Systems Modeling Reveals Shared Metabolic Dysregulation and Novel Therapeutic Treatments in ME/CFS and Long COVID

[Treeman]

Abstract

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Long COVID are complex, multisystemic conditions that pose ongoing challenges to healthcare professionals. Emerging research suggests that ME/CFS and Long COVID exhibit overlapping metabolic symptoms, indicating possible shared metabolic dysfunctions. This study aims to systematically explore these shared metabolic disturbances and their potential treatments. Utilizing our novel metabolic modeling method, GPMM, we identified the key metabolic irregularities in patients with ME/CFS and Long COVID, notably the downregulation of the alanine and aspartate metabolism pathway, and the arginine and proline metabolism pathway. Genome-wide knockout analyses indicated that supplementation with aspartate (ASP) or asparagine (ASN) could potentially ameliorate these metabolic deficiencies. Further metabolic assessments in Long COVID patients highlighted the significant downregulation of ASP in both blood and muscle, supporting our predictions. Consequently, we propose that the combination of l-ornithine and l-aspartate (LOLA) offers a promising approach to alleviate metabolic symptoms in both ME/CFS and Long COVID patients. This study not only elucidates the shared metabolic pathways in ME/CFS and Long COVID but also positions LOLA as a viable candidate for future clinical trials.

Gong-Hua Li, Feifei Han, Qing-Peng Kong, Wenzhong Xiao

Here

Anyone tried l-ornithine and l-aspartate? Seems overly simplistic.

 

[Wishful]

I'm pretty sure that plenty of us tried ornithine and aspartate ... with no significant results. I doubt that there's a magic combination of the two that would treat ME.

I've tried arginine (no effect) and I was intolerant of proline for a while, but that passed. I don't know what that means for their theory.

 

[Forummember9922]

I see that their method (GPMM) which they are touting is actually on Github. Not sure if that means its completely open source but interesting at least. https://github.com/GonghuaLi/GPMM

Skimming posts about asparagine, I see someone had mentioned the term 'mitophagy' (not to be confused with autophagy) where old mitochondria are cleaned out. I had not heard of that and I wonder how unique mitophagy is from autophagy. Further wikipedia reading said that PINK1 is important in mitophagy. Concepts of ‘polarized’ mitochondria also come up. Prusty suggested CFS mitochondria were hyper-polarized IIRC.

The study calls for LOLA but it also mentions asparagine as a potential treatment. Asparagine is a 'derivative' of aspartate. Will try a bottle.

GPT (which ill be honest its been sketchy lately for providing well-sourced info) suggested that asparagine may have better safety profile due to decreased risk of excitotoxicity + better for overall metabolic health and protein synthesis.

 

[Katt]

Anyone tried l-ornithine and l-aspartate? Seems overly simplistic.

Yes, it was helpful for me when I was having high ammonia levels due to protein metabolism issues. But I never took it long term nor at a consisten dosage. Maybe it could help some metabolism issues but I don't see it doing a cure.

 

[Mary]

Anyone tried l-ornithine and l-aspartate? Seems overly simplistic.

I took l-ornithine several years ago for sleep. It helped quite a bit at one time, and then stopped helping. I don't know if I had issues with ammonia or not - I wouldn't know how to tell if I did. I've since tried ornithine a few times but with no apparent benefit. As I recall, it never did anything for me aside from helping with sleep at one time.

This LOLA combo does have me interested but I'm also concerned about l-aspartate as it's an excitatory neurotransmitter. I think almost everyone with ME/CFS has trouble with glutamate destroying their sleep, preventing them from calming down - I certainly do! Actually I have extreme sensitivity to MSG in all its iterations (https://www.truthinlabeling.org/names.html) Having any of those substances in my food at dinner will keep me awake almost all night.

So I wonder if l-aspartate would the do the same thing - anyone have any ideas about this?

 

[vision blue]

[edit

 

[Violeta]

There is a person on Twitter who has been talking about glutamate and the gene, GLAST.

She and others are having good results with rutin.

https://x.com/KatBoniface/status/1831771372370182323

 

[Violeta]

we identified the key metabolic irregularities in patients with ME/CFS and Long COVID, notably the downregulation of the alanine and aspartate metabolism pathway, and the arginine and proline metabolism pathway.

I don't know if they measured ornithine or just jumped to the conclusion that it would be helpful.

This study actually measured ornithine.

Index markers of chronic fatigue syndrome with dysfunction of TCA and urea cycles​

https://www.nature.com/articles/srep34990

In the urea cycle, compared with those in healthy controls, there were significant decreases in the concentrations of urea and citrulline and a significant increase in the concentration of ornithine in CFS patients. Consequently, the ratio of ornithine/citrulline, reflecting metabolic activity in the urea cycle, was significantly higher in CFS patients than in healthy controls. The differences in these ratios between CFS patients and healthy controls were consistent between the training and validation datasets.

 

[Violeta]

I don't know if they measured ornithine or just jumped to the conclusion that it would be helpful.

This study actually measured ornithine.

Index markers of chronic fatigue syndrome with dysfunction of TCA and urea cycles​

https://www.nature.com/articles/srep34990

In the urea cycle, compared with those in healthy controls, there were significant decreases in the concentrations of urea and citrulline and a significant increase in the concentration of ornithine in CFS patients. Consequently, the ratio of ornithine/citrulline, reflecting metabolic activity in the urea cycle, was significantly higher in CFS patients than in healthy controls. The differences in these ratios between CFS patients and healthy controls were consistent between the training and validation datasets.

Ornithine aminotransferase (OAT) is an enzyme that helps break down ornithine and convert it into other molecules:



OAT is a key enzyme in the conversion of ornithine and arginine into the neurotransmitters glutamate and GABA. It also helps produce proline, a non-essential amino acid.



Deficiency
A deficiency in OAT is an autosomal recessive condition that causes gyrate atrophy of the retina and choroid. Symptoms include progressive chorioretinal degeneration, myopia, night blindness, hyperammonemia, and oric aciduria.


Treatment
Treatments for OAT deficiency include vitamin B6, lysine, or dietary changes to reduce arginine.



I am not saying that people with ME/CFS have a genetic issue with OAT gene, but just that the treatment could possibly be helpful if you have increased levels of ornithine.

I know that I have to be very careful with lysine:arginine ratio in food stuffs, and so does my daughter. Taking extra lysine is always helpful for both of us, too.

 

[Wishful]

To me, any study that compares with "healthy controls" is pretty much meaningless. They need similarly inactive controls, and maybe some with similar but unrelated diseases.

 

[Forummember9922]

There is a person on Twitter who has been talking about glutamate and the gene, GLAST.

She and others are having good results with rutin.

https://x.com/KatBoniface/status/1831771372370182323

View attachment 54885

Can you link to the tweet where someone says they had good results with Rutin? I am a little fogged so maybe it's staring me in the face. That image shows Glutamate issues, which I'm glad is being talked about, but Im failing to find a positive testimonial RE Rutin and Glutamine? I bought some either way and thank you for bringing it up

 

[Violeta]

Can you link to the tweet where someone says they had good results with Rutin? I am a little fogged so maybe it's staring me in the face. That image shows Glutamate issues, which I'm glad is being talked about, but Im failing to find a positive testimonial RE Rutin and Glutamine? I bought some either way and thank you for bringing it up

Here is Kat Boniface talking about her results. I'll see if I can find anyone else.

https://x.com/KatBoniface/status/1860095932479734141

 

[Violeta]

The main helpful constituent of rutin is quercetin. I found this study about quercetin and glutamate.

I already have quercetin so I am using that and haven't purchased rutin. If I find someone who knows or can explain why rutin is better, I guess I will buy it.

Quercetin's Effects on Glutamate Cytotoxicity​

https://pubmed.ncbi.nlm.nih.gov/36364448/

 

[Violeta]

Quercetin can also help with mast cell activation syndrome.

https://annamarsh.co.uk/mcas-histam...in would be the top,see if both work together.

 

[mariovitali]

There is a second preprint version with me being added as a coauthor. I would like to take this opportunity to comment :

Here is the updated version of the paper : https://www.biorxiv.org/content/10.1101/2024.06.17.599450v2

I believe that the finding about low asparagine is a very important one. The reason is that low asparagine can affect N-Linked glycosylation which is crucial for a number of key biological mechanisms. A relevant thread can be found here, unfortunately there have been no replies from a number of researchers I tagged :

https://x.com/lifeanalytics/status/1863564681169838363

The second important -in my belief- mention on the second preprint is the mention regarding TUDCA and its ability to ameliorate ER Stress.

Finally,given the latest findings regarding liver disease (From Chris Ponting) I believe that the liver deserves more attention. Recall that the liver is one of the first research targets identified by the software framework I have been using.

 

[Violeta]

Abstract

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Long COVID are complex, multisystemic conditions that pose ongoing challenges to healthcare professionals. Emerging research suggests that ME/CFS and Long COVID exhibit overlapping metabolic symptoms, indicating possible shared metabolic dysfunctions. This study aims to systematically explore these shared metabolic disturbances and their potential treatments. Utilizing our novel metabolic modeling method, GPMM, we identified the key metabolic irregularities in patients with ME/CFS and Long COVID, notably the downregulation of the alanine and aspartate metabolism pathway, and the arginine and proline metabolism pathway. Genome-wide knockout analyses indicated that supplementation with aspartate (ASP) or asparagine (ASN) could potentially ameliorate these metabolic deficiencies. Further metabolic assessments in Long COVID patients highlighted the significant downregulation of ASP in both blood and muscle, supporting our predictions. Consequently, we propose that the combination of l-ornithine and l-aspartate (LOLA) offers a promising approach to alleviate metabolic symptoms in both ME/CFS and Long COVID patients. This study not only elucidates the shared metabolic pathways in ME/CFS and Long COVID but also positions LOLA as a viable candidate for future clinical trials.

Gong-Hua Li, Feifei Han, Qing-Peng Kong, Wenzhong Xiao

Here

Anyone tried l-ornithine and l-aspartate? Seems overly simplistic.

Supplementing ornithine and aspartate could be a way to address symptoms until root cause is dealt with.
If ornithine isn't helpful, perhaps citrulline would help.

Asparagine and urea cycle are also mentioned. Ammonia enters the picture here.

@mariovitali, Efthymios Kalafatis, suggests that the root cause is Endoplasmic Reticulum stress.
TUDCA is mentioned as a remedy in the paper.

 

[Violeta]

Does anyone know what is causing the dysfunction of alanine and aspartate?

 

[mariovitali]

Does anyone know what is causing the dysfunction of alanine and aspartate?

Good question!