Inactivation of ATG13 stimulates chronic demyelinating pathologies in muscle‑serving nerves and spinal cord, 2025, Drosen et al.

Abstract
Chronic muscle fatigue is a condition characterized by debilitating muscle weakness and pain. Based on our recent finding to study the potential effect of mTOR on ATG13 inactivation in chronic muscle fatigue, we report that biweekly oral administration with MHY1485, a potent inducer of mTOR, develops chronic illness in mice resulting in severe muscle weakness. As a mechanism, we observed that MHY1485 feeding impaired ATG13-dependent autophagy, caused the infiltration of inflammatory M1 macrophages (Mφ), upregulated IL6 and RANTES by STAT3 activation, and augmented demyelination in muscle-serving nerve fibers. Interestingly, these mice displayed worsened muscle fatigue during 2-day post-treadmill exercise, suggesting the critical role of chronic mTOR activation in potential PEM pathogenesis. Interestingly,
ATG13-repressor mice exhibited enhanced infiltration of M1Mφ cells, STAT3 activation, demyelination of nerve fibers, and PEM-like symptoms, suggesting the potential role of ATG13 impairment in post-exertional fatigue.

Link: https://link.springer.com/article/10.1007/s12026-024-09557-7
PDF: https://link.springer.com/content/pdf/10.1007/s12026-024-09557-7.pdf

 

Congrats to the entire team
@RedefiningMECFS
and
@AvikRoy74969264
on this breakthrough paper describing a disease-relevant model of PEM Here, we show that chronic mTOR activation disrupts autophagy function, leading to PEM and the production of IL-6 and RANTES via STAT3 phosphorylation!

https://twitter.com/user/status/1876635872633778616


re metformin

Yes. Perhaps even in combination with low dose rapamycin.
https://twitter.com/user/status/1876661323188126101

 

If we have something demyelinating wouldn’t this have been found before, or would it be hard to find/see?

 

I already use metformin for diabetes II and it does nothing special for me in PEM.
My PEM is sore muscles, more fatigue and more brainfog, no flu like symptoms.
Metformin did shorten the muscle pain after excertion (groceries) from 4 days to 2 days.
But that does not seem to work for everyone.

 

I find this very interesting because of an effect I've noticed when i'm on a diet: high risk but slow-building benefit.

if i reduce my food intake, I risk acute energy shortage if I push too hard, and that can cause PEM. However, if I succesfully avoid that acute problem, the calorie restriction periods seem to correlate with better health and a bigger PEM threshold.

I've wondered if maybe I usually eat a lot to avoid blood sugar variations that can spark PEM, but if I avoid eating a lot, perhaps I can stop activating mTor and slowly be better off overall. I'd like to go on metformin to see what happens.

 

I was excited to read this paper too, but I don't think they're describing ME/CFS: eg "we did not see any changes in neurocognitive behavior in these animals as tested by Barnes maze analyses."

I haven't seen evidence of demyelination in ME/CFS, and would the described histological changes recover in two weeks? (There are LC neuroimaging studies suggesting micro-integrity changes in myelin though.)

There's also the problem with the male mice not being anywhere near as affected.

 

In their drawbacks section —

(The mice heart rates reduced.)

 

It would be plain as a pikestaff. this model appears to have nothing to do with ME/CFS.

 

Why don't they have someone with a basic understanding of the ME/CFS in biological terms? One of the authors is Daniel Peterson, who is supposed to have that. Yet there is all this stuff about PEM being muscle pain after a treadmill.

What do they mean by 'Persistent muscle fatigue'? Do they mean weakness? Pain? It does not sound like ME/CFS to me. There is no inflammation in ME/CFS. And so on.

 

The first few sentences of this paper put me right off, as does the tweet about 'groundbreaking work' from one of the authors. These are supposed to be ME/CFS experts.

Do they really think you only get PEM after being on a treadmill, or is it the case that the authors write poorly....? Who knows!

 

Sorry I never remember details unfortunately, but did some autopsy studies from some years back find loss of both grey and white matter in the brains of people with severe ME?

 

Yes it’s full of falsehoods. It’s as if they made up a definition of ME/CFS to match their theory, but that definition reads nothing like how ME/CFS is usually described, in fact to me it reads a little closer to fibro.

 

I think so.

 

In discussing mTOR activation, I would like to see how this compares to mTOR activation in type 2 diabetes. If the model is to even try to explain PEM, it must explain how mTOR activation is different in ME compared to type 2 diabetes. It might be, or there might be something wrong with these claims.

I am unsure if there are detailed studies on mTOR in diabetes, I have yet to investigate, but elevated insulin will drive mTOR.

It is unlikely this new model completely explains PEM, but that does not rule out its a partial mechanism. There are indications that inhibiting mTOR might help with ME, but its very far from conclusive at this point. It might however help some individuals, but that might be for other reasons than ME.

 

I think not just the brain but some ganglions.