A Thought Experiment on Muscles

I'm the only one to have called it the Grand Theory of Everything because that's what it is in my head but it may well not be one!

 

Almost exactly what my PI said to me re: my malate hypothesis

I started by trying to hypothesize what might be a constant difference in pwME that would only start to cause problems during activity. That led me to look closer at previous papers that showed ATP production was not significantly different in pwME--which led to me to ask "ATP production by what method, and under what experimental conditions?".

Looking at the methodology of one paper (Lawson et al.) led me to malate, which happened to explain other semi-consistent findings in the literature (reduced levels of metabolites dependent on mitochondrial NADPH as well as increased metabolites related to beta-oxidation).

Testing it out on myself led to changes that would be consistent with the theory, which I then tried to verify by getting input from others and controlling for placebo effect/priming as much as possible.

In the meantime, I was confirming that the same mechanism seems to be at least consistent with some other findings that have cropped up repeatedly (enhanced glycolysis found in some studies, differences in sphingolipid metabolism, the incidence of alcohol intolerance, etc.).

So at this moment I have some very specific experiments in mind to see if malate-aspartate shuttle activity is different in cells from pwME. That experiment will almost certainly need to be refined based on available cell types, limitations of detection methods, etc.

My theory doesn't provide a clear explanation of how this mechanism would lead to PEM or how it would end up "broken" in the first place. However, if I can pinpoint a specific place in the malate-aspartate shuttle or TCA cycle that is broken, both those questions could be answered by trying to induce that issue in other contexts and see if it leads to other hallmarks of the illness.

The vague speculation I have re: macrophages/microglia would provide a starting point for trying to induce PEM-like effects via that mechanism, but I need to confirm the mechanism first. Or, it could be possible to identify a biomarker in PEM, see what celltypes it arises from, determine all the ways in which production of that biomarker could be triggered, and see if it lines up with my hypothesis or not.

 

I think what Sasha may have meant in a grand theory of everything was more a theory that could provide an explanation for all features of an illness. That would include age of onset, sex ratio, tissues affected, risk genes, blood results, etc. When we identified an effector mechanism for RA the thing that knocked us all for six was that a single interaction could explain the nine apparently unrelated features of the disease. And the context of processes that fed into that explained sex ration, age of onset, blood tests...

I am very much trying to generate a theory for ME/CFS that covers all these things. But part of that is likely to be predicting that some aspects will be variable or inconsistent. Most importantly the theory needs to be at least consistent with features rather than at odds. Perhaps the thing that intrigues me most is that ME/CFS rapidly becomes more common in teenage years. That has to be explainable.

 

But to get to Sasha's question, I think the answer is that this thread is part of asking the question - is there really nothing go on at all in muscle itself and is it all interaction between immune cells and neurons in various parts of the body. Maybe using tissues and consuming energy is not relevant at all. It is all about signals. In which case the apparent disparity between exertion and sensory stimuli would not be a big deal. It would all be neural signalling interacting with immune signalling.

 

I think I am just struggling to reconcile a theory that does not take exertion into account with my experience. If it was just neural signaling interacting with immune signaling, I would not expect to see such a strongly consistent pattern between my ME/CFS symptoms and period of activity beyond a well-defined threshold.

The only way this would make sense is if there was some neural-immune interaction that is unique to both physical and cognitive activity and would only trigger that immune signal at predictable thresholds of activity.

As we’ve already discussed previously on the thread, it seems to be harder to have any periods of “low” activity to clearly see this pattern when you’re already severe, so every single movement is exertive. However, being very mild myself, the relationship to activity could not be more clear. In my mild state, the symptoms that are triggered by exertion are reliably triggered by exertion, and they are never present without exertion.

I’ve spoken to other mild people who confirm the same pattern, though perhaps we just happen to be one small subset in the illness.

 

There are also those of us who are fairly severe yet do not get PEM from cognitive exertion - in my own case, cognitive exertion reliably produces brain fog (and perhaps contributes to my headaches, although that may not be ME related as I've had migraines since childhood) but does not cause PEM whereas significantly exceeding my usual physical activities will reliably do so. It would be interesting to know what % of pwME do get PEM from cognitive exertion & if they differ in any other subtle ways from those who do not.

 

It’s interesting that you mention that—the only times cognitive exertion produced PEM for me was when I was more severe than I am now and I was trying to force myself into a full time university courseload, so I was thinking and reading for 4-6 hours straight while already exhausted.

In my mild state, cognitive exertion produces brain fog, some heat on the back of the skull, and also some headaches, just as you describe. But it doesn’t tend to follow the same dynamics as PEM from physical exertion. Usually it’ll resolve overnight.

I wonder if I could actually trigger cognitive PEM in my mild state—it would probably take something like 8 hours of thinking in a row, which I don’t do anyway and don’t really intend to try.

 

I don't seem to get PEM from cognitive exertion but I do get a bit foggy in the evening sometimes. I wonder if it's PEM in disguise, but like @jnmaciuch' brain fog, it goes away overnight.

 

I agree that my devil's advocate approach calls for a pretty clever neural accounting system. But I could argue that if an ant's brain the size of a pin head can keep track of walking 50 yards and then 50 yards left so that it can then walk straight back to base at 45° then the human hindbrain may be able to keep track of activity in a more complex way. All muscle activity involves nerve impulses so the brain stem could keep track of usage as a way to predict likely food demands or overuse injury.

I have a step counter app and I have realised that my brain logs distances walked fairly accurately anyway, just not explicitly in miles or numbers of steps but having calibrated my sense of how far I can guess what the step counter will say.

 

Have you thought of contacting Robert Phair - he has built a very detailed model of the TCA cycle over many years specifically to test hypothesis and find weaknesses in the production of energy in ME/CFS. An in-silico emulation of your hypothesis could be a good first check.

 

It would have to be a pretty clever accounting system indeed! Since my functional capacity has stayed consistently mild for several years, I've been able to notice reliable factors that will change my "upper limit" on exertion for the same tasks.

Two of the most reliable predictors were waking up at the "wrong" part of my sleep cycle (drastically decreases the threshold, regardless of total amount of hours slept) and eating a high calorie, high fat meal before the activity (drastically increases threshold). So if the brain is doing that accounting, it's also integrating information about circadian rhythm and caloric intake at the very least.

The accounting would also have to be able to track cumulative activity over a period of days, since the activity level triggering PEM is not solely due to duration of one intense activity, but sometimes having to do too many low-to-medium intensity activities over the course of a week without enough "rest" days.

I have no doubt that the brain is involved at some step and that it is a miraculously complex machine. But to me it seems that it would be a much more parsimonious system if the brain is simply capable of detecting something like maximal respiratory capacity from a handful of its cells, rather than integrating all those inputs that would (in the abstract) be related to metabolism after-the-fact to generate a new neuro-immune signal independently from that metabolism.

 

Interestingly, one of the things I noticed in my malic acid experiments was that I no longer had a problem with executive function. It was like I no longer had to "negotiate" and work up the energy to do tasks.

The first time I tried it, I was able to get up and fix the hinges on my kitchen door that had become skewed--something that I had been putting off for days since I didn't feel that I had the energy for it--without a second thought. It was even more effective than my prescription ADHD stimulant in that regard.

If the brain is involved, my experiences would suggest that "motivational capacity" and executive function are actually downstream of cellular metabolism, unless malic acid happens to have some neuromodulatory capability outside of its role in cellular metabolism that has not been explored in the research yet.

I'm not sure how this might be alternatively explained by your theory @Jonathan Edwards, though given that I don't have much expertise in neuroscience I'd be interested to hear any speculation!

 

I have not reached out to Rob Phair but I am in contact with some of his collaborators! I'm interested in his itaconate shunt hypothesis since the primary enzyme involved--succinate dehydrogenase--would explain much of what I've put together independently.

At the moment I have some potential leads for checking the first part of my hypothesis in-vitro, though unfortunately I can't share many details at the moment since I don't have the explicit permission of those potential collaborators.

 

I am sure mine does all those. It even monitors the number of times we have eaten sausages or broccoli pasta in the last ten days and makes me pass by the sausage shelf in the supermarket if we have.

 

So then the question would be whether the brain is integrating all that information independently of metabolism, or whether it is simply tapped in to cellular metabolism where all that information would already be integrated.

[Edit: or perhaps the brain's ability to keep track of distance walked is logged through energy expenditure in the first place! I actually noticed that my perception of distance walked changed quite substantially both when taking a stimulant for the first time and with my malic acid supplement.]

Interesting question! I’d have to ponder how that could be answered experimentally.

 

As someone with quite severe cognitive PEM, the thing that most reliably triggers it is keeping track of mutiple variables at once.

So for example, editing a short story or essay, tracking all the grammar, punctiation issues, things that need rephrasing, sentences that should go in another paragraph etc etd.


Or for mixing music, you are simultaneously thinkng about the volume of each individual track, all of the different effects plugins, what mix busses the tracks are sent through, does that lead guitar fill need to be there, should it be louder, should I cut it from verse 2 for variety, how do I compile this vocal track from several takes etc.

Basically any time that I activate my 'editing brain' it can lead to PEM if I'm not very careful.

Talking to multiple people at once has a similar effect, especially if they talk across me to each other.

 

All of those examples are far more metabolically demanding compared to other tasks.

Memory recall and relying on intuition (I have the same problem with music, though I mix based on gut feel, but as soon as it comes to arranging in non-standard way, recomposing midi, or trying to work out why my synth track has yet again achieved a form of chaos because it sounds different everytime I mix it down, everything bogs down for me and I'm hit with severe brain fog and of course persistent PEM later.

 

I am absolutely sure it is not a change in the lungs.
It is not provision of fuels by the liver, we would see different hormonal responses (insulin, cortisol) if that was the case.
A reduction in the ability to drive the heart due to metabolic factors may limit VO2Max (and cause chronotopic incompetence), but this cannot explain the reduced power at the ventilatory threshold.

I have discussed previously:

The reduced power at the ventilatory threshold can ONLY be explained by increased fatigue-sensing type III/IV muscle afferent feedback and the first ventilatory threshold. Notably this threshold is always coincident with the non-linearity in the reported sense of *****muscular***** effort on the Borg scale during the CPET too (in all participants not just ME/CFS patients). This level of exertion is still way below VO2Max and so participants are far from being out of breath at this level of exertion.

This also matches the experiences reported in this thread, eg. the "lactic acid" feeling is caused by that muscle afferent stimulation.

So the real question is if it is due to a sudden drop in metabolic efficiency leading to increased feedback generating metabolites, or increased nerve sensitivity of these specific afferents, or perhaps both. If it is a metabolic problem, is this problem in the muscles, or is it a problem of oxygen availability? (and there could be related issues with stimulation of autonomic nerves)

Note that the afferent feedback has both attenuating and excitory aspects (this is an important point as the NIH intermural study researchers fundamentally did not understand this) - there is a generalised reduction in motor cortex excitability due to afferent feedback, however there is also spinally mediated excitory effects that adjust the sensitivity of specific motor units as a compensatory mechanism, allowing for increased turnover of use of motor units as they fatigue as well as an overall compensatory increase in excitation to overcome the reduction in motor cortex excitability during fatiguing tasks.

Note that the altering the motor unit recruitment patterns itself can alter muscular metabolic efficiency - there is a spectrum of capillarisation density, O2 transport latency, mitochondrial density etc) and as the recruitment of motor units during a fatiguing task shifts towards fresher but less efficient (in terms of O2 consumption) motor units.

So there is a negative feedback loop whereby lower metabolic efficiency leads to greater fatigue that leads to greater afferent feedback that leads to (compensatory) altered motor unit recruitment patterns (higher threshold groups that have a lower balance of O2 consumption) and so on.

There may be different underlying causes in different ME/CFS patients, I don't assume the underlying pathology is the same in all patients, simply that there is a common factor (persistent and prolonged stimulation of those particular muscle afferents)

Note this also means the effect of afferent feedback can vary based on the task and muscle group that is used. We should not assume there is exactly the same effect in every muscle group or task because the degree of afferent feedback, balance between positive and negative excitory effects, particularly the effect on motor cortex excitability for example, depend on the overall metabolic demand that the muscle group can place on the body - measuring the finger or thumb might have poor sensitivity compared to large muscle groups in the body.

Grip strength during PEM may be reduced, but this is a symptom of altered motor cortex excitability, not the cause of that altered excitability. What new information does it really provide? You can ask the patient if they are experiencing PEM or not.

The brain has it's own parallel system of sensing metabolic state and regulating vascular responses ("neurovascular coupling"). The brain requires a lot of energy/oxygen during intensive tasks and it makes sense that it would have it's own metabolic fatigue sensing mechanism that serves a similar function to that of large muscle groups. And the hypothesis is that problem could go wrong in the brain for the same reason it goes wrong in the muscles.

We literally did a poll and found that ~80% of people people reported it did not feel the same.
https://www.s4me.info/threads/poll-physical-vs-cognitive-pem-same-or-different.16948/

For me, physical activity causes cognitive and physical PEM, whereas cognitive activity does not cause physical PEM, but only cognitive PEM.

I think looking at the absolute calories used is the wrong way to look at it. That is the same mistake as Noakes and others who think fatigue is a result of the brain somehow calculating the overall metabolic consumption of the body and scaling back as a result: "Fatigue is a brain-derived emotion that regulates the exercise behavior to ensure the protection of whole body homeostasis." (Noakes 2012).

We know now that no such system exists (instead, fatigue is regulated by muscle afferents and the effects on the motor cortex) and going down that path of looking at overall energy consumption to explain fatigue sensation is a fool's errand.

The issue is the local metabolic capacity. When that capacity is exceeded, metabolites are generated that stimulate afferents (whether it be the metabolic fatigue sensing afferents in the muscles or the same thing in the neurovascular coupling systems in the brain). Instead of predicting a need for increased ventilation and reduced motor activity a-priori, the brain responds to afferents instead.

There have been studies that show that brain fog is associated with altered metabolism and altered blood flow in the brain, so I still think there is something there to dig into.

The brain doesn't simply go "whoops, I ran out of ATP". Many things have to go wrong before that happens (and I'm not claiming to be an expert in emergency medicine) but the whole point about fatigue is it that it is part of a feedback mechanism that limits that from happening under normal functioning.

Many moderate to severe patients suffer from chronotropic incompetence, so we cannot pretend the performance of the heart is not affected at all.

The heart consumes around 5% of VO2 at rest and is only working at around a tenth of it's (VO2Max) capacity. It has the highest capillarisation density compared to any skeletal muscle in the body. And notably, no scientific study discusses any sort of metabolic fatigue sensing afferent feedback (muscle pressor reflex) within the myocardium itself analogous to that of skeletal muscles.

 

My grand unifying theory is that it is either damage to specific afferent nerves, or the subsequent sensitisation afferent nerves as they recover from afferent, including but not limited to small fibres. This idea expands the general neuropathic pain hypothesis.

The overall pattern of symptoms depends on the types of nerves affected and the organs they are located in.

This is not exhaustive, but:

Skin receptors:
Aβ, Aδ fibres: parasthesias, some forms of dysesthesia
C fibres: some forms of dysesthesia, fibromyalgia, allodynia, certain chronic pain conditions

Muscle receptors:
Type III/IV muscle fibres: sensation of muscular fatigue

Trigeminal nerve:
Aδ fibres- Burning mouth syndrome, Trigeminal neuralgia

Autonomic nerves:

autonomic neuropathy (a form of OI)
neuropathic POTS

Study investigating Oscillatory Cerebral Blood Flow causing impaired neurovascular coupling and brain fog in POTS:
https://pmc.ncbi.nlm.nih.gov/articles/PMC4326551/