Plasma metabolomics reveals disrupted response and recovery following maximal exercise in ME/CFS, Arnaud Germain, Maureen R. Hanson et al, 2022

When it comes to CPET tests I think we should not focus on the drop in performance that much, but more on the failure to increase performance. It is obvious that healthy people can increase their muscular and cardiovascular endurance trough training, but it seems to me that in people with ME this ability is either very compromised or non existent. I have personally confirmed this trough experimentation as have others and the CPET studies support this too. Unfortunately, these CPET studies have only 2 data points, but I am pretty sure longer duration studies would show the same results. So I think it is interesting to approach the CPET results from this angle, namely answering the question why we are unable to increase our muscular and / or cardiovascular endurance trough training?
 
Jonathan Edwards said:
As I think Hutan said, the surprising thing is that if PEM is really as terrible as people say, and I fully believe it is, then how come these people can even start a second CPET test? If I had 'flu' there is no way I would want to get on an exercise bike.
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My guess is that for most patients PEM is not that spectacular: not a crash where you suddenly can't do anything anymore but more an abnormal slow recovery where you feel extra sick for many days after overdoing it.
 
Mild PEM for me is just feeling somewhat worse on that day, and in particular feeling like I didn't sleep well, needing more rest. There is some reduction in ability to function as activities become more exhausting to carry out.

If PEM is defined strictly as marked reduction in function and increase in symptoms then such a mild PEM day wouldn't be considered PEM. In my experience however it's a gradient.
 
Jonathan Edwards said:
As I think Hutan said, the surprising thing is that if PEM is really as terrible as people say, and I fully believe it is, then how come these people can even start a second CPET test? If I had 'flu' there is no way I would want to get on an exercise bike.
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When I describe how terrible PEM can be at very severe and the higher end of severe I am not exaggerating. Thank you for acknowledging that you do believe what is expressed. It needs to be acknowledged and not invalidated.

It might also help to remember the levels of ME. I am now at moderate level, PEM is moderate. I could do a study like this without the terrible PEM that I would have experienced at very severe and higher end of severe.
 
Jonathan Edwards said:
One of the things that worries me is what Mithriel mentioned. PWME go in to this test motivated by wanting to produce an abnormal result - maybe the second result to look different from the first. Knowing just how much frame of mind affects one's physical performance on the running track I wonder how problematic this is.
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I seem to have missed this thread a week and a half ago.

Frame of mind has no impact at the levels of exertion involved because it is a ramped exertion test. You cannot deliberately put in more or less effort because workrate is set externally and anything else leads to failure of the test.

This puzzles me too. How do we now a voluntary reduction does not occur? We know almost nothing of the mechanism of 'voluntary effort'. If I am on an exercise bike and someone asks me if I am doing maximum voluntary effort I don't think I can say. One can get somewhere near to a sense that instantaneously but over a period of many seconds all sorts of things modulate the sense of effort being maximal. Effort isn't actually something we have any way of measuring. And if you feel ill you are in a completely different mindset.
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Effort is controlled during a ramped workrate exercise test. That is the strength of this method. The perceived effort on the other hand is proportional to the signal generated upstream of the motor cortex and is related to how our proprioceptive system works (dating back to Helmholtz).

Notably, CPET participants (regardless of healthy or athletic) have a nonlinear shift in perceived effort (on Borg scale) at the ventilatory threshold. It is not the baseline level of perceived effort or slope that we should care about, it is when there is a nonlinear shift in the curve.

Also, for what it's worth, I apparently reported lower perceived exertion (muscle exertion, not breath) during the 40w warm up on the second day. But as the workrate ramped up, it seemed much harder than the first test - any power I felt I had on the previous day was kind of missing - I can't remember when I first noticed this, but it was likely from around the VT1 and above based on the power (workrate) figures.

Regardless of whether it was kinetic limitations of metabolic sources of energy that required an increased shift in effort or not, the fact is this nonlinear shift will lead to a sudden increase in activation of (higher threshold, higher force) muscle fibres which have lower capillarisation, lower myoglobin, lower oxidative capacity, but higher glycolytic capacity. Hence there will be a noticeable shift in metabolic sources from this alone.

The 'bias' of the system is not the upstream signal, for if that changed significantly from day to day, there would be major problems with proprioception, which we do not see in patients.
Instead, the bias is determined by the feedback from type III/IV muscle afferents which in turn reduce the excitability of the motor cortex output ("central fatigue"). The purpose of this biasing system is simply to increase the level of ventilation for a given level of motor cortex output to account for fatigue related shifts in metabolism.
 
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Snow Leopard said:
Frame of mind has no impact at the levels of exertion involved because it is a ramped exertion test. You cannot deliberately put in more or less effort because workrate is set externally and anything else leads to failure of the test.
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But isn't that just the workrate as measured by force x distance in terms of useful output
(I assume a bike or treadmill). That isn't total workrate if there is inefficient muscle use. You would need a calorimeter - is that involved?

I think I had brought in effort because you were talking about maximal effort - and you talk a lot about effort above. I need to keep this simple to understand. If frame of mind doesn't matter let's forget 'effort'.
 
Jonathan Edwards said:
But isn't that just the workrate as measured by force x distance in terms of useful output
(I assume a bike or treadmill). That isn't total workrate if there is inefficient muscle use. You would need a calorimeter - is that involved?
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Which came first, the chicken or the egg? (The answer is that the question itself is wrong)

The biomechanics are largely similar because the same person is riding the same bike in the same position. The only difference is cadence. Participants are told to keep a somewhat constant cadence, continuing from the warm up period. In general, the cadence for inexperienced cyclists will mostly be constrained between 60-80 rpm which is what feels most natural and is close to what is energetically most efficient.

Actual citations ME/CFS citations reporting cadence:
https://translational-medicine.biomedcentral.com/articles/10.1186/1479-5876-12-104 (constant 60-70rpm)
https://journals.lww.com/cptj/Abstr...bility_of_Measurements_Obtained_During.4.aspx (constant 60-80 rpm)
https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-019-1836-0 (the study I participated in, the cadence was "self-selected", if I had to guess my cadence at VO2Max was in the low 80rpm range, but I do ride an ebike once a week and was an active biker before I became ill. High cadences of 90+ are quite uncomfortable for inexperienced cyclists and are thus unlikely)

Back to the chicken vs egg question,

"Freely chosen cadence during cycling attenuates intracortical inhibition and increases intracortical facilitation compared to a similar fixed cadence"
https://www.biorxiv.org/content/10.1101/2020.04.23.056820v1.full.pdf

The big picture conclusion is that there is peripheral feedback that helps guide optimum cadence. So saying that the observed findings could be due to a significantly different cadence on the second day is circular because the choice of a different cadence itself suggests increased fatigue.


But if the cadence is constrained within the limits described above, the O2 kinetics are largely similar (with very high cadences leading to poorer oxygenation):
https://www.physoc.org/abstracts/th...n-skeletal-muscle-oxygenation-during-cycling/
(Also note, several of the 2 Day CPET studies did not show a significant difference in VO2 at VT1, but did show a difference in workrate)
 
strategist said:
@Snow Leopard do you have any idea what could make me so hungry after exertion? This occurs immediately or shortly afterwards. Increased hunger can also occur on the next day after significant exertion. Eating tends to improve fatigue somewhat.
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I'm not sure exactly. The oversimplified answer is that leptin and ghrelin (hormone levels) are altered during exercise as the body wants to replace the stored glycogen in the muscles that was consumed.

Exercise have been known to transiently stimulate ghrelin levels:
https://www.sciencedirect.com/science/article/pii/S2212877817309481
(notably prolonged exercise doesn't necessarily lead to higher ghrelin levels than short bursts of exercise)
 
Jonathan Edwards said:
I can see that but did they demonstrate a poorer performance to explain? If they didn't I don't see the point.

There seems to me to be a confusion between PEM as defined as the symptom complex that occurs after exertion and PEM as defined as some fall in ability to do work - a sort of delayed fatiguability. From what I understand of the symptom of PEM these are two quite different things.

All sorts of other stimuli that might make people feel ill might have a similar effect on reducing ability to do work - with no connection in terms of specific metabolic pathways.
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This is actually a good point you raise here. Because there is a difference between the intensity of PEM I can get on any given day after doing too much, and the reduced function i may or may not get the next day doing the same. If I wanted to study PEM, I would definetely do it when I get the intense PEM.

I find this a bit hard to explain, but basically my point is that PEM is probably most measurable when a well reflected patient (like myself;) knows they have it, not neccesarily when they mobilize for any given activity.
 
borko2100 said:
When it comes to CPET tests I think we should not focus on the drop in performance that much, but more on the failure to increase performance. It is obvious that healthy people can increase their muscular and cardiovascular endurance trough training, but it seems to me that in people with ME this ability is either very compromised or non existent. I have personally confirmed this trough experimentation as have others and the CPET studies support this too. Unfortunately, these CPET studies have only 2 data points, but I am pretty sure longer duration studies would show the same results. So I think it is interesting to approach the CPET results from this angle, namely answering the question why we are unable to increase our muscular and / or cardiovascular endurance trough training?
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This highlights the problem with CPET testing - the risk of permanent deterioration. The experiments which would answer many questions would be unethical yet because the psychologists do not believe there is a physical problem in ME they feel perfectly happy pushing patients into permanent disability!

Someone said that the key point of ME is that you can't improve your fitness and it is very true. There will be complicated biological reasons for this that I do not understand but one thing occurs to me. Aerobic exercise is when you have to rely on anaerobic cellular energy production. This is hard to achieve in modern daily life so people go to classes and gyms yet we are forced to use it for the activities of living. My fitbit thinks I am fitter than 80% of women my age because the algorithms say I exercise for hours every day!

Basically, if we are using the emergency energy production a lot of the time anyway we have nowhere to go to increase it.

When the products of anaerobic respiration are not taken up by the citrate acid cycle (aerobic cycle) they accumulate and kill the mitochondrion. The breakdown products from that signal the cell to increase the production of mitochondria. Since our cells must be like that all the time we may be making new mitochondria all the time.

Some research has shown we actually have more mitochondria than healthy controls. If that is the case we are as fit as we can be. It could explain why most people with ME do not have the muscle wasting you would expect for the low levels of exercise many of us manage.
 
Has anyone managed to read the whole paper? I tried but it's too long and information-dense for me. The unfinished Epub ahead of print formatting doesn't help either.

This Danish blog (the site has an embedded Google translate function) has just started to run a series of short posts about some of the key metabolite findings.

Are they as potentially interesting as they sound?

To date there are 3 posts, the first introduces the study, the second focuses on tridecenedioate and the third on pyrroline-5-carboxylate and proline. The blog puts these findings into the context of the wider ME as well as non-ME research (I don't know if the context is drawn directly from the paper or ferreted out by the blogger).

http://followmeindenmark.blogspot.com/2022/04/metaboliske-ndringer-hos-me-patienter.html

http://followmeindenmark.blogspot.com/2022/04/me-patienter-har-lavt-niveau-af.html

http://followmeindenmark.blogspot.com/2022/05/efter-motion-har-me-patienter-forhjet.html
 
https://m.youtube.com/watch?v=Gv73uGSBLAQ

IACFS/ME October 2022 Virtual Journal Club - Dr. Arnaud Germain


121Views
19 Oct2022
Dr. Arnaud Germain from Cornell University (Ithaca, NY, USA) and his team compared metabolites in people affected by ME/CFS with healthy people during and after 2-day cardiopulmonary exercise testing. Previous studies did not track metabolites longitudinally following physical activity. They found significant differences in metabolites between the groups during the recovery period as well as differences between male and female study participants. The paper discussed is " "Plasma metabolomics reveals disrupted response and recovery following maximal exercise in myalgic encephalomyelitis/chronic fatigue syndrome." For the full-text, see:
https://insight.jci.org/articles/view/157621

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