Do you believe that “viral persistence” is the cause of ongoing MECFS and LC?

[Jonathan Edwards]

For me, despite individual inconsistencies in studies, I see a strong global pattern pointing specifically to impairment of OxPhos and concurrent upregulation of glycolysis, glutamine metabolism, and beta oxidation as compensatory mechanisms.

I agree that at least some studies suggest a diversion of metabolic pathways. But, like Mike Murphy (mitochondria, Cambridge, UK), I am sceptical that we have any evidence for inadequate ATP production. People who cannot generate ATP generally, as I end stage heart failure, or locally in muscle, as in late myositis or dystrophy, develop involuntary habits for minimising the impact of the deficit that are quite different from those I see in people with ME/CFS.

Disability in ME/CFS looks to me much more like a matter of inhibitory immune and/or neural signals shutting off usage of muscle or brain with a time course that does not look like any sort of ATP depletion.

Shift in pathway usage may be important clues to what the inhibitory signals are, of course.

As I have mentioned before, I am not very convinced by the importance of 'redox'. Again, I am not sure what it would explain to have redox imbalance.

I worry that a lot of ME/CFS research tries to find something that clinically we would not actually expect to find. 'Fatigue = not enough ATP' doesn't seem to me to be a good starting point.

 

[jnmaciuch]

I am sceptical that we have any evidence for inadequate ATP production. People who cannot generate ATP generally, as I end stage heart failure, or locally in muscle, as in late myositis or dystrophy, develop involuntary habits for minimising the impact of the deficit that are quite different from those I see in people with ME/CFS.

I would expect to see a big difference in cases where Oxidative Phosphorylation is almost completely inhibited as in your examples vs. cases where there is an abnormality leading to an upper ceiling in the ability of OxPhos to ramp up to meet demand across the body. That's where redox balance is vitally important, in my opinion--NAD+/NADH ratios between mitochondria and cytosol are the primary limiting factor in ETC activity. Some parts of the body may be able to function just fine on 50% OxPhos capacity + additional compensatory ATP production from other metabolic pathways. Others will not, depending on how much demand is present on them at any given moment. I think it’s no coincidence that the organs with the most fluctuation in short term energy demand (e.g. brain and skeletal muscle) are the sites of hallmark symptoms in response to activity.

I'm particularly encouraged by the massive boost of energy and complete avoidance of PEM I experienced once I started taking a malic acid supplement which would affect the malate-aspartate shuttle and directly increase electron shuttling to the ETC (described in another thread on here). It seems that there are some people who respond extremely well to it (even accounting for placebo effect as much as possible) and others who don't feel much of anything, which just tells me that there are multiple underlying pathologies at play in ME/CFS which may converge to a similar phenotype downstream.

I think there's also room for both our hunches to converge here--given the interplay between immune signaling and cellular metabolism, one may be a downstream effect of the other or vice versa. You're right that "not enough ATP = Fatigue" is oversimplistic, I agree. But I have to disagree on the role of redox and OxPhos in the etiology of ME/CFS symptoms--I think too many points of evidence converge in its favor to disregard, even if the finer details of those relationships are currently unclear.

 

[Jonathan Edwards]

That's where redox balance is vitally important, in my opinion--NAD+/NADH ratios between mitochondria and cytosol are the primary limiting factor in ETC activity.

But I don't see that fitting with the time course of PEM. Once PEM gets going people are often kyboshed for hours or days - or longer. The 'demand' has long gone.

 

[jnmaciuch]

But I don't see that fitting with the time course of PEM. Once PEM gets going people are often kyboshed for hours or days - or longer. The 'demand' has long gone.

I think that part is mediated by the immune system! Particularly macrophages, which would be shifted into a pro-inflammatory phenotype if they are unable to meet energy demand with OxPhos (which could be ROS-mediated, as I mentioned before, or a result of compensatory glycolysis activating a gene program, or an as-of-yet unidentified mechanism).

Then you have a longer term inflammatory cascade that fits the time frame of PEM, but the initial insult was still energy metabolism-related. And if the same mechanism (upper ceiling on mitochondrial NAD(P)H levels) prevents the body from ramping up production of cortisol or any other steroid with potent anti-inflammatory effects to counteract global inflammation, this could explain longer PEM timeframes in folks with more severe ME—you could get trapped in a pro-inflammatory feedback loop.

I’ve been very interested in emerging studies about how pro-inflammatory phenotypes can be elicited in macrophages solely by altering the balance between glycolysis and OxPhos. TCA cycle metabolites also play a role here—I remember seeing a paper where local administration of L-malate was able to almost completely reverse macrophage-mediated spinal cord inflammation in an anklyosing spondylitis mouse model. Iirc they attributed this both to enhanced OxPhos activity from increased malate levels, as well as direct actions of malate on signaling pathways.

Obviously much more work needs to be done to investigate the specific causal interactions here, but I think the existing evidence certainly shows plausibility

 

[Kitty]

I think that part is mediated by the immune system! Particularly macrophages, which would be shifted into a pro-inflammatory phenotype if they are unable to meet energy demand with OxPhos (which could be ROS-mediated, as I mentioned before, or a result of compensatory glycolysis activating a gene program, or an as-of-yet unidentified mechanism).

Then you have a longer term inflammatory cascade that fits the time frame of PEM, but the initial insult was still energy metabolism-related. And if the same mechanism (upper ceiling on mitochondrial NAD(P)H levels) prevents the body from ramping up production of cortisol or any other steroid with potent anti-inflammatory effects to counteract global inflammation, this could explain longer PEM timeframes in folks with more severe ME—you could get trapped in a pro-inflammatory feedback loop.

I'm not a scientist so I don't understand any of this, but does it fit with there being no shortage of "energy" (whatever that consists of) once the PEM threshold has been breached?

Because for people with mild and moderate ME/CFS at least, the problem with overexertion is that it often results in excess energy. People call it wired but tired, but that doesn't give a good picture of the sheer unpleasantness of it. Or that fact that it can easily persist for 36 hours, during which time no sleep is possible.

PEM then progresses to greatly worsened fatigue, but it's possible it's at least in part a response to what you could almost describe as a manic phase.

 

[jnmaciuch]

I'm not a scientist so I don't understand any of this, but does it fit with there being no shortage of "energy" (whatever that consists of) once the PEM threshold has been breached?

Because for people with mild and moderate ME/CFS at least, the problem with overexertion is that it often results in excess energy. People call it wired but tired, but that doesn't give a good picture of the sheer unpleasantness of it. Or that fact that it can easily persist for 36 hours, during which time no sleep is possible.

PEM then progresses to greatly worsened fatigue, but it's possible it's at least in part a response to what you could almost describe as a manic phase.

That’s a great question, I’ve definitely experienced it myself with PEM. I have a feeling it’s related to catecholamines (epinephrine/norepinephrine) since I’ve been able to stop that wired-tired effect (or at least lessen it) somewhat successfully with a beta blocker. Catecholamines would have an effect on glucose utilization, potentially firing up glycolysis even further to (inefficiently) compensate for OxPhos deficits in the short term until you finally crash.

There’s a well studied relationship between pro-inflammatory cytokines, norepinephrine release, and cortisol—and there are many positive and negative feedback loops between all three. If that balance is dysregulated by inability to increase cortisol to counter inflammation, it might lead to the rest of the system getting knocked out of balance.

That’s pure speculation based on my own experiences though—definitely worth more investigation.

 

[Murph]

I am sceptical that we have any evidence for inadequate ATP production.

At the risk of being pedantic on the any .... Hwang's study on the patient with Li Fraumeni and mecfs showed this.

"Measuring the regeneration of phosphocreatine (PCr) after its utilization by exercise in skeletal muscle using 31P-MRS can noninvasively assess mitochondrial ATP synthesis capacity" the paper says, and the charts show the me/cfs patient (s1) with slower PCr regeneration.

 

[SNT Gatchaman]

The acute or cumulative subacute demand might have gone, but the ability to return to normal levels of ATP production could still be delayed. Perhaps metabolic rescue pathways would come at a cost, including more ROS generation which further impairs the mitochondria. And as ATP itself is a signalling molecule lack of spare might also impede some of the messaging to other cells to unwind and "stand down".

Presumably this sort of situation would be different to that of inborn errors of metabolism (mitochondrial myopathies etc). As the defect is present from birth, different signalling may have developed. As far as we know we all initially had a normal healthy metabolic system, including its intercellular controls.

 

[Jonathan Edwards]

Particularly macrophages, which would be shifted into a pro-inflammatory phenotype if they are unable to meet energy demand with OxPhos

But there isn't any inflammation !!
What is a 'pro-inflammatory' phenotype anyway? The jargon in this area seems to me to have wandered away from histological reality in the last twenty years.

 

[Jonathan Edwards]

the paper says, and the charts show the me/cfs patient (s1) with slower PCr regeneration.

I am happy that there may be changes in metabolism but that does not imply that the ATP availability is actually inadequate in a way that might explain symptoms. Disability in ME/CFS does not look to me clinically to be due to lack of ATP per se. It is much worse and more prolonged than it would be if that were the case, rather as Kitty suggests.

 

[Jonathan Edwards]

Perhaps metabolic rescue pathways would come at a cost, including more ROS generation which further impairs the mitochondria.

But do we have evidence for this 'ROS generation'? Or damage from it? If this is the story why has nobody picked it up on MR spectroscopy of muscle? And they were doing that three doors along the corridor from me at UCL in the 1980s.

 

[jnmaciuch]

But there isn't any inflammation !!
What is a 'pro-inflammatory' phenotype anyway? The jargon in this area seems to me to have wandered away from histological reality in the last twenty years.

Can I ask what evidence you're looking at for lack of inflammation? I've certainly seen papers of the years showing a differential cytokine milieu, even in the LC paper I just worked on assessing physical function post-COVID. FGF21 has come up repeatedly, as well as cytokines associated with vascular inflammatory conditions. I agree there's a lack of constant acute inflammation, and that the profiles might be inconsistent. Furthermore, there's a possibility of localized inflammation signature that doesn't strongly reflect in the blood in all studies--given the ubiquity of muscle pain and stiffness and their responsiveness to NSAIDs (at least somewhat responsive, in my case), I don't think localized inflammation can be discounted, but happy to read more and revise my thoughts based on the evidence.

I agree that "pro-inflammatory phenotype" is an oversimplistic way to refer to macrophage polarization, which is itself oversimplistic. General phenomenon I'm referring to is induction of a GM-CSF signaling, local release of pro-inflammatory cytokines phenotype in macrophages by inhibition of OxPhos

 

[Jonathan Edwards]

Can I ask what evidence you're looking at for lack of inflammation? I've certainly seen papers of the years showing a differential cytokine milieu, even in the LC paper I just worked on assessing physical function post-COVID.

Patients. Friends. Arms, legs, MRI scans.

Cytokine milieus aren't inflammation. I know that has become the fashionable way to look at things but inflammation is a physiologic change based on blood vessels which is not seen in ME/CFS. It produces redness, heat, swelling and pain. Chronic inflammation is less red and painful and the swelling has a different basis but it is still based on local changes in vessel physiology.

All this cytokines are known to be 'pleiotropic'. They do lots of different things, one of which may be taking part in inflammation, but they can also contribute to non-inflammatory pathways.

If you start changing the meaning of words and take them out of context you tend up with the sort of muddle that clinical immunology has sunk into in the last two decades. I suspect because immunologists aren't trained in histopathology any more. Immunology is, above anything else, about compartments - very specialised compartments, each with different and sometimes opposite rules.

 

[Jonathan Edwards]

I agree that "pro-inflammatory phenotype" is an oversimplistic way to refer to macrophage polarization, which is itself oversimplistic.

It's another aspect of the muddled thinking since 2000. We separated out all sorts of different macrophage states long before that - crucial to understanding disease, but if nobody knows any histology they don't understand so everyone gets lost with in vitro artefacts. In a lymph node there are macrophages within a millimetre of each other with maybe half a dozen different phenotypes, all location specific. The idea that all your macrophages are feeling a bit 'pro-inflammatory' because of a shift in metabolism seems to me totally implausible.

 

[jnmaciuch]

@Jonathan Edwards thanks for the clarification, I will be more specific in my language to avoid confusion.

As a follow up, what do you think is behind the widespread pain and muscle stiffness in PEM if not inflammation? And why might it be responsive to NSAIDs?

 

[bobbler]

@Jonathan Edwards thanks for the clarification, I will be more specific in my language to avoid confusion.

As a follow up, what do you think is behind the widespread pain and muscle stiffness in PEM if not inflammation? And why might it be responsive to NSAIDs?

It’s an interesting one because I have other issues/injuries that mean I’m on pretty continual NSAID (and I can tell when it has actually worn off by symptoms - stiffness / burning pain on those in particular)

and in pem I’ve always specifically had ‘rheumaticky’ symptoms that flare up with pem then go when it’s rested off particularly in wrists and ankles (although I get ‘stiff ankles’ more constantly particularly the ‘front’ from lower leg to over foot flares up and I get achy hands anyway but my wrist feel as tho they are hot and achy and with both I’m ’chasing cold sheet’) and that’s still the same since being on NSAIDS

oh and when eg my calf muscles get so inflamed feeling/stiff in pem (if I’ve used them) I can lose my balance seems to be the same.

however interestingly my injuries also seem to flare in line with the pem (timing wise too interestingly) - even exempting / factoring in the ‘joint cause’ of eg of if exertion has taken place. Except those tend to need heat for relief (rather than cold - although when they’ve been acute I’ve used ‘cold’ as required on certain bits). And of course they flare due to other things too as well and of course that is much more marked whereas the pem is just exacerbating what level is already there from that

 

[Utsikt]

As a follow up, what do you think is behind the widespread pain and muscle stiffness in PEM if not inflammation? And why might it be responsive to NSAIDs?

Where do you get NSAID for PEM pain from? Afaik, there are many patients that report that nothing helps for their pain, so at best, it must be a subgroup that responds to NSAID?

 

[jnmaciuch]

It’s an interesting one because I have other issues/injuries that mean I’m on pretty continual NSAID (and I can tell when it has actually worn off by symptoms - stiffness / burning pain on those in particular)

and in pem I’ve always specifically had ‘rheumaticky’ symptoms that flare up with pem then go when it’s rested off particularly in wrists and ankles (although I get ‘stiff ankles’ more constantly particularly the ‘front’ from lower leg to over foot flares up and I get achy hands anyway but my wrist feel as tho they are hot and achy and with both I’m ’chasing cold sheet’) and that’s still the same since being on NSAIDS

however interestingly my injuries also seem to flare in line with the pem (timing wise too interestingly) - even exempting / factoring in the ‘joint cause’ of eg of if exertion has taken place. Except those tend to need heat for relief (rather than cold - although when they’ve been acute I’ve used ‘cold’ as required on certain bits).

That’s interesting! In my case, I’ve been able to increase the amount of time I can be continuously active and substantially lessen PEM by taking 2-3 naproxen sodium tablets before I start an activity, like if I’m commuting for a doctor’s appointment. It seems to be less effective if I take it once I’m already in the full swing of PEM, though it does help somewhat if I take more at once (being mindful not to give myself stomach ulcers). I always attributed that to the NSAID just not being effective enough to counteract the full force of whatever’s happening during PEM, but it can prevent things from ramping up too strongly to begin with.

Edit: In addition to taking some before activity, I normally have to continuously take one tablet every few hours until I’m sure PEM is over, as well. If I don’t, PEM immediately ramps up again and can’t be controlled by more NSAIDs. But taking it beforehand and then continuously seems to keep things under control.

Funny that you mention stiff ankles—I had a workup by a D.O. a couple years ago and she mentioned that she’s only ever seen someone with my level of ankle stiffness in former athletes. There was even an audible crack when she rotated my ankles in a specific way. She was shocked that I didn’t have any other signs of rheumatological issues.

 

[jnmaciuch]

Where do you get NSAID for PEM pain from? Afaik, there are many patients that report that nothing helps for their pain, so at best, it must be a subgroup that responds to NSAID?

See above message, I also personally know two people with ME/CFS that have reported similar experiences with taking NSAIDs ahead of time. (Small sample size, obviously)

Interestingly, another pwME I know also has anklyosing spondylitis, and normally has to take huge amounts of THC/CBD for any pain relief. Upon taking the malic acid supplement, they experienced a level immediate pain relief that surpassed an extremely strong THC gummy.

you’re right that it might only be a subset, though. Also, when my condition was worse and I was already 24 hours into PEM, NSAIDs would do very little for reasons I’ve already speculated on.

 

[bobbler]

That’s interesting! In my case, I’ve been able to increase the amount of time I can be continuously active and substantially lessen PEM by taking two naproxen sodium tablets before I start an activity, like if I’m commuting for a doctor’s appointment. It seems to be less effective if I take it once I’m already in the full swing of PEM, though it does help somewhat if I take more at once (being mindful not to give myself stomach ulcers). I always attributed that to the NSAID just not being effective enough to counteract the full force of whatever’s happening during PEM, but it can prevent things from ramping up too strongly to begin with.

Funny that you mention stiff ankles—I had a workup by a D.O. a couple years ago and she mentioned that she’s only ever seen someone with my level of ankle stiffness in former athletes. There was even an audible crack when she rotated my ankles in a specific way. She was shocked that I didn’t have any other signs of rheumatological issues.

Is it weird or tactless to say it’s good to hear from a fellow sufferer of ankle stiffness?

it’s one I don’t know if I mention much so no idea if loads of pwme have it but it certainly seems one most laypersons don’t expect!

I did used to train in athletics and do lots of other sports etc until mid-teenager ie pre-ME but I’m assuming she was talking about people who did it for enough years that it’s like the worn out knee scenario

the burning calves (that I edited to add) was one my days of sport/training definitely gives me insight for because it was so distinctive as someone who was used to muscle aches from crazy amounts of training and the ME thing is just a totally different level to that… from just eg driving (at the time.. now it is tiny steps into an appointment or in house or sitting with legs down even)

yes mine is pretty high dose but time release so only difference I can think of bs your naproxen is that you are hitting it with a big shorter term dose vs mine