A Thought Experiment on Muscles

The PEM limit seems to always be lower than the limit for what you could physically do when you have ME/CFS.

And my experience is that the limit for what you can physically do drastically decreases when you’re in PEM.

 

I don't think I can. If I'm really exhausted, I really struggle to get home, and if I were worse or if it were just a bit further I think I'd collapse.

 

I used to have the confidence to do this many years ago, but after I had a relapse in 2001 I no longer have that confidence because of a couple of bad experiences. I have a fear now I guess. In the evenings I'm ok, but during the day I'm not so sure I'll make it back home.

My muscles don't hurt btw, there is a weakness that starts up and I have to stop.

 

Yes - I'm much better in the late afternoon to early evening, often when the places I need to go are shut!

It's very frustrating at times, e.g. having to make an appointment to have my electric meter changed, the options available don't include 1500 onwards.

I don't often have pain either; just weakness.

 

I've literally had nightmares about that, for years - recurring ones. There would come a point in real life where I coudn't go on, but I've never allowed myself to get into a situation where I've been forced to do that. It's just been in the nightmares.

 

There have been occasions when I've collapsed in those scenarios but it's been more due to dizziness and a sort of momentary loss of information processing from the world around me - I briefly become unsure of what I can see and hear, or which way is up. It feels like my legs stop working at those times not because the muscles can't work but because they don't know what to do.

 

I have had multiple episodes of complete physical collapses. In those instances, I’m not sure I would have been able to get out of my bedroom in the case of a fire.

 

I don't know how much analogy we can draw between engineered systems and biological ones, although on that I would assume the same ideas apply, but any stable system worth a damn would have privileged sub-systems that continue working even when all the rest has been put on hold. So that even if nothing else works, this will continue to draw on minimal reserves because once they shut down, the organism dies.

 

I suspect that there are also overlapping levels of cellular metabolism regulation at both the cellular level and systemic level. For example, we know that the brain and heart have different glucose uptake transporters than other tissues, and that both hypo and hyperglycemia can affect their relative levels (review on this). Brain cancer cells are known to increase their own glucose uptake compared to their neighbors as well (source), indicating a existing mechanism for changing which cells get the lion's share.

I don't think it's out of the question that in conditions of impaired oxidative phosphorylation, there is still preferential distribution of metabolism substrates to the brain and heart. So tissues that can get on with less, like skeletal muscles, are left with pittance rations and the amount of exertion that those tissues can maintain is now lowered.

There doesn't seem to be evidence of mitochondrial myopathies or damage in ME/CFS, but the downstream effects of those issues can be likely be mimicked by other issues in cell metabolism.

Ah you beat me to the thought after I started tying up my response!

 

I'll do my best to summarize my working hypothesis briefly. It mostly addresses the question of why some but not all activity triggers PEM, and why a malic acid supplement may have provided me and some others with such substantial increase in functionality.

The malate-aspartate shuttle is the main process responsible for shuttling electrons (H-) between cytosolic and mitochondrial NAD pools. Mitochondrial NADH then begins oxidative phosphorylation at complex I. The G3P shuttle (via FADH2 reducing ubiquinone to ubiquinol) can also do this, though it is less efficient.

If an impairment in the TCA cycle led to reduced levels of malate, or made the malate-alpha ketoglutarate transporter less efficient, this would result in a reduced maximal rate of electron shuttling.

This may not be an issue most of the time if the cell's current ATP demand can be sufficiently maintained with that reduced maximal shuttling rate. If you had not been active in days before the first day of a CPET challenge, even a less-than-ideal rate of shuttling would have allowed sufficient mitochondrial NADH to already be built up to sustain a few minutes of cycling.

However, once you go beyond that rate limit, ATP usage exceeds what can be maintained by malate shuttling. It's like a battery that is being used at the same rate it is being charged.

In those events, additional ATP can be generated outside of oxidative phosphorylation by upregulated beta-oxidation and glycolysis. However, both of those backups produce substantially less ATP per turn than OxPhos (~2 per glucose molecule or ~5 per fatty acid chain as opposed to 32-38 for OxPhos, depending how you count).

Furthermore, we already know that many immune cells, particularly macrophages, are quite sensitive to shifts in metabolism. For example, increased extracellular lactate has been tied to microglial activation in Parkinson's (source), and impairment of complex I results in macrophages that highly sensitive to stimuli (source). I suspect that they are mediating immune signaling that drives PEM symptoms.

This system in macrophages is quite complicated--we are also learning that some OxPhos activity (particularly Complex I) is required for ROS generation and upregulation of certain cytokines associated with sepsis, for example (source). I'm still in the early stages of hypothesis generation, but I feel like this discrepancy may hold the key for why we don't see vascular inflammation in ME/CFS.

There is much more basic investigative work to be done here, but I think this provides a plausible link between exertion and delayed PEM reactions that occur on the timescale of immune signaling. And it explains why I and others who experienced an effect from the malic acid all described being able to avoid PEM (despite this detail not being shared between us ahead of time).

Added: There is also probably an additional piece of CNS involvement, which I can only speculate about, having to do with neurological sensing of mitochondrial NADH capacity resulting in the feeling of fatigue. I'm thinking that there might be a perfectly rational biological explanation for that "reduced activity motivation" that the BPS crowd loves to harp on about.

 

I'll reiterate that this theory, if correct, never implies a "shortage" of ATP. It simply shows how during exertion, ATP production in the ME/CFS body would more quickly shift to methods that are only able to produce substantially less ATP per "food molecule."

This explanation also provides an answer for why many are able to recover more ability after extended, non-stimulating periods of rest. You would need to reduce ATP capacity below the maximal rate of malate shuttling such that mitochondrial NADH stores can be built up again. If you're very severe and that maximal rate is quite low to begin with, it might be extremely difficult to actually reduce ATP demand enough to start "recharging" again.

This is why I don't see it as an issue that cognitive activities only result in a "small" change in ATP demand. What matters is whether that threshold is surpassed. In an organ that is as constantly metabolically active as the brain, very little increase might be needed to go over that limit.

I'm also particularly interested in descriptions of a "poisoned feeling" that more severe folks on this forum have described. Obviously we can't say for sure without testing, which would require being able to make home visits when someone is in extremely awful PEM, but I am struck by the similarities between what they describe and descriptions of lactic acidosis, which could result from increased reliance on glycolysis (even in only some tissues) if both mitochondrial NADH and fatty acid synthesis cannot be sufficiently replenished due to continued use from the cellular tasks that keep you alive.

 

Jonathan, thanks for sharing your thinking. In the second case, involving autonomic neural circuitry, how would the signals eventually result in signaling pain or no pain? I’ve always been struck by the pain/no pain divide in ME/CFS patients.

 

Just posting this because it seems relevant - my attention was drawn because it talks of the whole musculoskeletal system not just muscle in isolation - for me I'd place disabling pain most frequently/significantly in tendon and ligament rather than the muscle mass, with pain in the muscle mass near constant but at low/medium level:

Endocrine Crosstalk Between Muscle and Bone
Marco Brotto & Mark L. Johnson
2014

https://link.springer.com/article/10.1007/s11914-014-0209-0

Abstract

The musculoskeletal system is a complex organ comprised of the skeletal bones, skeletal muscles, tendons, ligaments, cartilage, joints, and other connective tissue that physically and mechanically interact to provide animals and humans with the essential ability of locomotion. This mechanical interaction is undoubtedly essential for much of the diverse shape and forms observed in vertebrates and even in invertebrates with rudimentary musculoskeletal systems such as fish. It makes sense from a historical point of view that the mechanical theories of musculoskeletal development have had tremendous influence of our understanding of biology, because these relationships are clear and palpable. Less visible to the naked eye or even to the microscope is the biochemical interaction among the individual players of the musculoskeletal system. It was only in recent years that we have begun to appreciate that beyond this mechanical coupling of muscle and bones, these 2 tissues function at a higher level through crosstalk signaling mechanisms that are important for the function of the concomitant tissue. Our brief review attempts to present some of the key concepts of these new concepts and is outline to present muscles and bones as secretory/endocrine organs, the evidence for mutual genetic and tissue interactions, pathophysiological examples of crosstalk, and the exciting new directions for this promising field of research aimed at understanding the biochemical/molecular coupling of these 2 intimately associated tissues.

Sci Hub: https://sci-hub.se/10.1007/s11914-014-0209-0

 

Thanks for the resumé, but it doesn't seem to address my question.
What would be forcing the cells to use these different paths? Where does the problem start?

To be honest the phrase 'we are learning' tends to ring the bell on my bullshitometer rather loudly. So often what a review articles say 'we are learning' is some new fashionable blind alley or, very likely, a reinvention of a blind alley from the 1980s by people who have not read the old literature. I like to decide what I am learning and am not too bothered what others think they are learning!!

 

My best guess is one of the many regulatory mechanisms that act on succinate dehydrogenase.

Okay. I meant it was a recent finding.

 

A good question.
Maybe genetic risk factors determine the symptom expression. Maybe signalling thresholds vary for different people.

 

Yep.

Also by the number of the who get burning muscle pain (particularly in the quads) after activity, who report that the pain only sets in when the muscles relax fully and can be partly relieved by pressure.

There was a discussion about it—maybe 20 – 25 years ago?—among people who were usually well enough to walk around the house and could occasionally tackle cleaning jobs or cooking. It seemed to be a reasonably common experience in that subgroup.

Lying face down so that my quads are compressed against the mattress relieves that pain by about 80%. I can only do it for five minutes because having my neck bent at the wrong angle's nearly as painful, but it ought to tell us something about the nature of it.

 

Strangely that reminds me of the old joke:
Doctor, why do I get pain in the right eye when I drink tea?
Mrs Etherington, have you tried taking the spoon out first?

But I sympathise. I am now so riddled with crumbling joints that there is only one position I can sleep in and I am wondering what happens when that shoulder goes. But then I know how lucky I am to have one position.

 

Yea that’s absolutely me. On my best days I could cook a whole dinner but by the end of it the soles of my feet, legs, and back were absolutely screaming at me. Once I collapsed it would be incredibly painful to stand back up again.

Added: interestingly the lack of that pain was the first thing I noticed from a malic acid supplement. Made me think that the cell metabolism piece had to be upstream of the pain somehow.

 

I would slightly amend that to say that even mild ME can have that 'poisoned feeling'. To me it's pretty much the first warning sign that I have overdone it. In fact I've experienced it long before I had a disabling level of fatigue.

I think it's pretty common, definitely not restricted to the severe end, and it could be some early step in that cascade.