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The 4th in a series of blogs on the 2022 IACFS/ME International Conference finds two new metabolomic studies that  highlighted three problems that have cropped up recently in other studies: fatty acid metabolism, cell membrane damage, and energy production. The first comes from Maureen Hanson’s very vigorous NIH-funded research center, and the second from longtime ME/CFS and GWI researcher, James Baraniuk.

“Urine metabolomics exposes anomalous recovery after maximal exertion in ME/CFS female patients.” Katherine Glass PhD.

Not many urine metabolomic studies have been done. Metabolomics were done before baseline and 24 hours after maximal exercise. This was a pilot study – 9 healthy controls and 10 ME/CFS patients.

No differences were found at baseline. That, however, was not surprising given the small study size and the many metabolites measured. Twenty-four hours after exercise was a different story. Thirty-three metabolites popped up.

EKG Asystole

While approximately 400 metabolites were altered by exercise 24 hours in the healthy controls, none were in the ME/CFS patients: they showed no evidence of a “healthy metabolic response” to exercise at all. (from Wikimedia Commons)

The most eye-opening chart – which, unfortunately, can’t be shown because the study has not been published – showed the difference in metabolite levels before and after exercise in healthy controls and people with ME/CFS. The healthy controls show a veritable explosion in altered metabolite levels. Even 24 hours later, the levels of over 400 metabolites had been altered. Their systems had clearly responded quite dramatically to the maximal exercise bout.

Not so with the ME/CFS group. Their metabolites flatlined. In fact, no metabolites were significantly altered 24 hours after the exercise in ME/CFS. The “healthy metabolic response” to exercise, as Dr. Glass put it, had disappeared. This seems to jive perfectly with Germain’s presentation indicating the same.

Germain found that exercise triggered a  much bigger change in the proteins found in the sedentary, but healthy, controls than in the ME/CFS patients. The healthy controls responded to the rigors of the second exercise test by scrambling their protein mix more. Lacking the same ability to do so, the ME/CFS patients did not.

Myoglobin, Platelets and Monocytes, Oh My: The IACFS/ME Conference Review #III

Note that we now have – thanks to Maureen Hanson’s use of exercise stressors throughout her studies, that ME/CFS patients’ bodies respond, at two very fundamental levels – at the level of the proteins (which do the work of the cell) and at the level of metabolites –  very poorly to exercise. The exercise period itself is problematic, but it’s in the post-exercise period that symptoms really crop up in ME/CFS, and Glass’s small study appeared to capture the dysfunction there in spades.

The levels of 33 metabolites were significantly different – most of them lower – in the ME/CFS patients post-exercise. The composition of those metabolites was telling: two of the three largest groups were lipids and amino acids, with unknowns making up the other category.

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The lipids were involved in fatty acid metabolism – the same problem that the recent Lipkin study centered on, the same issue that the Fisher mitochondrial study picked up on, and the same issue that a recent fibromyalgia study highlighted. That all of them were found in significantly lower concentrations than the healthy controls fits the Lipkin study perfectly.

Next, they performed a ranking analysis called MEBA that ranked which metabolites were the most different between groups.  Thirty-nine percent of the metabolites were unknown. Lipids and amino acids comprised, respectively, 29% and 10% of the top metabolites that were altered.

Actetyl-carnitine transfer

Acetyl-L-Carnitine moving Acy-CoA from the cytosol of the cell into the mitochondria.

The acyl-carnitine fatty acid metabolism pathway (six were shown) was the most altered sub-pathway affected by exercise in the ME/CFS patients. In all cases, the graphs showed dramatic increases in the metabolites associated with these pathways in the post-exercise period in the healthy controls but either no increases or slight reductions in the ME/CFS patients.

Germain’s recently published metabolomic study put a big “X” on the carnitines with its finding that “Many of the most altered metabolites contain carnitine.”. Sixty-five percent (13/20) of the lipids that were significantly altered by exercise in the ME/CFS patients contained carnitine. Plus the pathway analysis suggested that two problems with carnitines may exist “oxidation of branched-chain fatty acids” (that’s the peroxisomes) and “carnitine synthesis”.

If this work stands up – and Lipkin’s blood metabolomic study also highlighted reductions in carnitines – it may be pointing an arrow at a key feature of post-exertional malaise – the inability to produce sufficient amounts of carnitines.

Acyl-carnitines’ main function, as we learned in the Lipkin paper – is to transport long-chain fatty acids from the cytosol into the peroxisomes.  Another analysis found that pathways involved in sugar metabolism – an important part of energy production – were also altered in ME/CFS.

The Hanson group is going to be  digging into lipids in more detail soon and hope to expand the study greatly – to the 169 participants they have urine samples from – and to include males as well. If any study is crying out to be expanded, this one is. They also hope to use machine learning to then uncover diagnostic biomarkers at baseline.

Something Different from Dr. Baraniuk

“Dysfunctional cerebrospinal fluid metabolites and lipids infer white matter dysfunction in ME/CFS and mitochondrial dysfunction in Gulf War Illness (GWI).”

Dr. Baraniuk has been digging into both Gulf War Illness (GWI) and ME/CFS for quite some time. He’s come up with some differences. After a submaximal exercise test, for instance, people with ME/CFS showed activation of the midbrain during a cognitive test, while the people with GWI showed significantly reduced activity.

I found Dr. Baraniuk’s presentation hard to follow – hopefully, this overview is correct. It involved a metabolomic analysis of the cerebral spinal fluid before and after an exercise study. Be prepared – Baraniuk stated that metabolomic findings in the CSF can be quite different from those found in the plasma and urine – and indeed, some of them were.

dopamine fatigue ME/CFS

High dopamine levels in the cerebral spinal fluid led Baraniuk to suggest that “dopamine fatigue” may be present.

Dopamine Fatigue?

A ranked analysis pre-exercise that showed increases in serine, homocysteic acid, phenyalanine as well as dopamine left Dr. Baraniuk asking whether the elevated dopamine fits in with the dopamine fatigue hypothesis. The dopamine fatigue hypothesis – which was developed to explain the fatigue in multiple sclerosis – suggests that a dopamine imbalance causes a reduction in communication between the basal ganglia and the prefrontal cortex. One of the studies cited in that hypothesis was a 2006 ME/CFS study which found that methylphenidate (2 x 10mg/day) decreased fatigue.

Whither acetyl-carnitine?

The Gist

  • First off was a small pilot exercise/urine metabolomic study that some really interesting results – like the ME/CFS patients were able to muster virtually no metabolic to exercise! That was shocking given . the dramatic response to exercise (the levels of approximately 400 metabolites were altered) found in the healthy controls. 
  • This finding jived really well with Germain’s recent study (also from the Hanson group) which found reduced levels of protein production in the ME/CFS patients as well. 
  • These studies suggest that the problem is not that the systems of ME/CFS patients over-respond to exercise but that they under-respond and that the healing, muscle repair, antioxidant, and whatever  other systems that are supposed to respond to the stress of exercise just don’t kick in. It also shines a brigh light at what’s happening in the most mysterious period of all in ME/CFS – the post-exertional period.
  • The three largest groups of altered metabolite levels were pretty familiar: lipids, amino acids,  and unknown. That unknown category was the largest and the Hanson group thinks a lot of gold is buried in that group concerning ME/CFS. 
  • The lipids were involved in fatty acid metabolism – the same problem that the recent Lipkin study centered on, the same issue that the Fisher mitochondrial study picked up on, the same issue that a recent fibromyalgia study highlighted., and the same issue the recent Germain study found.  One wonders if a core finding has finally shown up. 
  • The Baraniuk cerebral spinal fluid metabolomic exercise study also highlighted acetyl-carnitine but instead of low levels, he found high levels in his ME/CFS patients. Baraniuk explained that metabolomic findings in the cerebral spinal fluid can differ from those in the plasma or urine and asserted that most important thing about the finding was that it was different. 
  • High dopamine levels in the cerebral spinal fluid lead Baraniuk to suggest that “dopamine fatigue” may be present.
  • Baraniuk also found evidence of lipid problems (altered serine, lipid levels before or after exercise), altered levels of metabolites involved in energy production, and increased levels of dopamine which he potentially linked with the “dopamine fatigue” hypothesis generated to explain the fatigue in multiple sclerosis. 
  • As other studies have – and as Germain’s recent study did – Baraniuk also found evidence that instead of employing more efficient energy pathways, people with ME/CFS were breaking down amino acids to produce energy. 
  • Finally, given his acetyl-carnitine and lipid findings, Baraniuk suggested that something had happened to cellular membranes; either they were damaged or the cells were being broken up. 
  • Lots of interesting strands showed up in these presentation including the long chain fatty acid/peroxisome/carnitine connection that Lipkin found showed up in spades as well as problems with energy metabolism. Time will tell how this all works out but it certainly seems that, right now, things are cohering rather nicely. 

Reduced acetyl-carnitine has shown up big time recently in ME/CFS metabolomic studies, but this time we were in for a surprise. This time, pre-exercise acetyl-l-carnitine levels were higher in ME/CFS patients’ cerebral spinal fluid. Increased metabolites that were associated with energy (creatinine, creatine, and others) were found as well.

Post-exercise – which involved a smaller group – increased serine, homocysteic acid, and phenylalanine again, showed up again and, this time, some lipids were decreased in ME/CFS.

A Metaboanalyst analysis that again plucked out serine suggested that exercise had caused reductions in phosphatidylglycerols (a small component of membranes) and glutathione in ME/CFS. A linear model that pooled all the analytes found in the various tests together found significantly altered levels of 26 metabolites. Again, Baraniuk found higher acetyl-carnitine levels.

In conclusion, in the pre-exercise period, serine, which is important for lipid metabolism and mitochondrial functioning, was highlighted, as were several energy-related metabolites (creatine) and several lipids, most prominently acetyl-carnitine. Exercise resulted in drops in phosphatidylglycerols (fats) and reduced glutathione indicating oxidant injury.

Mentioning the Warburg effect, Baraniuk stated that the results from his and other studies “pretty conclusively” show that people with ME/CFS are metabolizing incorrectly; i.e. they are bypassing the regular glucose pathways and finding other ways to produce energy. Germain’s recent study also mentioned the Warburg effect and we can now add  it to the list of studies that have found a strange and more inefficient pattern of energy production in ME/CFS. This finding seems ever more solid as time moves on.

Baraniuk was asked if the elevated acetyl-carnitine levels indicated problems with beta-oxidation. Noting that carnitines carry long-chain fatty acids from the cytosol into the peroxisomes, Baraniuk stated that anything that disrupts that system will interrupt the metabolism of the fats.

While other studies have found reduced acetyl-carnitines in the urine and plasma, and his study found it increased in the CSF, Baraniuk stated that the important fact was that acetyl-carnitine levels were significantly different from the controls.

The fats, he stated, are supposed to stay in the cell in the membranes and if they are higher in the cerebral spinal fluid – you have to ask why. Has something gone wrong with the membranes, are the cells being chopped up or what?

Germain’s recent metabolomics study from Maureen Hanson’s group – which is really knocking it out of the park right now – The effects of exertion in the ME/CFS cohort predominantly highlighted lipid-related as well as energy-related pathways and chemical structure clusters, which were disparately affected by the first and second exercise sessions.

Conclusion

With two more metabolomic exercise studies pointing fingers at problems with energy production, the lipids (cellular membranes), and, in particular, fatty acid metabolism, one wonders if we’re getting closer to some core problem in ME/CFS.

With another study suggesting that ME/CFS patients’ systems essentially flatline after exercise and are unable to produce a “healthy metabolic response” to it, we also may be getting a handle on what’s causing post-exertional malaise (PEM). It’s not that the system is overreacting to exercise – it’s quite the opposite – it’s simply not responding – which suggests that the muscle repair and antioxidants and whatever other systems that should be ramping up to ameliorate and heal are on vacation in ME/CFS.

The lipids – the fats found in the cellular membranes – are also showing up big time. Problems with the cellular membranes could be rendering cells unresponsive, leaving the mitochondria unable to produce normal amounts of energy. On that note, it’s good to see that the Hanson group plans to be digging deep into the lipids in ME/CFS in the future. Since these are potentially very basic problems that could be affecting many cells, they could be affecting many systems in ME/CFS.

Could some pieces be fitting together? Time will tell…

These are pretty new themes and time will tell if fatty acid metabolism really is a core problem, if the peroxisomes represent some sort of ground zero for ME/CFS, or if cell membrane issues play a large role in ME/CFS.

One of the more interesting findings from the Hanson metabolomic studies is how many unknown metabolites showed up in ME/CFS. Germain et. al. noted that determining the identity of those metabolites will have “far-reaching consequences in our ability to decode ME/CFS“. So long as these big studies keep coming, surprises are surely in store.

Lastly, let’s hope the RECOVER crowd is keeping an eye on this intriguing ME/CFS research as few metabolomic studies have been done in long COVID thus far.

  • Coming up – an interview with Suzanne Vernon on the central role that peroxisomal dysfunction (fatty acid metabolism) could be playing in ME/CFS.

 

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