When I want to feel hopeful I re-read this paper. The irony is that while Wallitt was wasting $8million on his silly preconceived notion, on the other side of the NIH Hwang was doing this work with cancer funding. And I'm increasingly hopeful he has cracked it wide open. To me this puzzle piece fits better than any other.
He finds that some aspects of the unfolded protein response are in action, but it's not working like the textbooks say (there are 3 arms to the UPR, Hwang finds one of them is running hot, PERK, but not activating the downstream thing it should be activating (called EIf2a).)
If that is right, then the unfolded protein response (UPR) could be central to PEM - the triggers and timing are right. UPR can be started by exercise and - this was the aha! moment for me - it is one of a few mechanisms in the body that runs on a delay.
After trying to solve the protein folding problem for a number of hours, the unfolded protein response causes cells to destroy themselves via apoptosis and/or necroptosis. The timing could match PEM. You exercise, you feel kind of okay for a bit, then at a certain point afterwards the body decides to blow up a million muscle cells at about the same time and you are flooded with damage signals, making the whole body freak out: brain, endothelium, immune, energy, everything.
In our case it seems the standard UPR is not
exactly what's happening, it depends on EIF2a and leads to apoptosis. But when apoptosis is compromised, ER stress can leads to necrosis:
Death sentence: The tale of a fallen endoplasmic reticulum (2021)
3.2.2. ER stress-induced necroptosis (Fig. 2)
Necroptosis, or regulated necrosis, is a form of cell death induced by diverse stimuli and involves signaling molecule RIPK3, and its effector MLKL, which forms pores in the plasma membrane [26]. Necroptosis is thought to be engaged as a back-up when apoptosis is compromised, and switches between these modes of cell death upon TNF-signaling are dependent on the PTM of TNFR1-associated complex components, in particular regulation of RIPK1 which activates RIPK3 [33]. Mouse fibroblast L929sA cells die via necroptosis upon treatment with TNF, and chemical ER stressors. Suppression of RIPK1, RIPK3, or MLKL in these cells is sufficient to switch the mode of ER stress-induced cell death from necroptosis to apoptosis; and JNK signaling enhances both cell death modalities. Though L929sA cells could be considered atypical in their response to ER stress, this study indicates that the UPR may induce necroptosis in particular circumstances through a hitherto undescribed mechanism [34]. Indeed, necroptotic machinery can interact with ER stress sensors (Section 3.3) and chemical chaperones which reduce ER stress can prevent necroptosis [35,36], but little or no mechanistic link has been reported between the UPR sensors and execution of necroptosis. For example, CHOP induction by small molecule LGH00168 was reported to induce necroptosis in the human lung cancer cell line A549, but via Reactive Oxygen Species (ROS) production and not via CHOP-driven expression of necroptosis machinery [37]. One confounding study initially reported two PERK inhibitors as preventing RIPK1-mediated necroptosis however, it was subsequently found that these compounds also inhibited RIPK1, and that PERK was not involved in the necroptotic phenotype [38]. This lack of precise molecular links could suggest that the effect of ER stress on necroptosis may in fact be independent of the UPR, and come as a result of other physiological effects of ER stress.
Whether or not it involves the canonical parts of the UPR, everyone agrees unresolved ER stress causes cell death after a delay. I think there's a strong chance we will find the basis of PEM here, and a theoretical basis for pacing - keep your ER stress below the necroptotic threshold.
I'd love to trawl the microRNA and extracellular vesicle data we have for any signs of these necroptotic pathways being activated.
