Is ME a metabolic problem or a signalling problem?

Thank you for that!

 

I've got very behind with these threads, but the reason may be of interest here. I went down with ME in 1999, but in 2005 went down with polymyalgic rheumatica: (PMR) the treatment for that is steroids. On 25mg for a few days, my comfortable performance level went up from what I describe as ME 20% to more like 40 to 50%. Then, of course the dose was reduced steadily, and fairly quickly down to 15mg, then more slowly to 10mg. My comfortable performance level (aerobic threshold) dropped with it.

I've been on 10mg pretty much ever since. Every now and then various doctors feel it is appropriate to cut back, so I gently drop to 7.5mg, get terrible sinus-headaches, muscle pain etc. (above the usual ME stuff), and go back to 10mg. I'm currently on another very slow reduction routine, and am down to 7mg, with the vitality of a slug.

No doubt it will be another pointless blood test, and a return to 10mg and a more reasonable life.

As I understand it, some doctors have reported that some of their ME patients improve with steroids. Many people with ME seem to suffer very badly with them, and suffer when they come off them.

So, are steroids slowing down the signalling? Are they increasing my aerobic threshold in some other way? Or is it just that the PMR is still there and keeps emerging?

Solutions please: entry fee £2 with a chance of winning a free weekend in Winnie-the-Pooh country.

 

Just realised I must have been missing something this thread (I think) makes very obvious here. Is it the case that our blood acts as a transmission carrier for much of the body's signalling information? Sort of broadcast signalling. If so then faulty signal information could presumably adversely affect multiple parts of the body simultaneously, to varying degrees in different people.

Not really kept up with this thread.

 

If that's the case, it sounds like something that would be extremely complicated to treat imho

 

Not necessarily I would have thought, in my completely medically uneducated opinion.

If a single particular signalling problem were identified as the root cause, even if it in turn triggered other signalling problems and a myriad other effects, then fixing that one signalling problem might sort things. The big conundrum that precedes all of that, is identifying the root cause in the first place. And of course as you say, depending what that is, it could prove simple or complex to fix.

 

As I understand it, (mind goes blank while searching for a name that I should know) the researcher, my age, with a son severely affected, has filtered the blood serum/plasma and found that it is a large molecule that is doing the signalling. I would interpret it as "signalling" rather than being a key player as it appears to be a small trace.

Perhaps if I block out all the large molecules entering the brain in my blood stream, I won't feel so useless when it comes to remembering important names. Mind you, it might block out the red cells as well: I gather they can be important.

This is where I wonder about my experience with steroids: do they affect that trace signal? If so, is the trace signal always there, but in minimal quantities, so that the steroid can lower that signal even further and produce performance gains even in healthy people?

 

Ron Davis?

Hope you feel a bit better soon Graham.

 

Ditto.

 

Thanks for your good wishes, but it's just a temporary phase while I'm cutting back on the steroids. Once I return to my usual dose I'll be back to my usual irritating self. That's more than many of you can hope for, so sympathies should be with you.

 

Hey! Who said that any of us have irritating selves?!

 

Interesting question. Strikes me there is no knowing at this juncture. From my own experience and others' reports, people often experience inflammatory reactions of all kinds consistent with TH2 shift at the very least. This involves a plethora of inflammatory issues any one of which could make a normal person feel a degree of fatigue and it may be that the energy dysfunction in ME is a cumulative symptom of various inflammatory responses. Whether the PEM / metabolic dysfunction symptom is improved by steroids I do not know but it seems likely that other inflammatory reactions would be, so it is not possible to say for sure if you feel a subjective improvement because steroids help the PEM response or because they are helping with other inflammatory responses so reducing the overall burden of inflammation etc on top of the PEM response. If that makes sense

 

I've thought for a while that the delay in PEM (for me, 24-36 hours generally) is closest in experience for a healthy person to an extreme form of delayed onset muscle soreness (DOMS). Any of you that used to run regularly will have experienced the fact that the pain from pushing oneself is generally at its worst the day after the day after. So, for me, I don't feel that the process delay is any longer to that in DOMS, but the response is several magnitudes of order worse - including additional symptoms than just muscle pain - and requiring significantly longer to recuperate.

If PEM were to be an extreme form of DOMS, I think that would still lead to a question similar to that which opened this thread: what is causing the extremity? Do ME/CFS patients have something that interferes with metabolism causing damage to tissues/metabolic capacity in PEM? Or does exertion cause a signalling issue that reduces future capacity? Or are the tissues pretty much fine, and our nervous systems effectively 'over-report' DOMS?

I have no idea of the answers to those questions but if I were a betting person I would take a punt that in ME/CFS patients post-exertional changes that occur in healthy people (causing DOMS) go awry somewhere and cause much more extreme versions at a much lower activity threshold. (And it is a punt, this is just speculation)

 

You just diagnosed me right there.

 

Impaired/slowed signalling from the brainstem is a finding/theme in the work of Leighton Barnden and also Michael VanElzakker. I wanted to bring this up as soon as I scanned this thread, to add it in to your considerations. Personally, I do see the brainstem as the headquarters of the problems I and many others have with ME. Couldn’t it be the impaired “command and control center” that @alex3619 also refers to?

Please excuse my inexpert formatting of the thread title below, but this is the one I hope you might look at, to broaden your considerations on impaired signalling:

Question collection thread for S4ME Q&A with Dr Michael VanElzakker

 

I wonder whether this will turn out to be relevant:
https://www.quantamagazine.org/nobel-prize-awarded-for-cells-adaptations-to-oxygen-20191007/

 

Regarding PEM I am guessing there is some kind of cycle in the body of an ME patient which goes like this:

Overexertion -> affects X -> affects Y -> affects Z -> produces PEM symptoms.
(There could be more intermediate steps as well as X, Y and Z.)

This cycle would take a while after the overexertion to lead to the PEM symptoms.

As for when we get permanently or semi-permanently worse after overexertion... Perhaps it could be a vicious cycle where, for example, being exposed to too much Z for too long leads to long-term worsened function of, for example, X process.

 

What is your opinion on this?

The scientists showed that when oxygen is in short supply, a protein complex that Semenza called hypoxia-inducible factor, or HIF, builds up in nearly all the cells in the body. The rise in HIF has a number of effects but most notably ramps up the activity of a gene used to produce erythropoietin (EPO), a hormone that in turn boosts the creation of oxygen-carrying red blood cells.

 

I am not aware of any evidence of increased RBC or erythropoietin in ME patients.

The early response of local oxygen problems is an increase in lactic acid, and usually this is in the presence of lots of carbonic acid. This acidification causes RBCs to dump more oxygen due to enzymatic effects. If sustained over long periods, as in days, this can decrease synthesis of a critical enzyme, resulting in lower oxygen release and potentially leading to lactic acidosis, which creates a feedback loop. I have yet to read about any ME patient with lactic acidosis, but I am alert to the possibility.

An increase in EPO would be interesting, but has anybody even tested for this?

 

I agree with Alex.

 

Theres a FB-group where ME-patients upload their lactic acid tests results, and given that these devices are somewhat reliable, many of them have readings in lactic acidosis territory.

Saw this on Wikipedia: "Lactic acidosis sometimes occurs without hypoxia, for example, in rare inborn errors of metabolism where mitochondria do not function at full capacity. In such cases, when the body needs more energy than usual, for example during exercise or disease, mitochondria cannot match the cells' demand for ATP, and lactic acidosis results"