ER proteostasis regulators cell-non-autonomously control sleep. (Kawano et al, 2023)

[Murph]

Cell Rep

2023 Mar 28;42(3):112267.
doi: 10.1016/j.celrep.2023.112267. Epub 2023 Mar 15.

ER proteostasis regulators cell-non-autonomously control sleep​

Taizo Kawano 1 , Mitsuaki Kashiwagi 2 , Mika Kanuka 1 , Chung-Kuan Chen 3 , Shinnosuke Yasugaki 3 , Sena Hatori 4 , Shinichi Miyazaki 4 , Kaeko Tanaka 1 , Hidetoshi Fujita 5 , Toshiro Nakajima 6 , Masashi Yanagisawa 7 , Yoshimi Nakagawa 8 , Yu Hayashi 9

Abstract​

Sleep is regulated by peripheral tissues under fatigue. The molecular pathways in peripheral cells that trigger systemic sleep-related signals, however, are unclear. Here, a forward genetic screen in C. elegans identifies 3 genes that strongly affect sleep amount: sel-1, sel-11, and mars-1. sel-1 and sel-11 encode endoplasmic reticulum (ER)-associated degradation components, whereas mars-1 encodes methionyl-tRNA synthetase.

We find that these machineries function in non-neuronal tissues and that the ER unfolded protein response components inositol-requiring enzyme 1 (IRE1)/XBP1 and protein kinase R-like ER kinase (PERK)/eukaryotic initiation factor-2α (eIF2α)/activating transcription factor-4 (ATF4) participate in non-neuronal sleep regulation, partly by reducing global translation. Neuronal epidermal growth factor receptor (EGFR) signaling is also required. Mouse studies suggest that this mechanism is conserved in mammals. Considering that prolonged wakefulness increases ER proteostasis stress in peripheral tissues, our results suggest that peripheral ER proteostasis factors control sleep homeostasis. Moreover, based on our results, peripheral tissues likely cope with ER stress not only by the well-established cell-autonomous mechanisms but also by promoting the individual's sleep.

 

[Murph]

Ever since the Hwang paper on WASF3 came out i've been reading about the endoplasmic reticulum (ER) and thinking about its possible role in mecfs.

The ER's job is to make proteins. When the ER gets overwhelmed it turns on a crisis mode called the "unfolded protein response" (UPR), which shuts everything down until it can get a handle on things. This seems to me like a potentially massive part of our condition.

However, there's not been a lot of research on the link. As the next picture shows if you search for mecfs and upr on pubmed you get nothing. (By comparison upr cancer has 3134 results and mecfs metabolism has 244 results).

UPR could be relevant to us. It turns on during exercise. You need to make more proteins when you've exercised, to build muscle and repair muscle damage. Healthy people have a brief burst of UPR during exercise (but fit, trained people have less upr than unfit).

If we're always on the brink of UPR or already in UPR, or unable to get back out of UPR easily, it could explain why even a little bit of exercise tips us into crisis.

So I was fascinated to learn via the above study that if the endoplasmic reticulum is deeply stressed it makes the person sleep. Sleeping 18 hours a day is pretty classic in mecfs! It does seem like another clue (only circumstantial evidence for, but certainly not evidence against) the idea UPR activation is involved in mecfs..

 

[Wishful]

Your arguments for this being involved in some ME symptoms sound plausible to me. My first thought is whether this feedback mechanism works on a short time frame (exercising a few hours affects sleep that night) or if it works on a longer frame (several days of strenuous activity is needed to affect sleep).

Have any studies noticed abnormal levels of UPR or general protein levels in serum? That's assuming that the variation needed to show noticeable effects is large enough to find without requiring a very large cohort.

 

[Murph]

Your arguments for this being involved in some ME symptoms sound plausible to me. My first thought is whether this feedback mechanism works on a short time frame (exercising a few hours affects sleep that night) or if it works on a longer frame (several days of strenuous activity is needed to affect sleep).

Have any studies noticed abnormal levels of UPR or general protein levels in serum? That's assuming that the variation needed to show noticeable effects is large enough to find without requiring a very large cohort.

Good type of question. I've been trying to find the right search terms to use to find what length of time the UPR is on for. Is it minutes, hours, days? But there aren't many studies that seem to address this. I did see one that said it turns on as soon as exercise starts and turns off a while after exercise ends. I started wondering if its end might correlate with the start of delayed pem. Not sure the answer here yet.

edit, found a good study on this. Looks like upr can go on for ages after exercise. This chart says 48h. (this was an intense bout for untrained people, i.e probably very tiring):

I have other quesstions: Is it done in the whole body or just a few cells? can cells in upr communicate to other cells to also turn on upr? in other words, could it cause a whole body sickness response feeling?

There are some very specific proteins involved in UPR. (PERK, ATF6, IRE1) I'm not sure they've been studied in mecfs. There's also more general cytokines associated with ER stress, I could try to define a few of those in advance and see how they've turned out in various studies.

 

[Murph]

It does seem that fish oil is a way to reduce endoplasmic reticulum stress in disused muscles.

https://pubmed.ncbi.nlm.nih.gov/34371808/

Endoplasmic Reticulum Stress and Autophagy Markers in Soleus Muscle Disuse-Induced Atrophy of Rats Treated with Fish Oil​

Gabriel Nasri Marzuca-Nassr 1 2 , Wilson Mitsuo Tatagiba Kuwabara 2 , Kaio Fernando Vitzel 2 3 , Gilson Masahiro Murata 4 , Rosângela Pavan Torres 5 , Jorge Mancini-Filho 5 , Tatiana Carolina Alba-Loureiro 2 , Rui Curi 2 6 7

Abstract​

Endoplasmic reticulum stress (ERS) and autophagy pathways are implicated in disuse muscle atrophy. The effects of high eicosapentaenoic (EPA) or high docosahexaenoic (DHA) fish oils on soleus muscle ERS and autophagy markers were investigated in a rat hindlimb suspension (HS) atrophy model. Adult Wistar male rats received daily by gavage supplementation (0.3 mL per 100 g b.w.) of mineral oil or high EPA or high DHA fish oils (FOs) for two weeks. Afterward, the rats were subjected to HS and the respective treatments concomitantly for an additional two-week period. After four weeks, we evaluated ERS and autophagy markers in the soleus muscle. Results were analyzed using two-way analysis of variance (ANOVA) and Bonferroni post hoc test. Gastrocnemius muscle ω-6/ω-3 fatty acids (FAs) ratio was decreased by both FOs indicating the tissue incorporation of omega-3 fatty acids. HS altered (p < 0.05) the protein content (decreasing total p38 and BiP and increasing p-JNK2/total JNK2 ratio, and caspase 3) and gene expressions (decreasing BiP and increasing IRE1 and PERK) of ERS and autophagy (decreasing Beclin and increasing LC3 and ATG14) markers in soleus. Both FOs attenuated (p < 0.05) the increase in PERK and ATG14 expressions induced by HS. Thus, both FOs could potentially attenuate ERS and autophagy in skeletal muscles undergoing atrophy.