Exercise Intolerance: Insights from Invasive Cardiopulmonary Exercise Testing of Patients with ME/CFS (Joseph et al., 2021)

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I think the general rule for staying under 100 relates to PEM caused by physical activity. PEM caused by cognitive activity could be a different matter based on what you identify happening without the use or much physical effort. We can also get PEM from emotional expenditure. I was recently told it’s because the same metabolic pathways are used during all exertion.

Some of us, including me, find cognitive effort more taxing then physical activity and vice-versa.
Yeah, makes sense. I also get PEM from physical activity below a HR of 100, but yeah, maybe it is useful for some. At least it increases mindfulness regarding physical exertions.
 

livinglighter

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Yeah, makes sense. I also get PEM from physical activity below a HR of 100, but yeah, maybe it is useful for some. At least it increases mindfulness regarding physical exertions.
As anaerobic threshold is age dependent. Perhaps the rule of thumb of 100 bpm is adjusted according to age and severity. I'm in my mid 30’s and considered moderate-severe and was advised to stay under 100 earlier this year.
 
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Great study, disappointed I missed it when it came out. I'm utterly convinced there are vasodilation/constriction aspects to PEM and indeed have recently seen some results on midodrine, which improves vasoconstriction.

What I think this study lacks however is a bridge to the immune aspects of MECFS. I think most of us would agree that PEM feels similar in some ways to the way your immune system activates at the start of a cold, or after getting a vaccine, etc. The delay in onset is also remniscent of the way the immune system fires up with a delay after provocation.

So how can we link the pair? A humble theory:

I like to think about the role of ATP in red blood cells. Red blood cells release ATP to get blood vessels to dilate. This is a signalling mechanism that works quite simply: the red blood cells get squeezed and jostled when they go into a tube that's too narrow, they squirt out ATP which the tube receives as a signal telling it to relax and widen up. (yes, ATP the energy molecule, I think it's highly relevant here that the energy molecule is also a vaso-dilation signalling mechanism). This is called "shear stress".

If the blood vessels don't respond, presumably they dump more ATP. Dumping ATP into the body is also a cellular distress signal (Naviaux 2013) that could (Here I am straying into a personal theory as I've seen no papers on this) trigger a broader activation of the immune system.

Here's a paper on rbc atp release https://www.pnas.org/content/105/43/16432

ATP is a purine. Purinergic signalling was once a major topic in this forum! https://forums.phoenixrising.me/thr...-in-pursuit-of-a-unified-me-cfs-theory.55801/
 

Pyrrhus

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The authors interpret the findings as clinical evidence for dysautonomia of the nerves that control constriction of the veins that transport blood from the extremities back to the heart, which means that:
the insufficient oxygen in the legs leads to death of the small nerve fibers in the legs. (Small Fiber Neuropathy)
SFN in the lower leg/feet and forearms/hands is consistent with poor circulation, since the lower leg/feet and the forearms/hands are the parts of the body that are furthest away from the heart/spine - but there can be many other possible explanations for the SFN as well.
Were the authors trying to imply that the observed Small Fiber Neuropathy (SFN) was a cause or a result of the underlying dysautonomia?

For anyone interested, note that small fiber neuropathy (SFN) is well-documented to occur when there is an inconsistent supply of oxygen or nutrients to the small nerve fibers. This is notably demonstrated in the case of diabetes, where a lack of a consistent supply of glucose leads to SFN.

From a 2006 paper by SFN expert Anne Oaklander:
https://doi.org/10.1126/sageke.2006.6.pe7
Any disruption of the [...] energy supply (oxygen, glucose, [...], or mitochondria) required to keep axonal transport functional can thus cause distal axonal damage.
("distal axonal damage" = SFN)
 

SWAlexander

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Do Core Abnormalities Connect ME/CFS, Fibromyalgia, Long COVID, POTS and MCAS?
THE GIST



  • Small fiber neuropathy concerns damage to the small, unmyelinated nerve fibers found in the skin and eyes of people with fibromyalgia, chronic fatigue syndrome, POTS, long COVID, and other diseases.
  • Because small nerve fibers are also found in other areas, damaged fibers could conceivably, cause many more problems.
  • A neurologist in Boston, Peter Novak, has been exploring the role small nerve fiber problems, blood flows to the brain, and dysautonomia play in a number of different diseases. Over the past couple of years, Novak has uncovered two different kinds of orthostatic intolerance.
  • Novak and others have found a similar signature: high levels of small nerve fiber damage, reduced blood flows to the brain, and dysautonomia in long COVID, POTS, ME/CFS, and post-treatment Lyme disease (PTLD). When it was assessed, low CO2 levels (hypocapnia) were found.
  • In the PTLD disease paper, Novak suggested that the vascular problems in PTLD may be similar to those found in diabetes.
  • Larger studies are needed to confirm these findings in long COVID. If they do, they could provide the impetus for: a) long COVID researchers to demonstrate how important they are, and b) get at the cause and explore new treatment options that could apply to all these diseases
  • Several COVID-19/long COVID studies have proposed a raft of treatment options that are available but have never been considered in ME/CFS, FM, etc.
https://www.healthrising.org/blog/2...id-postural-orthostatic-tachycardia-eds-mcas/
 

Pyrrhus

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...And this is just a reminder that the phrase "exercise intolerance" only refers to the inability to perform aerobic exercise. It is not the same as "exertion intolerance", which refers to any type of bad reaction to any type of exertion:

Exercise Intolerance vs. PEM/Exertion Intolerance
https://forums.phoenixrising.me/threads/exercise-intolerance-vs-pem-exertion-intolerance.86876/

This study only looks at how dysautonomia results in exercise intolerance, and possibly SFN, but it does not address PEM. PEM may be an entirely separate phenomenon, or it may be related.