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A Deep Dive into the Muscles Pays Off

Xiao_Wengzhong

A leader in computational analysis, Wengzhong Xiao, of the Open Medicine Foundation, co-led the study.

It’s so good to see the muscles getting more research in chronic fatigue syndrome (ME/CFS). Rob Wust’s recent long-COVID study exploring the effects of exercise on the muscles reaped dividends, and right on the heels of that, we have a very different dive into them – and this one suggested a treatment possibility.

Note that both these studies were largely funded by patient organizations: Wust’s study by the Solve ME/CFS Initiative, and the Patient-Led Research Collaborative for Long COVID, and the Xiao co-led study, below, by the Open Medicine Foundation.

Patient organizations are great at getting ahead of the curve and opening up new insights and even new fields of inquiry. They boldly go where the big funders like the NIH won’t, and in these two cases (and others), they hit paydirt. We should expect more on these topics in the future.

THE GIST

  • It’s so good to see the muscles getting more research in chronic fatigue syndrome (ME/CFS). Rob Wust’s recent long-COVID study, exploring the effects of exercise on the muscles, reaped dividends, and right on the heels of that, we have a very different dive into the muscles – and this one even suggested a treatment possibility.
  • Note that both these studies were largely funded by patient organizations: Wust’s study by the Solve ME/CFS Initiative, and the Patient-Led Research Collaborative for Long COVID, and the Xiao co-led study, below, by the Open Medicine Foundation. Exploring and opening up ground in new topics is what patient organizations do best. They play a crucial role in ME/CFS research.
  • The “Systems Modeling Reveals Shared Metabolic Dysregulation and Novel Therapeutic Treatments in ME/CFS and Long COVID” study, co-led by the Open Medicine Foundation’s Wenzhong Xiao, employed advanced analytic techniques to explore what’s going on in the muscles.
  • The researchers integrated gene expression, proteins and “kinetome” data to predict the metabolic networks at play in the muscles of people with ME/CFS. Those networks work together to produce energy and the essential building blocks of the body (proteins, fats, nucleic acids and some carbohydrates). If something is awry with energy production, it may very well show up in our metabolic studies, and these kinds of studies have, indeed, proven invaluable in ME/CFS.
  • The findings highlighted six metabolic pathways, the most prominent of which was a downregulation of the alanine and aspartate metabolism pathway. A comparative analysis of Rob Wust’s long-COVID muscle study concurred with the result of the ME/CFS study.
  • They concluded that “a fundamental disruption in amino acid metabolism and energy metabolism” involving, in particular, the breakdown and conversion of alanine and aspartate has occurred in both ME/CFS and long COVID.
  • The low alanine finding had a startling tie-in with both ME/CFS and long COVID: alanine plays a key role in getting rid of ammonia, and studies suggest that ammonia – a byproduct of anaerobic energy production – may be building up in the bodies of ME/CFS patients and causing fatigue, brain fog, etc.
  • The authors proposed that using the L-ornithine plus L-aspartate (LOLA) supplement regimen “could potentially rescue the metabolic changes observed in ME/CFS patients” (!). LOLA is a supplement combination that is readily available and has been used for decades to reduce ammonia levels in people with liver problems. That’s intriguing given that some researchers believe the liver is involved in ME/CFS. (See Kalafatis’s recovery story).
  • Note that the authors do not suggest that L-alanine and L-ornithine supplementation will cure ME/CFS. They suggest that doing so “could potentially mitigate some of the core symptoms”; i.e. make less severe some of the core symptoms.
  • L-aspartate has been used to increase endurance and reduce fatigue. It has also been shown to decrease lactate and increase fatty acid oxidation – which appears to be impaired in ME/CFS. It may also be able to increase nitric oxide levels, improve blood flows, and reduce ammonia levels. L-ornithine helps eliminate ammonia and fatigue-causing metabolites in the muscles.
  • Given the current interest in oxaloacetate in ME/CFS and long COVID, L-aspartate, interestingly, is converted into oxaloacetate outside the mitochondria, and once inside the mitochondria, oxaloacetate is converted back into aspartate. One wonders if using LOLA in combination with oxaloacetate could be helpful.
  • In conclusion, the study was too small (25 MECFS patients) for us to assume that it was representative, but the fact that its core findings were validated in separate tests within the ME/CFS group, and then in the long-COVID group, suggests that it might very well have legs. LOLA’s known ability to remove ammonia, possibly improve endurance and blood flows, and liver functioning as well, and its connection to oxaloacetate makes it an intriguing substance indeed.
  • Congratulations to the Open Medicine Foundation for helping to fund this study.

Metabolic Dysregulation and Treatment Possibilities?

The “Systems Modeling Reveals Shared Metabolic Dysregulation and Novel Therapeutic Treatments in ME/CFS and Long COVID” study was led by the Open Medicine Foundation’s Wenzhong Xiao and researchers from the Laboratory of Genetic Evolution & Animal Models (Chinese Academy of Sciences). It was not large – included 13 ME/CFS patients and 12 healthy controls (as well as an outside long COVID group in part of the study) – but it employed advanced analytic techniques and most importantly, took a deep dive in the muscles.

The researchers used a cutting-edge modeling technique called “genome-wide precision metabolic modeling (GPMM)” that integrates gene expression, proteins and “kinetome” data to predict what metabolic networks are involved. In other words, this technique is able to do just what we want to do with these large datasets – bring all the factors together.

It was no surprise to see Wenzhong Xiao, the senior author, lead this type of study. The Co-Director of the Open Medicine Foundation’s Ronald G. Tompkins Harvard ME/CFS Collaboration at the Harvard Affiliated Hospitals and Director of the Immuno-Metabolic Computational Center at Massachusetts General Hospital (MGH), Harvard Medical School, Xiao’s main focus is on bringing big datasets together to better understand illnesses.

Note that this study was all about metabolism – it used modeling techniques to determine how multiple factors (gene expression, proteins, kinetome) affected the metabolic networks in the body. Those networks work together to produce energy and the essential building blocks of the body (proteins, fats, nucleic acids and some carbohydrates). If something is awry with energy production it may very well show up in our metabolism. Indeed, over the past ten years or so, metabolomic studies have gained more and more prominence in ME/CFS.

The study also demonstrated the importance of open data: it used muscle data from Nath’s intramural study to assess the metabolic networks involved. Then they compared those findings to data from Rob Wust’s recent long-COVID muscle study to determine how similar ME/CFS and long COVID were.

Results

Chronic Fatigue Syndrome (ME/CFS)

The findings highlighted six metabolic pathways (downregulated: alanine and aspartate metabolism, pyrimidine catabolism, aminosugar metabolism, arginine and proline metabolism pathways; upregulated: pentose phosphate) with the alanine and aspartate metabolism pathway being the most downregulated.

Then they did an “all-knockout analysis”, which perhaps refers to something like the pathways being matched against each other pathway until the most significant pathway emerged (???). In any case, the analysis highlighted the alanine and aspartate as the most prominent “agonist” metabolites; i.e. metabolites, if I’m reading it right, that would most enhance the metabolism in ME/CFS.

Long COVID

Next, they assessed the metabolic changes from pre to post-exercise in Rob Wust’s illuminating long-COVID study – and found that asparagine was the most downregulated amino acid metabolite in both blood and muscle samples.

ME/CFS and Long COVID

The authors concluded that “a fundamental disruption in amino acid metabolism and energy metabolism” has occurred in both ME/CF and long COVID. The most significant metabolic alteration found involved the breakdown and conversion of alanine and aspartate.

Indications that something is up with alanine have showed up a couple of times in ME/CFS. McGregor’s 1996 “Preliminary determination of the association between symptom expression and urinary metabolites in subjects with chronic fatigue syndrome” study proposed that beta-alanine (and an unknown metabolite) might “provide a molecular basis for developing an objective test for CFS”. In 2006, his “Preliminary determination of a molecular basis of chronic fatigue syndrome” singled out reductions in alanine as a key factor in ME/CFS. Reductions in gut alanine levels showed up in a recent retrospective of gut microbiome studies. A 2022 mass spectrometry study found alterations of beta-alanine (and arginine and proline metabolism).

Effects

ammonia

Chris Armstrong is checking whether higher than normal levels of ammonia are being produced in ME/CFS.

What do these two amino acids do in the body? Alanine traps and scavenges ammonia and plays a role in the TCA cycle in the mitochondria. The dramatic reduction in alanine found in ME/CFS suggested that the ammonia removal process had been impaired.

That could be a particularly big deal for these diseases. Study after study has shown that amino acids are being preferentially used in ME/CFS to produce energy. Amino acids, though, have a pesky nitrogen atom attached to them that needs to be taken care of.

The body usually eliminates the nitrogen from amino acids using a variety of “safe” forms, but those safe forms have been found wanting in ME/CFS metabolomic studies. Chris Armstrong – who leads the Australia Open Medicine Foundation Research Center – believes the nitrogen byproducts of amino acid breakdown may be showing up as “unsafe” forms such as ammonia or peroxynitrite in ME/CFS.

There’s, of course, nothing good about increased ammonia levels in the body. It inhibits cell growth and damages cells and generally mucks things up. Armstrong is tracking cells from ME/CFS patients to determine if this is so.

Chris Armstrong and the Hunt for the Metabolic Underpinnings of ME/CFS

One wonders if the toxic feeling that some people experience is, in part, due to increased ammonia levels? In another possible tie-in, the liver is a major source of ammonia metabolism and several researchers believe that liver issues may play a role in ME/CFS as well.

Rescue helicopter

Could LOLA supplementation help “rescue” the metabolic problems in ME/CFS and long COVID?

Treatment Suggestion

The authors proposed that “Administering these two amino acids (LOLA – see below) could potentially rescue the metabolic changes observed in ME/CFS patients” (!). This is the first metabolic study I can remember that suggested a specific treatment.  (A metabolomic study did lead to Dr. Kaufman’s use of oxaloacetate, but he gloomed onto that supplement after seeing low oxaloacetate results to find it.)

LOLA 

LOLA is the term used for the L-ornithine L-aspartate supplement. LOLA has been used to reduce ammonia levels in non-alcoholic fatty liver disease for decades. Note that the authors do not suggest that L-alanine and L-ornithine supplementation will cure ME/CFS. Let’s not put that on them. They suggest that doing so “could potentially mitigate some of the core symptoms”; i.e. make less severe some of the core symptoms.

In the U.S. the L-ornithine L-aspartate (LOLA) supplement mix is available in powder or pill form on Amazon. (Health Rising does not benefit from Amazon sales. 

One wonders, though, how they might work with oxaloacetate – given its very close connection with L-aspartate (see below) – and other mitochondrial supplements, or in conjunction with the liver supplementation regimen that artificial intelligence analysis came up with. 

Efthymios’s Artificial Intelligence-Aided ME/CFS Recovery Story

Check out what the two components in LOLA (L-ornithine L-aspartate) can do.

L-aspartate

L-aspartate would enhance the ASN/ASP pathway. One website stated that L-aspartate is being used to increase muscle strength, improve sports performance, and reduce fatigue. One study found while L-aspartate did not increase power, it did appear to increase endurance during repeated sprints. It has also been shown to decrease lactate and increase fatty acid oxidation – which appears to be impaired in ME/CFS. It may also be able to increase nitric oxide levels and improve blood flows.

Given the current interest in oxaloacetate in ME/CFS and long COVID, L-aspartate, interestingly, is converted into oxaloacetate outside the mitochondria, and once inside the mitochondria, oxaloacetate is converted back into aspartate. It also helps with the removal of ammonia. It also may be able to enhance the production of testosterone.

Oxaloacetate: the Best Mitochondrial Supplement for ME/CFS (and Long COVID?)

L-aspartate supplementation can improve energy levels, help remove ammonia, increase muscle mass, improve liver functioning and help with atherosclerosis. It can also produce side effects like bloating and diarrhea.

As always, best to start low and go slow.

L-ornithine

Adding L-ornithine could enhance the downregulated arginine and proline metabolism pathways, and help eliminate ammonia by turning it into urea, which is then disposed of in the urine. As one site puts it, L-ornithine “helps remove bodily wastes and fatigue-causing metabolites in the muscles”. L-ornithine may also be able to promote lipid metabolism – an area of growing interest in ME/CFS. The same study suggested it can help with fatigue as well.

No side effects were mentioned.

Conclusion

In conclusion, the study was too small for us to assume that it was representative, but the fact that its core findings were validated in separate tests within the ME/CFS group and then in the long-COVID group suggests that it might very well have legs. LOLA’s known ability to remove ammonia, possibly improve endurance and blood flows, and liver functioning as well, and its connection to oxaloacetate makes it an intriguing substance indeed.

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