Trial By Error: Professor Jonathan Edwards’ View of ME (includes discussion of exercise and long-term harm)

I understand the respiratory pathways involved but I don't like the term energy demand. Somebody mentioned 'response to demand'. Physical systems respond to signals. They do not respond to 'needs' - that is just our teleological gloss. And if, as Barry suggests, the regulatory pathways are at fault then what might seem to be needs might not seem to be needs after all if one takes into account faulty setting of signalling systems.

My guess is that the sort of inability to do either physical or mental activity during a bout of flu may be in some ways similar to ME. I very much doubt that the problem there is shortage of energy to supply. The energy demand of needing to go to the loo or ringing up work to say you cannot get in is not the problem. The problem is the signalling system that says everything is too much.

I make the point because teleological terms like demand or 'immunity' are widespread in immunology and they badly confuse attempts to understand disease. Disease tends to involve screwed up regulation more than too much or too little of anything in the first place.

Maybe another example would be hypothalamic lesions that generate insatiable hunger. The poor person gets obese because they cannot say no to the 'food demand' that isn't there.

 

I think ortostatic intolerance can muddy the waters here as standing, reaching up is far worse than moving about.

 

This seems relevant to the last few posts (from reddit)

I think observing the normal function during an emergency (or more generally when the patient really wants it) has led some people to believe that there is no real problem, presumably because they don't see what happens afterwards.

 

@Barry what do you mean by "power"?

 

Thanks. I have now shared this online.

https://twitter.com/user/status/1204782408761053184

 

If you apply a given force to move something by a given distance, then it requires a given amount of energy to do that. It does not matter if it takes you a second or a year to do it, it still takes the same amount of energy to do it. But power is about how fast it gets done. To do it twice as fast needs twice as much power. Power = energy per unit time. So a joule is a unit of energy, and power (watts) = joules/sec. Which is why fast cars need more powerful engines.

 

this.

I have had people suggest that I cannot possibly be as ill as I & my carer report me to be, because if I *were literally unable to stand up, for long periods of the time, & having to crawl, then I wouldn't be 'allowed' to live alone… because what if there was a fire....

But I feel confident that in an emergency, while I wouldn't be able to *run*, the effects of adrenaline will for sure lift me from crawling to staggering. The effects of adrenaline/cortisol (or whatever it is) are the most spectacular thing.
I can be struggling to speak & slurring badly, but if something happens to frighten me (which happens occasionally as I live in a rough area) I can be speaking slowly but normally within a few minutes.
It's the reason no Dr has ever seen me at my worst - Drs scare me therefore I am never ever 'bad' around them, regardless of how bad I would be if I were calm & relaxed. Which is very inconvenient frankly.

 

my bold

It feels exactly the same. To the extent that I have mistaken flu/infections for PEM a few times. I only realise that it's actually flu/infection when it doesn't fluctuate at all for a few days & I decide thats weird & therefore take my temperature.... or if I get a bad cough

That message of 'everything is too much' is a very good description of what it feels like.

 

But a self-regulation system adjusts its signals according to the needs of the system being regulated. If a furnace temperature starts dropping below its setpoint (target) temperature, then appropriate signals influence the controller to increase the power into the heater; if it gets too hot the signalling requests the heating power to reduce. The control signals are influenced by the 'needs' of the controlled system - i.e. primarily by the deviation of its measured temperature from its setpoint temperature.

And we have to be very careful what we mean when we use terms like "shortage of energy", because it depends whereabouts in the energy path the shortage is occurring at. A car's tank might be full of fuel, and the fuel might be getting as far as the fuel control valve, whatever, but if the engine management is screwed up it might not be letting enough fuel through to the injectors. So there is no shortage of available fuel supply, but its still not getting to where it is needed - the injectors - at the rate it is needed.

Presumably there could be equivalent issues with people. My wife eats a relatively healthy diet. She does not go short of food. Nor is she excessively overweight. But for whatever reason something seems to prevent her utilizing that energy adequately. If the mitochondria are the point where energy gets finally converted into usable energy within cells, then something is going wrong along the way. And yes, I appreciate that is a very complex puzzle to unravel. But given biological systems have no shortage of their own self-regulation systems, including power regulation presumably, then I don't see why a faulty regulation signal could not be one possible cause of available energy (at the point it is required) being less than it would otherwise be if the regulation was healthy.

I'm not sure if biologists especially think of things in terms of power or not, but nonetheless if a regulation system is managing the rate at which energy is being transferred from one place to another, then it is really about power regulation.

Do please note Jonathan that I'm fully aware you understand all this, and I'm not trying to teach granny to suck eggs. Just trying to let you see where I'm coming from.

 

Me too. I've learned how to discriminate now after many years' experience, but it's not immediate. I have to wait to find out whether my nose actually streams or just feels as if it's about to; whether I actually have coughing fits, or just a painfully tight chest; and whether I have a real raised temperature, or just feel feverish.

There's one other clue, which is that I get a painfully stiff neck with about four out of five viruses, which doesn't happen with an ME flare.

It can take anything from two days to a week to work all this out, as both viruses and flares can start with a long prodrome phase of feeling 'weird' for several days.

 

Likely

 

yes me too. For me it usually takes 4 days. For me it's the lack of any fluctuation whatsoever with flu/virus... & it's on day 4 of thinking 'wow I really ddidnt think i'd overdone it but here we are in PEM anyway'…. day 4 of continually rather than intermittently alternating between sweating& shivering, that I think ... hang on... maybe I actually have a fever this time & hey presto 39degrees. I am always surprised to find an actual temperature.... Thisis why despite the pejorative nature of it, I always preferred 'yuppie flu' to 'chronic fatigue'... at least it was vaguely near my experience even if I not a yuppie.

anyway....

 

Yup. I haven't had PEM for a little over 3 years from carefully pacing. I've had a viral/vertigo thing going on for a month, but was able to go out the other day and walk for 15 minutes. Next day I got what felt like PEM where my symptoms fluctuated for several hours. It caught me off guard because it was delayed.

I can normally power walk for one hour w/o PEM.

 

The signal comes from the brain, mental or physical exertion to achieve a task. A key fact many people don't realise is that effort perception has no direct peripheral feedback, rather it is entirely related to the strength of the signal generated in the brain, as predicted over 150 years ago by Helmholtz. (We also know from the 2 day CPET studies, that effort perception in CFS patients still works normally.)

How do motor units magically switch between ox phos and glycolysis under high demand? The larger motor units that are recruited at high % of maximal voluntary contraction (MVC) already have a metabolic balance favouring higher rates of anerobic glycolysis due to a variety of reasons - structural reasons such as muscle fibres further from capillaries, and being kinetically attuned for high burst output. Above around 70% of MVC, all motor units are recruited (depending on muscle of course) and all additional force is generated through increased firing rates.

Put into perspective, the peak power over 30 seconds (during Wingate test) can be over three times (or more, given specially trained athletes) the amount of power generated at the ventilatory threshold (during CPET). It is not a shortage of venous oxygen, nor muscular ox phos capacity (at least in large muscles such as in the legs) that leads to the anerobic threshold, but kinetics.

During physical activity, you will get a reduction in force if the metabolism kinetics are unable to meet the demand.

Glycolysis is always sufficient, given sufficient glucose delivery and no disease of glycolysis. (otherwise symptoms of low-blood glucose!) The peak demand isn't anywhere near as high as high force output from large muscles. But I suspect too much mental exertion will inevitably lead to feedback.

See also:
"Sugar for the brain: the role of glucose in physiological and pathological brain function"
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3900881/

I don't know. Anorexia is different, because it causes low blood glucose.

This is an interesting discussion. The difference in the analogy between a car and a body is there would be several types of engine all working together in the body.

Some of those engines can run on almost anything, but don't produce much power. Some are efficient but cannot ramp up power production quickly. Some produce high power and can ramp up power quickly, but are very inefficient and polluting.

 

Interesting discussion. Would appreciate your thoughts on this question @Jonathan Edwards, @Barry and @Snow Leopard :

How do the findings by e.g. Fisher - that mitochondria are already running at full speed at rest and then are unable to ramp up further when extra 'demands' are placed on them - fit with your thoughts on 'energy demand' versus 'response to demand' and flux and signalling problems?

But is it normal function though? Or is the adrenaline boost still relative to our reduced function? I can imagine at least jogging away from a fire, if not exactly running, rather than my usual slow walk. But healthy people under the influence of adrenaline can lift cars off accident victims and similar heroics; I rather doubt even the biggest adrenaline boost would enable me to do anything like that. And healthy people also feel flat the day after a major adrenaline-fuelled exertion but not to the degree we do with full on PEM.

 

Is this unpublished research?

I think it's nonsense to say that the "mitochondria are already running at full speed at rest". It is possible in principle that something within the cell is inhibiting the oxidative metabolic pathways. Given the results of the 2 day CPET vs 1 day, it is likely this is somehow triggered as a result of exercise/exertion.

But the key point is that this isn't going to occur with isolated mitochondria (eg. traditional Seahorse test) and indeed other studies have shown that the isolated mitochondria seem to function fine.

 

I don't think we can say this as I'm not aware of evidence that ME patients are producing less ATP than healthy people. (And not just 'statistically less', but 'boxplots effectively don't overlap' less).

Wracking my brain back to biology days, I'm not sure of any reason that any metaphorical wrench in the works would need to be directly impacting respiratory output.

 

Spot on. For me, PEM is not 'tiredness' or 'fatigue'. Rather, I feel sick.

I think even our CFS-friendly researchers are losing sight of this critical point. Most of them appear to be studying 'tiredness' rather than why we feel sick.