ME/CFS might be caused by defects in cellular housekeeping

This idea has come up before and I thought it would be interesting to write down some of my thoughts on this. Housekeeing processes have a role in keeping cells healthy by doing things such as maintaining structural integrity and degrading and recycling intracellular components (like mitochondria). Various neurological diseases are caused by defects in housekeeping processes.

PEM for me tends to appear in the morning, on the day after excessive exertion. PEM seems to appear during sleep, and sleep is especially important for the body to repair itself. It's as if the body fully notices that there is a problem only during sleep. This seems to fit with a defect of some housekeeping process, although I have no idea what exactly that might be.

One could propose that what we're experiencing is not a lack of ATP due to a defect in mitochondria (this is a popular theory) but a lack of proper maintenance. This also seems to fit better with the observed cumulative nature of PEM.

If this idea is true, then with normal activity levels, a person with ME/CFS would be accumulating cellular damage faster than it can be repaired. And if they really overdid it, they might even suffer unrepairable damage.

 

I've often wondered about something very similar - that the delayed 24hr + PEM we see in the condition is due to some regulatory processes (like the cellular housekeeping you mentioned) that go on in sleep being impaired in patients with ME/CFS. I have no biomedical training so I have no idea if it's a plausible idea or not.

 

My cognitively-induced PEM would occur 30 minutes to an hour or two after the trigger (chatting, driving in poor conditions), so I don't think there's enough time for housekeeping to fail, and it definitely rules out the 'sleep maintenance failure' hypothesis. I think my physically-induced PEM occurred 24 hours after the exertion, regardless of time of day.

A better fit for my physically-induced PEM observations is the release of cytokines (IFN-g increases (fairly abruptly I think) 24 hrs after exertion). This would trigger glial activation, which i8n turn resulted in PEM. Cognitively-induced PEM might involve direct activation of glial cells, or might involve some other transmission mechanisms (exosomes or whatever).

 

A crossover occurs between ATP production and cellular housekeeping. First, housekeeping is energy intensive, and involves both catabolic and anabolic processes, plus their regulation. Second, during severe ATP deficits the cell can cannibalize its own energy substrates such as ADP and AMP. It probably also degrades available proteins, though I am not sure if this is significant. It then has to repair and rebuild these processes.

I am doubtful of a sound conclusion from PEM being worse after sleep or rest can be made. The time is somewhat empirical, the interpretation is hypothetical. For example, an alternative explanation along very similar lines, and not the only possible interpretation, is that housekeeping processes detect molecular damage and put a slow on things to give the cell time to repair. This may or may not involve the new Itaconate hypothesis, which is an immuno-metabolic-inflammatory mediator.

As always we can hypothesize, and that can be useful, but what we really need are specific predictions that can be tested, or might already have been tested. Otherwise we need deep investigatory studies at the subcellular level, though as a proxy we can use biopsies, plasma and CSF. I have no problems with investigatory studies. They can not only show things are wrong, they can show things are not wrong. We need to know both kinds of things. Currently that includes Itaconate metabolism.

Most of our hypotheses will eventually either be proven wrong or insignificant. Until one isn't.

I am currently awaiting the publication of the NIH deep study, for which they are claiming they have found things.

ETA I still want to know the deep molecular issues involved with all our excess lactate going to the liver. There seems to be nothing published on this.

 

I should mention that I can have PEM before sleeping too, but my typical presentation is next day PEM after sleep.

I don't know enough about the topic to make specific predictions, if that's even possible at the level of knowledge we have.

I also remembered that there was this recent paper which found "autophagy-related protein ATG13 is strongly upregulated in the serum of ME/CFS patients, indicative of impairment in the metabolic events of autophagy"
https://pubmed.ncbi.nlm.nih.gov/35487443/

 

I find this cellular housekeeping idea very attractive. The ATG13 / defective autophagy paper was intriguing for me as I'd noticed a pretty reliable pattern that a disturbed night's sleep led to a paradoxically better day. A possibility would be reduced opportunity for the overnight autophagy limiting the production (and exocytosis?) of the abnormally phosphorylated ATG13.

 

I found out the opposite is true. Less sleep = a lowered PERI threshold and also a lowered PTLT. This is why I say ME isn't a single illness.