Lactic acid, lactate in ME/CFS

[Jonathan Edwards]

Also, does it matter that I’m lactate intolerant?

That's lactose. Lactate and lactose are both called lact- because they are found in milk but that's about it I think.

Edit: I guess lactose gets broken down to lactate by bacteria but that is probably not where the name came from.

 

[Trish]

That's lactose. Lactate and lactose are both called lact- because they are found in milk but that's about it I think.

Lactose is a sugar found in milk. The enzyme lactase breaks it down to its component parts glucose and galactose. I think lactose intolerant people lack this enzyme.

Lactate or lactic acid is an organic acid formed from glucose in anaerobic respiration.

 

[Jonathan Edwards]

Lactate or lactic acid is an organic acid formed from glucose in anaerobic respiration.

Indeed, so presumably the lactobacilli in milk turn the glucose into lactate through anaerobic respiration.

And lactate makes the taste of yoghurt?

 

[jnmaciuch]

Also, does it matter that I’m lactate intolerant?

ba dum tsss

It doesn't, but lactic acidaemia can occur as a result of organ failure, e.g. liver.

Right, where it’s usually assumed to be a byproduct of insufficient oxygen supply or lactate clearance in a damaged organ. But we don’t fully know what it is about the organ damage that leads to elevated lactate levels—ischemia nearly always co-occurs with macrophage polarization and lactate production from them as well, for example.

So I don’t think it’s out of the question that you can have something like immune perturbation in tissue (maybe even somehow triggered by low levels of exertion, without necessarily being a result of passing “anerobic threshold”) and end up with elevated lactate. Which in the absence of an actual infection doesn’t necessarily implicate irreversible organ damage.

 

[Jonathan Edwards]

So I don’t think it’s out of the question that you can have something like immune perturbation in tissue (maybe even somehow triggered by low levels of exertion, without necessarily being a result of passing “anerobic threshold”) and end up with elevated lactate.

That seems pretty unlikey if people with massive immune perturbation all over, in joints, bone marrow liver and spleen and so on with RA don't have raised lactate? The cellular activity in an RA joint is enough to drop local glucose levels to zero but I have never heard of it leading to lactic acidaemia.

If it was that easy to raise lactate I think that would be widely known in intensive care medicine.

 

[jnmaciuch]

That seems pretty unlikey if people with massive immune perturbation all over, in joints, bone marrow liver and spleen and so on with RA don't have raised lactate? The cellular activity in an RA joint is enough to drop local glucose levels to zero but I have never heard of it leading to lactic acidaemia.

So perhaps not “immune perturbation” in general but a specific set of processes that overlap between ischemia, sepsis, and some cases on the more severe end of ME/CFS.

 

[Jonathan Edwards]

So perhaps not “immune perturbation” in general but a specific set of circumstances that overlap between ischemia, sepsis, and some cases on the more severe end of ME/CFS.

Hard to see what that would be?

If lactic acidaemia was a real phenomenon in ME/CFS I find it hard to believe that it has not been documented. People like David Jones and Mike Rennie at UCL studied basic metabolites in blood and muscle in ME/CFS patients and found nothing as far as I know.

 

[jnmaciuch]

If lactic acidaemia was a real phenomenon in ME/CFS I find it hard to believe that it has not been documented. People like David Jones and Mike Rennie at UCL studied basic metabolites in blood and muscle in ME/CFS patients and found nothing as far as I know.

Unless it's transient--I'm inclined to think not every report of abnormal test results here is a fluke because transient lactic acidosis would be entirely consistent with the transient "poisoned" feeling that some pwME describe.

And it's been described as the most profoundly uncomfortable state of their fluctuating ME/CFS, so it makes sense that few pwME are making it to a sample collection appointment for a study when it might be evident in their blood or muscle. There's probably lots of signaling that we don't know about because it would only be detectable in the blood during peak PEM.

Hard to see what that would be?

STING activation, perhaps? Documented in ischemia from apoptotic cell DNA, and would be triggered in sepsis both by uncontrolled infection itself and corresponding cell death.

https://www.sciencedirect.com/science/article/pii/S0753332223012568

 

[Jonathan Edwards]

Unless it's transient--I'm inclined to think not every report of abnormal test results here is a fluke because transient lactic acidosis would be entirely consistent with the transient "poisoned" feeling that some pwME describe.

As far as I am aware there is no suggestion from clinical documentation that lactic acidaemia makes people feel poisoned. If it occurs with competitive exercise I know it doesn't from personal experience. Phenformin poisoning can produce a gross lactic acidosis. I looked after a young woman who had taken an overdose and required massive bicarbonate infusion to correct the metabolic shift and she said nothing about feeling poisoned.

And these lactate levels do not seem to relate to transient episodes after exercise. They are reported without reference to that.

It all looks an uninterpretable mess to me. Maybe with peripheral blood pooling in people not moving about venous lactate is unreliable anyway.

Documented in ischemia from apoptotic cell DNA

Surely in ischemia cell death would be necrotic? And there clearly isn't any ischemia producing cell death in ME/CFS on a daily basis. There would be local pain and an inflammatory response. This just seems completely out of proportion.

 

[jnmaciuch]

Surely in ischemia cell death would be necrotic?

Mostly necrotic but apoptotic as well from hypoxia. Both would lead to STING activation, though only the latter would be intracellular from mtDNA ejection through the BAX pore.

And there clearly isn't any ischemia producing cell death in ME/CFS on a daily basis.

Cell death isn’t necessary for STING activation, just cytosolic DNA. Cell death would just be the source of STING activation in the specific case of ischemia, likely not in ME/CFS if it is a feature there as well.

As far as I am aware there is no suggestion from clinical documentation that lactic acidaemia makes people feel poisoned.

I’ve heard anecdotes that it can, but yes I agree it’s not something explicitly mentioned in literature, which tends to be pretty limited in what gets documented anyways. There also may be substantially different presentations for lactic acidosis from exercise vs. other causes—exercise would also mobilize lots of other metabolites and pathways, and it may matter where/how the lactate is produced.

 

[Kitty]

transient "poisoned" feeling that some pwME describe

They do, but not as transient. Some severely ill people speak of having it most of the time, others every time they get PEM. I've only had it once, but it persisted for months. It was there when I was on bed rest during that crash, and when I was starting to come out of it, and when I'd recovered enough to return to work. No relationship to activity.

 

[jnmaciuch]

Some severely ill people speak of having it most of the time, others every time they get PEM.

Those would be the least likely to end up in a study assessing blood analytes, then.

No relationship to activity.

Yes, I don’t think there necessarily has to be any relationship to “anerobic threshold”.

 

[Arfmeister]

Yes, I don’t think there necessarily has to be any relationship to “anerobic threshold”.

Why not ?

• Is this not part of what frequently is happening with PEM
• Exertion above certain aerobic threshold ⇒ glycolysis outpaces aerobic metabolism ⇒ forcing pyruvate ⇒ causing lactate accumulation
• I presume my main energy production in my muscle cells is impeded because of an impaired oxygen uptake from the blood into the cells or mitochondriaI resume

And these lactate levels do not seem to relate to transient episodes after exercise. They are reported without reference to that.

1) I’m one of those very severe bedbound that have constant burning muscles and muscle pain, worsened by the minimal exertion
- mostly in my arms as those are most used
- but also often jaw muscles after eating / talking
- and my legs explode after my max 2 steps a day.

And IF it’s really bad, I go to sleep with it, and wake up with burning muscles + including poisoned feeling (horrible)
- This poisoned feeling feels very similar to how I used to feel when I ran 10 K ; but in this case, this feeling never drops
- While after high exercise - when healthy - it used to drop in less than 5 minutes


2) in my experience there’s a clear correlation between
Overexertion - and - PEM / poisoned feeling / high lactate
- Correlating with anaerobic glycolysis

But currently it happens even in the morning from the get-go by just moving my arms on the iPad


3) my high lactate measurements
As my doctor and myself have taken an interest in this, my lactate levels have been measured at regular time points since 2017
- consistently the height of the L-lactate in blood corresponds with how bad I feel - including all my symptoms e.g poisonous feeling

Since 2017 consistent high measurements* > 2 mmol/L at rest - while typically is <1.5 mmol/L at rest

• 2017
• 2018 (4x above)
• 2019
• 2024
• 2025 (7x above)

*Some as high as 9 mmol/L
⇒ Measurements >4 are typical of sepsis and will lead to hospitalization and aggressive treatment !!

 

[Arfmeister]

“Some severely ill people speak of having it most of the time, others every time they get PEM.”
- Those severe would be the least likely to end up in a study assessing blood analytes, then.

Yes. 100%
My conviction is that it does not show up more because when this phenomenon happens, you’re in no state to go to a hospital / participate at a trial

 

[Amw66]

ba dum tsss


Right, where it’s usually assumed to be a byproduct of insufficient oxygen supply or lactate clearance in a damaged organ. But we don’t fully know what it is about the organ damage that leads to elevated lactate levels—ischemia nearly always co-occurs with macrophage polarization and lactate production from them as well, for example.

So I don’t think it’s out of the question that you can have something like immune perturbation in tissue (maybe even somehow triggered by low levels of exertion, without necessarily being a result of passing “anerobic threshold”) and end up with elevated lactate. Which in the absence of an actual infection doesn’t necessarily implicate irreversible organ damage.

ischemic cardiomyopathy - impacts mitochondrial activity too ?

 

[Jonathan Edwards]

Why not ?

• Is this not part of what frequently is happening with PEM
• Exertion above certain aerobic threshold ⇒ glycolysis outpaces aerobic metabolism ⇒ forcing pyruvate ⇒ causing lactate accumulation
• I presume my main energy production in my muscle cells is impeded because of an impaired oxygen uptake from the blood into the cells

The idea that anaerobic threshold is important in ME/CFS has been put about by some of the physiology reearchers but I don't see any good evidence for it. Lots of things happen in a muscle when exercised and any one of those might send signals that lead on to PEM. Moreover PEM does not seem to be limited to the muscle used so it seems likely that the signals are systemic or neural.

Lactate does not seem to me to be a plausible source of PEM symptoms because the timing is wrong.

 

[Arfmeister]

The idea that anaerobic threshold is important in ME/CFS has been put about by some of the physiology reearchers but I don't see any good evidence for it. Lots of things happen in a muscle when exercised and any one of those might send signals that lead on to PEM.

Would it make a difference for you if it said : exerting above a certain threshold causes PEM ?

Moreover PEM does not seem to be limited to the muscle used so it seems likely that the signals are systemic or neural.

Yes, brain fog / neural symptoms is (probably) not explained by exercising beyond an anaerobic threshold
- although I’ve read a study about lactate levels in the brain.
(I will post this one in another post)

Lactate does not seem to me to be a plausible source of PEM symptoms because the timing is wrong.

Can you elaborate that?
“What do you exactly mean with the *timing is wrong*?”

In my case the correlation seems to be perfect : lactate = PEM

I’m actually NOT implying that Lactate = cause PEM, but it corresponds

• there are either upstream processes that cause glycolysis and lactate in group of (more severe) patients
• OR feedback loops that enforce these difference forms of PEM (brain fog, tachycardia, nausea, etc.)

 

[Arfmeister]

but I don't see any good evidence for it.

With regards to evidence for lactate in ME CFS or with PEM - there are 2 Research publications

1) Elevated blood lactate in resting conditions correlate with post-exertional malaise severity in patients with ME CFS

From abstract : The study included 123 patients.
- Elevated (n = 55; 44.7%) and normal (n = 68; 55.3%)
- lactate groups were comparable except for PEM, which was more severe in the elevated lactate group after adjusting
- ME/CFS patients with elevated blood lactate at rest may be at higher risk for more severe PEM

*I have checked the data and it seems that:
- research required 3 days with 8 consecutive measurements - which probably excludes the more severe patients with rolling PEM
- which is exactly the group that have consistent high lactate
- No extreme levels measurements like my 9 mmol : most around 2 mmol, one patient with various measurements close to 4 mmol

Elevated blood lactate in resting conditions correlate with post-exertional malaise severity in patients with Myalgic encephalomyelitis/Chronic fatigue syndrome - PMC

Elevated blood lactate after moderate exercise was reported in some of patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). We hypothesised that blood lactate could be also elevated in resting conditions. We aimed investigating ...

pmc.ncbi.nlm.nih.gov

2) Abnormal blood lactate accumulation during repeated exercise testing in ME CFS

Abnormal lactate levels are also shown in the 2 day CPET
- mind you ME CFS patients that can do 2 day CPET are not severe, but Mild - maybe Moderate

Abnormal blood lactate accumulation during repeated exercise testing in myalgic encephalomyelitis/chronic fatigue syndrome - PMC

Post‐exertional malaise and delayed recovery are hallmark symptoms of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Studies on repeated cardiopulmonary exercise testing (CPET) show that previous exercise negatively affects oxygen ...

pmc.ncbi.nlm.nih.gov

 

[jnmaciuch]

ischemic cardiomyopathy - impacts mitochondrial activity too ?

Sure, but my point is that it’s possible to get lactate spikes from various causes, and macrophages have been identified as one such source

 

[Jonathan Edwards]

Would it make a difference for you if it said : exerting above a certain threshold causes PEM ?

People with ME/CFS report that doing more than a certain amount induces PEM.We can speculate that there is some 'threshold' but I am not sure that tells us any more. The thing that makes me worried about a simple concept of a threshold is that it seems to matter a lot how long people are active for. So the threshold involves some integral over time rather than just a value above some specific level at a point in time. From what people say, quite low level activity over an hour or two can be a major problem in a way that five minutes would not.

I find it hard to explain that on any metabolic basis.