Sestrins are evolutionarily conserved mediators of exercise benefits, 2020, Kim et al

Andy · Jan 13, 2020

In animal models.

Exercise is among the most effective interventions for age-associated mobility decline and metabolic dysregulation. Although long-term endurance exercise promotes insulin sensitivity and expands respiratory capacity, genetic components and pathways mediating the metabolic benefits of exercise have remained elusive. Here, we show that Sestrins, a family of evolutionarily conserved exercise-inducible proteins, are critical mediators of exercise benefits. In both fly and mouse models, genetic ablation of Sestrins prevents organisms from acquiring metabolic benefits of exercise and improving their endurance through training. Conversely, Sestrin upregulation mimics both molecular and physiological effects of exercise, suggesting that it could be a major effector of exercise metabolism. Among the various targets modulated by Sestrin in response to exercise, AKT and PGC1α are critical for the Sestrin effects in extending endurance. These results indicate that Sestrin is a key integrating factor that drives the benefits of chronic exercise to metabolism and physical endurance.
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Open access, https://www.nature.com/articles/s41467-019-13442-5

Article.

Summary: Sestrin, a naturally occurring compound, mimics many of the effects of exercise in mouse and fly models. The findings could help with the development of medications to help combat muscle wasting associated with aging and neurodegenerative diseases.
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https://neurosciencenews.com/exercise-replacement-15458/

Ravn · Jan 14, 2020

Andy said: ↑

https://neurosciencenews.com/exercise-replacement-15458/
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"Exercise replacement" - love it!

Very long and technical article so haven't been able to read all of it but it does sound potentially relevant, even if it is about fruit flies and mice.

The paper looks at dysregulated TORC function, something that also pops up in ME research. Unfortunately I can't work out if it's the same sort of dysregulation - can anyone enlighten me? For example TORC features here: https://www.s4me.info/threads/an-is...me-cfs-patients-missailidis-et-al-2019.11121/

The main molecule looked at is sestrin which only seems to have had minor attention in ME. The search terms "ME/CFS sestrin" came up with a single study from 2006 (for which we don't seem to have a thread). It states "The single most influential gene was sestrin 1 (SESN1)" - so I wonder why there hasn't been more interest. Have there been failed replication studies that went unpublished or that my quick search didn't find? Or just another case of lack of funding at the time and then forgotten?

Pharmacogenomics. 2006 Apr;7(3):407-19.
Identifying illness parameters in fatiguing syndromes using classical projection methods.
Broderick G1, Craddock RC, Whistler T, Taylor R, Klimas N, Unger ER.

OBJECTIVES:
To examine the potential of multivariate projection methods in identifying common patterns of change in clinical and gene expression data that capture the illness state of subjects with unexplained fatigue and nonfatigued control participants.

METHODS:
Data for 111 female subjects was examined. A total of 59 indicators, including multidimensional fatigue inventory (MFI), medical outcome Short Form 36 (SF-36), Centers for Disease Control and Prevention (CDC) symptom inventory and cognitive response described illness. Partial least squares (PLS) was used to construct two feature spaces: one describing the symptom space from gene expression in peripheral blood mononuclear cells (PBMC) and one based on 117 clinical variables. Multiplicative scatter correction followed by quantile normalization was applied for trend removal and range adjustment of microarray data. Microarray quality was assessed using mean Pearson correlation between samples. Benjamini-Hochberg multiple testing criteria served to identify significantly expressed probes.

RESULTS:
A single common trend in 59 symptom constructs isolates of nonfatigued subjects from the overall group. This segregation is supported by two co-regulation patterns representing 10% of the overall microarray variation. Of the 39 principal contributors, the 17 probes annotated related to basic cellular processes involved in cell signaling, ion transport and immune system function. The single most influential gene was sestrin 1 (SESN1), supporting recent evidence of oxidative stress involvement in chronic fatigue syndrome (CFS). Dominant variables in the clinical feature space described heart rate variability (HRV) during sleep. Potassium and free thyroxine (T4) also figure prominently.

CONCLUSION:
Combining multiple symptom, gene or clinical variables into composite features provides better discrimination of the illness state than even the most influential variable used alone. Although the exact mechanism is unclear, results suggest a common link between oxidative stress, immune system dysfunction and potassium imbalance in CFS patients leading to impaired sympatho-vagal balance strongly reflected in abnormal HRV.
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Red highlight mine. https://www.ncbi.nlm.nih.gov/pubmed/16610951

Tongue in cheek observation: Did they accidentally create the best mouse model for ME yet? Poor mice.

Notably, RER[respiratory exchange ratio], a marker for metabolic exhaustion30, was strongly elevated right around exhaustion in both WT[wild type] and TKO[triple knock-out] mice (Fig. 4i) and remained high during early recovery period (Fig. 4i), indicating that TKO mice did not simply choose to stop running but were metabolically exhausted. Notably, at time points when the Sestrin TKO mice were exhausting (around 20–25 min after running), the RER levels of Sestrin TKO mice were significantly higher than WT mice (Fig. 4i). Furthermore, RER induction during exercise (ΔRER) was substantially stronger in TKO mice compared to WT mice (Fig. 4j, k). These results indicate that defective running capacity in TKO mice is not due to a behavioral change but a metabolic alteration associated with respiratory defects.
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ETA: from Open access, https://www.nature.com/articles/s41467-019-13442-5

Snow Leopard · Jan 16, 2020

Ravn said: ↑

Tongue in cheek observation: Did they accidentally create the best mouse model for ME yet? Poor mice.
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Perhaps you jest, but you may well be right - Sesn triple knockout mice undergoing ramped exercise while measuring gas exchange parameters is more useful than any other model I have seen.

Interesting commentary here:
"Sestrin family of genes and their role in cancer-related fatigue"
https://link.springer.com/article/10.1007/s00520-018-4139-8
10.1007/s00520-018-4139-8

(edit) Also:
https://www.karger.com/Article/Pdf/366571

Sesns are a highly conserved gene family among eukaryotes. There are three Sesns (Sesn1, Sesn2 and Sesn3) in mammals but one ortholog in Drosophila. Sesns are regulated by many stress insults including DNA damage, oxidative stress, hypoxia, growth factor deprivation, hyperactive TOR and RAS signaling via p53 and FOXOs, and result in enhanced autophagy, reactive oxygen species reduction, reduced protein synthesis, reduced anabolism, and reduced cell growth. These Sesn-dependent effects are conserved in Drosophila and in mammalian cells. Sesns are inhibitors of TOR signaling.
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On the latter point, Sestrins inhibit MTORC1, but can activate MTORC2.

I wonder what effect the following would have.
https://en.wikipedia.org/wiki/NV-5138

NV-5138[2] is an orally and centrally active small-molecule drug which is under development by Navitor Pharmaceuticals for the treatment of major depressive disorder (MDD).[3][1][4] It directly and selectively activates the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway by binding to and modulating sestrin2, a leucine amino acid sensor and upstream regulatory pathway.[1][4][5]
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Mithriel · Jan 16, 2020

Basic biology is very similar among mammals and anything which is the same in flies and mice is relevant to us. This is the sort of research that can lead to new ideas about ME that could be more accurate than we have.

It is whether anything that helps mice would help us that is more doubtful.

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