Substrate utilisation of cultured skeletal muscle cells in patients with CFS

[Hufsamor]

https://www.nature.com/articles/s41598-020-75406-w

This study has shown that the ability of CFS skeletal muscle cells to utilise glucose as a substrate is diminished compared to healthy control cells. However, CFS skeletal muscle cells were shown to oxidise galactose and fatty acids normally as well as demonstrating normal glycolytic function. The study indicates that the cellular bioenergetic dysfunction in CFS lies upstream of the TCA cycle.

 

[andyguitar]

Thanks for posting that @Hufsamor looks interesting!

 

[ljimbo423]

I seem to need a constant supply of glucose or my ability to think (what little I have ) goes rate down the tubes. After I eat, I often feel like somebody flipped a switch in both my body and brain.

Conclusion

CFS skeletal muscle cells show similar dysfunction in mitochondrial respiration as PBMCs.

The inability of CFS cells to utilise glucose as a fuel source to the same extent as healthy controls results in decreased mitochondrial respiration at both basal and maximal levels.

The ability of CFS skeletal muscle cells to utilise galactose and fatty acids to the same extent as healthy controls suggests that the dysfunction is in the link step between glycolysis and the TCA cycle.

The similarities between dysfunction seen previously in PBMC and those seen here in muscle cells suggests that CFS is a multi-tissue disease, which reflects what patients report and the symptoms they present with.

 

[andyguitar]

I seem to need a constant supply of glucose or my ability to think (what little I have ) goes rate down the tubes. After I eat, I often feel like somebody flipped a switch in both my body and brain.

So @ljimbo423 are you thinking that the problem identified in skeletal muscle cells is present in other cells? The brain maybe?

 

[ljimbo423]

So @ljimbo423 are you thinking that the problem identified in skeletal muscle cells is present in other cells? The brain maybe?

I think it's possible. This paper showed the muscle cells have this problem. Another paper showed the same issue in PBMC's, which are immune cells. It makes sense to me that whatever is causing this issue in the body could be doing something similar in the brain.

BTW, I think the study on PBMC's is the Fluge and Mella study. They hypothesized that it was immune system activation that was causing the mito. dysfunction in their paper.

If it is the immune system causing both of these findings, it makes even more sense to me that the brain mito. could also be affected.

 

[andyguitar]

I think it's possible. This paper showed the muscle cells have this problem. Another paper showed the same issue in PBMC's, which are immune cells.

So then the next step could be to see if other cell types have the same abnormalities. Should'nt be to difficult.

 

[andyguitar]

After I eat, I often feel like somebody flipped a switch in both my body and brain.

Insulin release perhaps?

 

[ljimbo423]

So then the next step could be to see if other cell types have the same abnormalities. Should'nt be to difficult.

I would think the more different cell types they find this same dysfunction in, the more credence that would give to deep diving into researching what's causing it.

Insulin release perhaps?

I don't know if it's just insulin, although that might be part of it. I say this because I feel soooo much more clear-headed and have a very noticeable increase in energy from my evening meal, which is almost all fat and protein. So it wouldn't raise insulin very much.

I'm now thinking it might just be anything that feeds the TCA cycle, so there are more substrates for the creation of ATP. Fat and some amino acids feed the TCA cycle after pyruvate dehydrogenase. So according to this paper they would bypass the dysfunction somewhere between the TCA cycle and pyruvate.

The normal basal functioning of CFS skeletal muscle cells when using galactose or fatty acids as substrates, coupled with normal glycolytic functioning may indicate that the problem is in the link step between pyruvate and the TCA cycle.

This could potentially include defects to pyruvate dehydrogenase complex (PDH), pyruvate dehydrogenase kinase (PDK), or mitochondrial protein carriers (Fig. 6).

This fits with a study which used a PDK inhibitor in an open-label proof-of-principle trial and a study by Fluge et al. looking at PDH dysregulation in CFS blood samples7,20.

I wonder if this could also be happening in the brain as well as the body. That might explain a lot.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5161229/

 

[sometexan84]

The article says...

"may indicate that the problem is in the link step between pyruvate and the TCA cycle. This could potentially include defects to pyruvate dehydrogenase complex (PDH), pyruvate dehydrogenase kinase (PDK)"

and that sounds about right...

The new healthrising article with Dr. Ina Katrine Petterson mentions the PDH inhibition through increased PDKs (pyruvate dehydrogenase kinases).

She says this in regards to why there is increased PDKs....

Petterson proposed that some sort of immune response that is causing metabolic stress is responsible

Then, let's go back to this 2016 (EDIT - SORRY, this is actually 2018) article on treating ME/CFS with sodium dichloroacetate. (that's where the graphic above came from)

It's basically talking about the exact same thing. Except they are actually talking about treating the PDH inhibitory effect of the PDKs.

Now let's take another detour. This is a 2011 article on Epigenomic deregulation in the immune system. It mentions our old friend EBV in the section Virally driven epigenetic deregulation in the immune system.

And now we're looking at it this way...

EBV is causing epigenetic DNA alterations, deregulating the immune activity of the T-lymphocytes. This leads to PDH inhibitory effects, making the mitochondria work extra hard, and inefficiently.

 

[ljimbo423]

Then, let's go back to this 2016 article on treating ME/CFS with sodium dichloroacetate. (that's where the graphic above came from)

While I think that impaired PDH from up-regulated PDK might be part of the problem, it doesn't seem to be the whole problem.

As we know, there are many, many different infections that can trigger ME/CFS. There are also many things that can up-regulate the immune system and activate PDK, therefore impairing PDH function.

The results from DCA, vitamin B-1 and ALA intervention only showed improvement in 45% of patients and they didn't fully recover. They had about a 43% decrease in fatigue. So there seems to be pieces of the puzzle missing. Maybe effects ME/CFS is having on the brain.

From the study you posted-

Results

One responder experienced an adverse effect, namely the occurrence of generalised moderate tremor, which disappeared immediately after the dose of DCA was decreased.

Ten patients (45%) responded favourably, and their FSS decreased from an average of 6.00 points (SD: 0.68) before treatment, to an average of 3.48 points (SD: 0.98), corresponding to a decrease of 42.7% (SD: 17.8%; student’s t-test for paired observations: P = 0.0001). In the 12 non-responders the FSS was 6.43 points (SD: 0.47) before treatment, and 5.96 (SD: 1.06) after treatment (P = 0.13).

 

[Murph]

This is a small study but a good one (one likely reason it is small is not many people are willing to do muscle biopsies, which are painful!)

It shows a failure in the energy cycle. It identifies that failure as being related to the use of glucose, and suggests the body can work better on other types of energy.

One reason I'm interested in this study is it provides more research backing to a suggestion I got from my doctor a few years ago, which was to take whey supplements. I began doing that and got great benefit. (Thread: https://forums.phoenixrising.me/thr...ng-identified-by-researchers-which-one.48557/). His suggestion was based on research from Fluge and Mella in Norway. They first identified the PDH blockage mentioned above in this thread.

There's also a fascincating suggestion of a compound that could (maybe, possibly, in vitro, in a small study) fix the problem.

This work has shown that CFS skeletal muscle cells have decreased OXPHOS compared to healthy control cells when glucose is used as a substrate. This is also similar to what has been shown previously in PBMCs4. When using glucose as a cellular substrate we treated skeletal muscle cells with two AMPK activators—compound 991 and metformin. Compound 991 (which is yet to be tested in clinical trials in humans) is a direct AMPK activator12. Compound 991 treatment appears to bring the OXPHOS levels of CFS patient cells up to the same level as untreated control cells. It is unclear whether this effect would extend to cells undergoing exercise in vitro using electrical pulse stimulation (EPS) as there is currently no way to incorporate EPS within seahorse experiments.

Compound 991 will stimulate AMPK, which is a molecule whose role is sensing how much energy we have. It looks at the ratio of AMP (spent energy cartridges) to ATP (full energy cartridges) and makes cells react.

AMPK is not necessarily the thing that's broken though. It might be correctly sensing a ratio of ATP to AMP that is wrong.

I did an analysis of Naviaux's metabolite findings and found that ATP is not unusually low in our blood but the chemicals into which it degrades (AMP and Adenosine) are low. This could be evidence that ATP in the blood is not being broken down properly.

 

[andyguitar]

Compound 991 (which is yet to be tested in clinical trials in humans) is a direct AMPK activator12.

It could be a long time before it is available but........

—compound 991 and metformin.

Metformin is available now.

 

[xebex]

I have heard of people using metformin for me/cfs but I have no idea how. Anyone got an ideas or can link to anyone who would know?

 

[andyguitar]

If you put "metformin for me/cfs" into google you will get a few ideas @xebex

 

[Rufous McKinney]

After I eat, I often feel like somebody flipped a switch in both my body and brain.

I am very very similar.

Then, let's go back to this 2016 article on treating ME/CFS with sodium dichloroacetate. (that's where the graphic above came from)

In my back cabinet- I purchased several bottles of sodium dicholoroacetate- this happened in late January and I bought it for COVID. It was recommended - in some Japanese research paper.

so now, I should be really giving DCA a try. there is sits in the cabinet looking very chemical and I"m nervous about trying it. Which is not helpful when experimenting.

 

[Rufous McKinney]

Metformin is available now.

My chinese herbalist does not want me on metformin...but I"m forgetting the reason....so I need to ask him again about that..it sounded rather miraculous at first, then he suggested it would do any number of - adverse side effects I should be trying to avoid.

 

[Rufous McKinney]

Just read there was a May 2020 recall on time release metformin...due to a contaminant.

 

[andyguitar]

My chinese herbalist does not want me on metformin

Ask him about goats rue.

 

[raghav]

Metformin inhibits mito complex I. Avoid it.

 

[andyguitar]

You might find page 6 of this research interesting @raghav