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This University of Colorado/ National Jewish Health Center study, “Signatures of Mitochondrial Dysfunction and Impaired Fatty Acid Metabolism in Plasma of Patients with Post-Acute Sequelae of COVID-19 (PASC)“, follows on the heels of another study published earlier this year that highlighted fatty oxidation and lactate.

That study found that all 50 of the long-COVID participants produced significantly lower levels of fatty acid oxidation. That meant that a key source of the electrons needed to produce energy in the mitochondria was impaired. It also happens to be the same problem that recent studies have found in ME/CFS.

Long-COVID Exercise Study Points to Mitochondrial Dysfunction and Twitchy Muscles

Increased levels of lactate early in the exercise test, however, suggested that their anaerobic energy production system had kicked in early. They proposed that the lactate increase might result from a switch in the production of muscle fibers from slow-twitch muscle fibers to fast-twitch muscle fibers. A similar finding showed up in ME/CFS back in 2009.

Slow-twitch muscle fibers – which we use for things like walking – use aerobic metabolism to produce energy. Fast-twitch muscle fibers – which we use for short bursts of energy like weightlifting – use anaerobic metabolism.

Now they’ve returned with a rare (thus far) metabolomic study of long-COVID patients. The study – which was relatively small – contained 29 non-hospitalized long-COVID patients, 16 people who had recovered from COVID-19, and 30 healthy controls. The metabolomics analysis was “untargeted”; i.e., they looked at as many metabolites as possible and analyzed what popped up.

Their goal was to see if their metabolomic findings matched up with their earlier findings; i.e., did they indicate, on a molecular level, that problems with fatty acid metabolism and lactate production were present?

Results

“These results, which, to our knowledge, provide the first characterization of the plasma metabolome in individuals with PASC, indicate several major metabolic derangements.”

They did. They even called their findings “derangements” – a word that packs some punch.  A look at some of the study graphs shows dramatic changes indeed.

Check out at the top how highly segregated the long-COVID patients (PASC – red) are from the recovered long-COVID patients (blue) and the healthy controls (grey); then see the dramatic shift in fatty acid levels (bottom figure) in the long-COVID patients (bottom right- red) as well as lactate, pyruvate and others at the top.

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They stated that the “results of this plasma metabolomics study… support the hypothesis that a dysfunction in substrate utilization in mitochondria underlies the metabolic manifestations of PASC.” The key phrase here is “substrate utilization”. We’ve seen similar phrases used again and again in ME/CFS as study after study has found that people with ME/CFS are not using high-energy “substrates” like glucose and fatty acids to power their mitochondria. Instead, they’ve turned more to inefficient substrates like amino acids to feed their mitochondria. Given that, it’s no wonder that energy production is impaired.

They found higher levels of plasma carnitine-conjugated and free fatty acids in the long-COVID patients. The carnitines and other fatty acids provide quick and efficient food for the mitochondria, but in this context, high levels are not good because it means they’re not being broken down and being used by the mitochondria. Interestingly, this pattern has shown up early in COVID-19 and seems to persist in the long haulers.

This went along with reductions in multiple amino acids, including branched-chain amino acids, suggesting that the people with long COVID were, as appears to be happening in ME/CFS, using amino acids to produce energy.

Again, look at the dramatic changes in the levels of the acylcarnitines and fatty acids in the long-COVID patients (red) compared to the other groups.

Not only is a valuable energy resource not being used but higher than normal levels of just about anything can have consequences, and so it is with these fatty acids. The authors speculated that they could be triggering red blood cell dysfunction – which could impair oxygen delivery.

The Gist

  • A University of Colorado/Jewish Health Center team jumped on long COVID early and in mid-2020 began having their patients do exercise tests.
  • That resulted in an earlier paper that found significantly lower levels of fatty acid oxidation in all 50 of the long-COVID participants. Because fatty acids provide an energy source for our mitochondria, problems with fatty acid oxidation or breakdown could help explain the fatigue and exercise problems in long COVID.
  • Their goal in their latest study was to see if their metabolomic findings matched up with their earlier findings; i.e., did they indicate, on a molecular level, that problems with fatty acid metabolism and lactate production were present?
  • The study did – to the extent that the authors referred to the “metabolic derangements” found.  The study found evidence that fatty acid metabolism was impaired and the long-COVID patients were turning to less efficient amino acids to power their mitochondria.
  • They also found evidence of problems with taurine and tryptophan metabolism.
  • The authors stated that “compelling evidence of metabolic dysfunction in PASC (long COVID)… that should fuel future investigations of oxygen and lactate kinetics and mitochondria biology. Interventions aimed at restoring promoting mitochondrial activity and restoring fatty acid oxidation should be explored.
  • Then, ignoring the dozen or so ME/CFS studies that have found similar metabolic issues, they turned to sepsis and type II diabetes to explain how their findings could help explain exercise intolerance.
  • Interestingly, similar findings in fibromyalgia (FM) have recently shown up.
  • ME/CFS with its bigger, more complex metabolomic studies is ahead of the game and several causes (peroxisomal dysfunction, hypoxia, mitochondrial problems) have been proposed.
  • With the exception of some ME/CFS studies, most of the studies have been small and these findings need to be validated.  Still, they suggest that core metabolic abnormalities may be present in long COVID, ME/CFS, and FM.  
Taurine was also low. Low taurine levels have been found in COVID-19 but at least in this study carried over into long COVID. That’s an interesting finding as taurine can be supplemented. The same pattern: depletion starting in acute COVID and continuing on in long COVID – showed up with tryptophan.

After noting several limitations – small sample size, and a lack of stratification on gender and age – the authors stated that their data offer:

“compelling evidence of metabolic dysfunction in PASC… that should fuel future investigations of oxygen and lactate kinetics and mitochondria biology. Interventions aimed at restoring promoting mitochondrial activity and restoring fatty acid oxidation should be explored.”

The Chinese Study

The Colorado study came right on the heels of a Chinese long-COVID study that produced similar findings. Its findings (increased levels of fatty acid metabolites) and its outcome, “Our findings clearly revealed that their general metabolism is still in a state of disorder and exhibited abnormal fatty acid and amino acid metabolism”, could have come right out of an ME/CFS paper. The Chinese study also found evidence of suppressed tryptophan metabolism (low levels of kynurenine, arginine, and tryptophan).

Frustrating

It was frustrating to see the Colorado authors ignore the now substantial metabolomic literature in ME/CFS that’s shown similarly impaired fatty acid metabolism and carnitine issues, and turn to sickle cell anemia, type II diabetes and sepsis as examples of diseases with similar findings that exhibit exercise intolerance.

A quick review found ME/CFS studies dating back ten years have used different techniques in multiple compartments (cultured cells, the mitochondria, metabolomics (Che, Nagy-Syzkal, Fluge, Hoel, Germain, Germain, Germain, McGregor, Armstrong)) to come to essentially the same conclusion: a substrate shift away from using fatty acids/glucose toward amino acids has occurred that is affecting energy production.

While fatty acid metabolism isn’t the end of the story for ME/CFS the conclusions, particularly from the more recent studies, are refreshingly consistent.

“Peroxisomal β-oxidation of very long-chain fatty acids leads to their breakdown into short-chain products that serve as substrates for mitochondrial β-oxidation. We posit that (peroxisomal) dysregulation contributes to the fatigue and cognitive dysfunction that are hallmarks of ME/CFS.” Che

“Some changes were common in the patient group, and these were compatible with … altered utilization of fatty acids and amino acids as catabolic fuels.” Fluge

“Some changes were common in the patient group, and these were compatible with effects of elevated energy strain and altered utilization of fatty acids and amino acids as catabolic fuels.” Hoel

“Carnitine is an ammonium compound essential for fatty acid oxidation, and both “oxidation of branched-chain fatty acids” and “carnitine synthesis” were affected in ME/CFS patient pathway analysis.” Germain

“In our study compounds in the choline-carnitine pathway were decreased in ME/CFS patients. Our results are consistent with earlier reports that suggest that metabolites linked to lipid and energy metabolism are affected in ME/CFS. Nagy-Szakal

Noting that this metabolomic study was done at rest, the Colorado authors asserted that future studies should examine the effects of exercise on fatty acid metabolism. The authors missed a metabolomic ME/CFS exercise study that did just that and came to a conclusion – “The recovery period of participants with ME/CFS is highly disrupted compared with healthy controls” – that would have supported their call for something similar in long COVID.

Fibromyalgia as Well?

A similar signature (including problems with carnitine synthesis, lipid oxidation, and tryptophan metabolism) has shown up in several small metabolomic fibromyalgia studies. The latest one highlighted “lipid and amino acid metabolism networks“.  A mitochondrial study suggested that problems metabolizing fatty acids are present as well in FM.

Mitochondrial Abnormalities in Fibromyalgia Suggest Low Long-Chain Fatty Acid Diets May Be Helpful for Some

Exciting

Still, these studies – many of which are admittedly rather small – provide preliminary evidence that some core abnormalities may be present at the molecular level in long COVID, ME/CFS, and fibromyalgia. That would be a remarkable thing given their different triggers and one wonders if other post-infectious illnesses will join the crowd. What we now need are bigger studies that can solidify these findings (if they turn out to be accurate) in long COVID, ME/CFS, and FM.

Metabolically speaking, the ME/CFS field, at this point, is way ahead of the long-COVID and FM fields, with recent studies even fingering a possible culprit in the cell – the peroxisomes. The authors of the Colorado study did not propose a cause, but several have been proposed in ME/CFS including peroxisome dysfunction, tissue hypoxia, and mitochondrial problems.

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