climb a stair but it does not make you feel ill like ME.

His idea was that mitochondria might be relevant in terms of signalling. So if mitochondrial DNA got methylated (let us speculate) so that the signalling functions of mitochondria were perturbed then they might be involved in creating ME symptoms. So just as lymphocytes might generate cytokines without any good reason because of epigenetic changes to cytokine transcription factors muscle cells might throw out danger signals because mitochondria had got 'intolerant' through similar methylation of DNA (either mito DNA or chromosomal in fact).

We know that after surgery or trauma the whole body is reset in terms of metabolic responses to stimuli. The general pattern is catabolism - so ATP is being burnt up but not replaced because intake is suppressed.

An important aspect of any shift in which cells are responding differently because the 'writing is on the wall' in terms of signals painted on to matrix is that all usual tests will look normal. Nobody looks for TGF beta bound to matrix.

 

I contacted the author who replied. So he knows there is interest. He is doing some experiments now.

 

Is this something that can be looked for?

 

It can but I am not aware of any standardised method that would allow useful interpretation. You can see connective tissue fibres light up with all sorts of fascinating immune signalling molecules but how you measure that is another matter. It might be possible to standardise the signals against the fibres in some sort of elution assay but connective tissue is so heterogeneous structurally that one would need to be very careful and getting biopsies could be problematic.

 

Yes, exactly what my dear friend endured from day one of illness and for the next 18 years. He told me he felt 'poisoned'.

 

what does this mean exactly?

 

So all tissues are held together by a mixture of collagen and elastic fibres. In muscle, for instance, you have fibres forming networks like the net bags they sell citrus fruit in at various levels of structure - around bundles of a few muscle cells, around larger fascicles and around entire muscles - endomysium, perimysium and so on. Collagen fibres provide tear-resistant strength and elastic fibres stretch with movement and keep everything neat - like lycra.

In the past my group studied elastic fibres mostly and I know less about the collagen fibres. Both may be relevant but it is the elastic fibres that showed up things that were of interest to us, including TGF beta binding proteins, complement inhibitor proteins and free forms of immunoglobulin receptor.

I forget the details after thirty years but elastin protein itself forms crimpable fibres bound together with other proteins such as fibrillin (1 and 2 at least). These proteins form overlapping chains a bit like tiles on a roof and under electronmicroscopy you see banding. It seems that in association with this banding you have regular binding sites for immune signalling or regulatory proteins. It is a bit like the carriages in a train that each have a slot on the side where you can put boards saying 'First class' or 'Manhasset only' or 'Dining Car'. When you stain tissues to pick out the regulatory proteins with a fluorescent marker you see the fibres light up like LED Christmas light strings.

The really interesting thing is that each tissue stains up quite differently. Complement regulatory proteins like CD55, for instance, are painted on to the fibres supporting muscle and joint lining. TGF beta binding proteins are painted on to fibrillin chains almost everywhere I think but since fibrillin is predominantly found in stretchy tissues this will have more ability to bind TGF beta.

The reason why we were interested was to explain why certain immune disorders attacked specific tissues. We had already realised that in rheumatoid arthritis immune complexes produced inflammation in joints because of the specific presence of an immunoglobulin receptor on the macrophages of joint lining. But there is another disease called polymyalgia rheumatic where immune complexes seem to cause trouble in elastic ligaments and around muscles. The story was never sorted out but the strange thing about these structures is that they carry the same receptor we blamed in RA but not on macrophages as such - painted on to the fibres instead. That would mean complexes would stick but maybe activate complement rather than cytokines.

The other story is that ankylosing spondylitis is a condition specifically affecting the stretchiest parts of the body with the most elastin - spinal ligaments, wall of the aorta, ligaments around joints, lining of the cauda equine nerves at the base of the spinal cord, the ligaments that support the lens in the eye and the top ends of the lungs. (We know that these are the places most dependent on elastin because the genetic disease of fibrillin, Marfan syndrome, specifically affects these places as well.) And ank spond is almost certainly a disorder of non-specific T cell activation. Why should T cells get activated where there is elastin being stretched a lot? The answer that seemed likely to us is that TGF beta is the most powerful off signal for T cells. So if elastic fibres normally paint themselves with TGF beta it ought to be that T cells are supposed to be turned off where a lot of stretching is going on. If that turning off was interfered with then you would get a disease specifically causing inflammation in these tissues.

Another thing that may be relevant is that if you have musculoskeletal problems like back or joint pain you are almost bound to have more pain when you have a viral infection. It seems that the 'malaise' signals of cytokine activation light up tissues already primed.

And more generally, we probably forget that a huge amount of information must be painted on to tissue matrix in order for it to know how to heal correctly. A surgical wound will repair to an almost invisible scar despite going through a phase a being red and swollen. The tissue knows exactly how it should join itself up. That knowledge is partly in the cells but they have to be guided by feeling around in the matrix.

 

So these fibres are like charm bracelets. At regular intervals there are holes to plug in signals.

 

This is not true though.

“Data were compared with those for healthy control subjects and patients with Myalgic Encephalopathy/Chronic Fatigue Syndrome matched for age and gender. Sixty-two per cent of patients with mitochondrial disease reported excessive symptomatic fatigue (Fatigue Impact Scale ≥ 40); whilst 32% reported severe, functionally limiting fatigue symptoms (Fatigue Impact Scale ≥ 80) comparable to perceived fatigue in patients with Myalgic Encephalopathy/Chronic Fatigue Syndrome. Fatigue is common and often severe in patients with mitochondrial disease irrespective of age, gender or genotype.”

https://www.sciencedirect.com/science/article/pii/S0960896615000875

“12. What are the symptoms?
Lack of energy is a common outward symptom of Mitochondrial Disease but inside the body it's much more serious and complex. Mitochondrial Disease may literally cause any symptom, in any organ, with any degree of severity, at any age.”

https://www.thelilyfoundation.org.uk/get-informed/questions-answers/

Ive done a bit of reading about mitochondrial disease which is why I knew about the above. There are several case studies I came across of people who had symptoms such as exercise intolerance, chronic fatigue, post-exertional shortness of breath, headaches & seizures - all of these symptoms can make people feel very unwell - & have been found to have mitochondrial disease. Yes people with ATP problems might have difficulty climbing a stair or lifting an arm, and also have other (sometimes fatal) problems too, but a serious lack of energy & feeling exhausted / tired / fatigued is also a part of their illness.

So it’s not true that having ATP problems doesn’t make you feel unwell. I don’t see why ATP & mitochondrial issues can’t be implicated in ME too, even if it’s not the whole picture.
_____________

This post and the next have been copied and discussion of ME and mitochondrial diseases has been moved to this thread:
What differentiates ME/CFS from known primary mitochondrial diseases; could mitochondrial disease cause PEM?

 

No doubt people with mitochondrial disease will report fatigue but as everyone on this list says, that is not really what ME symptoms are about.

And I think this sort of account is fairly unhelpful. People with any disease can have any symptoms if you keep asking.

I have not looked after people with mitochondrial disease but Murphy, whose work is devoted to it, says that the symptoms of ME do not fit with a failure of mitochondrial function.

You also have to remember that people with mitochondrial disease develop progressive structural damage to tissues like muscle, over and above the ongoing metabolic deficiency, and it would not be surprising if that had an impact. People with ME do not.

 

On the other hand, I'd like to mention that ATP spilling over can lead to stimulation of purinergic receptors, which contributes to sensations of pain (from muscle afferents) that is often associated with fatigue.

"Exogenously applied muscle metabolites synergistically evoke sensations of muscle fatigue and pain in human subjects "
https://pubmed.ncbi.nlm.nih.gov/24142455/

 

They usually freak out when I don't sleep at all. They want to study sleep, not the lack of it.

 

The lab tech hooked me up with electrodes and told me to sleep, but when I explained that I needed to take trazodone in order to fall asleep, she told me to 'try to sleep' w/o it. I told her I can not fall asleep at all w/o the meds. She left the room and I stayed awake until 2 a.m, so she came back in and told me to take the meds. I was booted out at 5 a.m all dizzy and exhausted.