Opinion mTORC1 syndrome (TorS): unifying paradigm for PASC, ME/CFS and PAIS, 2025, Bar-Tana

mTORC1 syndrome (TorS): unifying paradigm for PASC, ME/CFS and PAIS

Jacob Bar-Tana

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Abstract
Post-acute SarS-Cov2 (PASC), Myalgia encephalomyelitis/Chronic fatigue syndrome (ME/CFS) and Post-acute infection syndrome (PAIS) consist of chronic post–acute infectious syndromes, sharing exhaustive fatigue, post exertional malaise, intermittent pain, postural tachycardia and neuro-cognitive-psychiatric dysfunction. However, the concerned shared pathophysiology is still unresolved in terms of upstream drivers and transducers. Also, risk factors which may determine vulnerability/progression to the chronic phase still remain to be defined. In lack of drivers and a cohesive pathophysiology, the concerned syndromes still remain unmet therapeutic needs.

‘mTORC1 Syndrome’ (TorS) implies an exhaustive disease entity driven by sustained hyper-activation of the mammalian target of rapamycin C1 (mTORC1), and resulting in a variety of disease aspects of the Metabolic Syndrome (MetS), non-alcoholic fatty liver disease, chronic obstructive pulmonary disease, some cancers, neurodegeneration and other [Bar-Tana in Trends Endocrinol Metab 34:135–145, 2023].

TorS may offer a cohesive insight of PASC, ME/CFS and PAIS drivers, pathophysiology, vulnerability and treatment options.

Link | PDF (Journal of Translational Medicine) [Open Access]

 

While I have no scientific credentials in this area, I am alarmed to read

Stressing ME mitochondria on the basis of a tenuous non-hypothesis implicating mTORC1 strikes me as a very bad idea.

 

Prescribing any risky treatment based on a tenuous non-hypothesis is a very bad idea. Even for less-tenuous hypotheses lacking supporting evidence. I've done plenty of experiments on myself based on tenuous hypotheses, but my ME history doesn't involve long-term consequences, so I consider things such as coconut oil or creatine to be low-risk. A drug that affects a critical function in all cells sounds very risky, unless it has a long history of being safe for most people.

 

Quoting Nietzsche in a medical journal is pretty lame too, specially when he's got the whole of Macbeth to go at.

 

It’s really ironic they’re quoting

in a paper about illnesses where people were often severely disabled by viral infections, and most decidedly not made stronger.

 

If exercise is effective for alleviating hyperactive mTORC1, and exercise makes people with PEM worse, wouldn’t that indicate that other mechanisms play a significant role in PEM?

If so, how can mTORC1 be a unifying theory for ME/CFS, LC, etc.?

At best, it would be one of multiple common denominators.

 

mTORC1 activation as a primary upstream factor driving the disease (across which compartments - the whole body?) doesn't seem to fit with a lot of the findings surrounding elevated fatty acid and amino acid usage in various types of cell/tissue. At this point pretty much everybody (I think? Correct me if anything recent disagrees) is seeing the same things with fatty acid usage: whether in primary cells, biofluids, cell lines, evidence for ME cells using more fatty acids keeps coming up pretty consistently.

There is evidence in ME research for glycolysis being either not upregulated or even bottlenecked (alongside the evidence for upregulated glycolysis - although all usually examined by different methods in different types of sample) - which might also contradict the model proposed in this review since glycolysis is upregulated by mTORC1 activity. Most of this particular evidence is not cited from what I can see, and so it does not counterbalance the section in the review that discusses potential elevation of glycolysis.

For those who aren't up to speed:

mTORC1 is the indicator of "plenty" - broadly promoting growth and storage. It gets turned on during nutritional excess.

AMPK is the opposite - it's the empty fuel gauge alarm bell.

Lipid metabolism is regulated modally - towards biosynthesis (canonically by mTORC1 activation) or towards breakdown (canonically by AMPK activation)

mTORC1 and AMPK regulate each other reciprocally but things can also break, where both are turned on at the same time. But this is not "normal" or documented particularly often.

So whatever is happening in affected ME cells or tissues, if it involves some kind of mTORC1 activation concurrent with fatty acid breakdown this is unusual and likely due to deregulation of the mTORC1 - AMPK dichotomy (or possibly some downstream regulatory hinge such as ACC). Perhaps, eg: in immune cells this could relate to abnormal response to stimulus that either causes or is caused by disturbed metabolism. In any case AMPK cannot be ignored.

I think that the most likely scenario is that because mTORC1 and AMPK are so central to cell metabolism, pretty much any notable challenge to cellular homeostasis is probably going to elicit feedback by changes in the activity of one or both. If anything is going wrong in metabolism they will almost certainly be involved or affected but I will repeat my catchphrase: cause effect determination is paramount. Proposing causal relationships without direct evidence is fine as a precursor to studies directly testing these things (that's what a hypothesis is) but as always speculating about what might work as a treatment based on little (or even contentious) evidence is dangerous, particularly in the ME environment where people will try anything out of desperation, have little money to spare and have the potential to lose baseline function.

PS: One might expect that positive responses to Rapamycin would be more prevalent (than what is reported anecdotally, we are obviously waiting on the results of the current trial) if mTORC1 activation is the unifying, primary upstream driver of disease. Perhaps mTORC1 is higher in the chain of events for responders - a subset?