BMJ letter from LongCovid doctors.

@Jonathan Edwards you also said once something along the lines of ME not being a mitochondrial disease because genetic mitochondrial disease causes death and coma, not ME-like symptoms. I think you asked an expert in mitochondrial disease and that is the answer you got.

Yet I read what other mitochondrial disease experts write (on an Italian website) and they say mitochondrial diseases are highly heterogeneous between each case, not necessarily evident at birth, and that exertion intolerance and rapid fatiguability are key symptoms.

 

There's all that, plus judgement. Whether it's judging how to go through a door frame without colliding with it, how to phrase a sentence without offending, how hot the food on your plate might be, how long you might be able to continue standing up before your legs go, how much money you need to keep aside to survive the rest of the week, or whether you should attempt a task today – it all goes out of the window!

 

When a disease is difficult to diagnose, what I think happens is that only the most severe cases are diagnosed, and the medical community forms a view of the disease that is biased towards the most severe and easy to diagnose presentations.

And the other patients might be told they can't have this disease because people with it are much more ill.

 

https://www.meaction.net/2017/02/22/stanford-team-announces-breakthrough-in-mecfs-research/

"The team’s metabolomics tests on severely-ill patients revealed problems with the citric acid cycle. Participants’ blood work showed that some of the chemicals involved in the citric acid cycle are very low, making it difficult for the patient to generate the chemicals we use for energy. Several chemicals were found to be two standard deviations away from those of healthy controls, which is serious, according to Davis. The problems found in the citric acid cycle of ME/CFS patients does not look like the result of a typical genetic defect in the mitochondrial metabolism, Davis noted".

This was also evident on my OAT. When I had my consult with the biochemist he was in shock, and asked if I was out of breath a lot, and almost fell off his chair when my functional doctor told him that I jogged

 

Yes it might not be a genetic mitochondrial problem but it could be something functionally very close to it. Like a molecule that disrupts mitochondria or some metabolic process just upstream of mitochondrial energy production.

 

Are you joking? It is not just weakness. Symptoms of both are wide-ranging.

https://link.springer.com/book/10.1007/978-3-540-79313-7 (quotes from textbook on dermatomyositis)

Now muscular dystrophies are quite varied, but also include intellectual/learning disabilities, cardiomyopathy, constipation etc.

Of course muscular dystrophies aren't strictly metabolic in nature, but metabolic diseases such as Glycogen storage disease cause symptoms like headache, along with morphological abnormalities.

ME doesn't necessarily share the same pattern of symptoms because ME is not a genetic disease like the muscular dystrophies and metabolic diseases.

As others have said, PEM is not merely a feeling of "malaise" and does include a reduced threshold of fatigability.

A straight CPET does not show a deficit as there is no baseline for comparison. The 2 day CPET provides a self-controlled baseline and shows earlier fatigability.
To be very clear, do you agree that if more motor units need to be recruited for the same force output on the day before, this necessarily is a reduced ability to do muscle work?

Let me ask you and other readers, what is the physiological relationship between the following parameters during a CPET (utilising EMG and MMG measurements)?

- MMG mean power frequency fatigue threshold. (the highest level of power that can be maintained, without a fatigue induced decrease in (mechanical) twitch frequency of the activated motor units - this is an estimate of the highest level of isometric torque that can be maintained, if cadence is constant)
- Gas Exchange Threshold (otherwise known as the first Ventilatory Threshold (VT1) - typically operationalised using the V-slope method, which notes the point of non linearity when VO2 is plotted against VCO2, but can also be operationalised by examining VE/VO2 and VE/VCO2 on the same graph).
- EMG amplitude fatigue threshold (estimate of the highest level of power that can be maintained without a fatigue induced increase in EMG amplitude)
- EMG mean power frequency fatigue threshold. (highest level of power that can be maintained without a fatigue induced decrease in EMG firing frequency)
- Respiratory compensation point (otherwise known as the second Ventilatory threshold (VT2) - this is the point at which reduced pH of the blood or cerebrospinal fluid pH activates chemoreceptors, which stimulate the respiratory centre of the brain, leading to compensatory hyperventilation to help restore the pH balance. This is the point at which some participants may start to feel "out of breath" and typically occurs at 85%-90% of VO2Max. I will however note that many participants, unlike COPD patients (or highly trained athletes) never indicate a very high score on the Borg Dyspnoea scale even at VO2Max.)

Bonus points if you can explain the role of peripheral afferents.

Concluding remarks - understanding of exercise physiology is very interesting (and I'd argue, essential) if you wish to understand the relationship between the brain and the body.

 

Personally I've come to the opinion that a greater understanding of exercise physiology in general would be extremely useful to ME research. It seems logical to me that the point where, in a normally healthy person, additional exertion triggers a "fitness improvement" process is the point where PEM is triggered in folks with ME, so if more was known about how that process works normally then it would make it easier to investigate what differences there are in ME.

 

I agree that understanding muscle physiology is of great interest.

But @Snow Leopard, your comments above seem to miss the point of what I was trying to say.
Of course dermatomyositis has lots of other symptoms but nobody would mistake a rash or pulmonary haemorrhage for ME. The point is that the symptoms that worry PWME most are very hard to ascribe to the inability of muscle to do work. The symptoms of inability of muscle to do work, as exemplified in dystrophies and DM are not like ME.

So although the suggestion that there are some abnormalities in muscle function in PWME is interesting I do not think it is useful to encourage PWME to believe that 2 day CCPET tests 'explain' their PEM, or show that ME is a problem of energy production.

One of the things that worries me about the whole CPET story is that it has never really got beyond some preliminary findings that cannot usefully be applied in clinical practice. I was particularly disappointed when Betsy Keller was asked to speak on muscle physiology at an IIME research meeting - which I was very much looking forward to - and instead said it would be more fun to show the audience some exercises. She spent her presentation getting the audience to stand up and do exercises. I was baffled to be honest.

 

So you disagree with me?

 

Great, that's your opinion, mine is that your improvement in upper body strength doesn't refute my general theory, which is fine as neither of us know for certain.

 

Thanks to you posting the first comment that provoked my reaction we now have a good discussion on another very relevant topic!

Nice example of an unintended good side-effect

As an(other) aside, I find it helpful when posting Tweets to either post the link (which will automatically embed them) or post the link as a code or both, so it is possible to go to the Twitter thread and see the context of the Tweet.

Edit: It also facilitates sharing or commenting for those who are on Twitter. Screenshots are of course good for the archive.

 

I think it depends (as always!) on what you mean by 'fitness'.

I too can build muscle in my shoulders, arms and core when ME allows me to swim – to the extent that people notice the increased shoulder tone, and I'm aware of being able to turn over and sit up in bed more easily. (I can't do the kick part of the stroke because it's too exhausting, so the same doesn't happen with my legs.)

I suspect I also improve my aerobic fitness slightly, though not as much as the muscle tone. I do get a bit less out of breath after the first couple of months of regular swimming, but some of this is probably due to improved skill from practice rather than improved fitness.

What I can't do is improve my overall exercise capacity. I'm never able to swim more than twice a week, and I always have to schedule two days of recovery. After the first few weeks, I can never swim any further or faster, no matter how hard I try. And in order to facilitate the swimming in the first place, I always have to cut back on other activities. This never changes, even during the periods where I was able to get in several years of consistent swimming before a downturn in my ME.

That lack of improvement in overall fitness is far from normal, especially in a young person (as I was when I went back to the pool during ME remissions). Someone who takes up an activity in their 20s or 30s can usually improve their capacity to the point where, within 18 months, a workout that would leave them floored at the beginning is just their warmup. They can also train more often and for longer – without needing to add the same amount of additional recovery time – and their athletic performance is significantly better.

 

On the contrary, electromyographic stimulation studies of fatigue in muscular dystrophies, peripheral neuropathies have the same patterns and the same conclusions as in ME/CFS studies. (Despite the association with peripheral disease, the conclusion is the same: central fatigue - and yes, this includes studies of Duchenne muscular dystrophy and myositis.)

Which begs the question, why?

Upon consideration, it is likely that that "peripheral fatigue" and "central fatigue" are not separate, but in fact coupled through afferent feedback.

The value isn't in clinical practise (due to the impracticality of the test), but the fact that there is an objective outcome that can be combined with specific experiments to uncover the specific pathology. Alan Light and colleagues have pursued one avenue of this sort of research.
But targeting specific afferents (inhibition or stimulation), or their sensory receptors can provide unique clues.

I personally do not believe that ME is due to a mitochondrial defect.
But I do believe there is an exercised induced impairment with a metabolic component, perhaps due to impaired blood flow in muscular capillaries*, and/or mechanical or metabolic sensing on peripheral afferents. I'm also implying that in some way this impairment will be involved with the other symptoms that patients experience.

*An aside, the physiological structure of motor units is fascinating, particularly the relationship between muscle fibre capillarisation, fatigability, metabolic balance, ideal twitch frequency and sensitivity.

Back to COVID, I note that many medical doctors were "surprised" when they discovered that COVID has a significant vascular component (though it should be obvious when ACE2 is involved). But the spike protein doesn't just target ACE2, but can bind to a variety of receptors that are involved with endothelial and vascular regulation. I also note an observation that infections that seem to trigger ME/CFS seem to have more surface protein interactions (or specific pathways of dysregulation) with such receptors than infections that don't seem to trigger ME/CFS.

 

Same for me. I do 15 a day now unless I feel too unwell. The gains in muscle mass are visible. It doesn't ever seem to trigger PEM.

Brief and intense activity seems to be safe. Sustained aerobic activity is where the danger is.

 

Indeed.
What i can say for sure is that when well rested i can lift a 4 pint bottle of milk - it feels like hard work but it's entirely doable. In a bad bout of PEM not only can i literally not lift the 4 pint bottle - it's as if it now weighs 20kg - but i even struggle to lift a 2 pint bottle and have to use both hands with muscles trembling as if i'd been doing a major, major workout. I struggle to lift a feather pillow to move it on the bed too.
So for me there is a clear difference in muscle power from in & not in PEM - when i say 'power' i obviously dont mean that in any scientific sense, i wouldnt have any idea why my muscles arent able to do what they can do when i am rested & not in PEM. I dont think it simply an issue of perception or expectation either, because i go to lift the larger bottle and am always surprised when i cant do it.

But what is noticable is if someone/something really stresses/scares me or makes me very angry, after about 20mins of what i assume to be adrenaline influence, i can then go from not being able to lift the 4 pinter, to being able to do it with both hands in the same way as i could only do the 2 pinter.

Lol i drink lot of milk!