Sestrins are evolutionarily conserved mediators of exercise benefits

Abstract

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.

The effects of genetic background on exercise performance in Drosophila

“…Additionally, exercised spargel-overexpressing flies gained little benefits to their endurance or flight ability. Together, these results support that spargel alone can mimic exercise training and is required for training adaptations [28,29].…”

“…Exercise training is performed for 3 weeks, Monday-Friday, and the time on the machine is increased by a half an hour each week making the Power Tower a good method for chronic training [17]. Studies using the Power Tower have shown improvements in exercise parameters such as climbing speed, endurance, flight performance, cardiac resistance to stress, neurological health, mitochondrial function and healthspan in both wild-type and disease models, as well as across Drosophila species [17,21,22,28,[32][33][34]. These results will be further dissected in subsequent sections of this review.…”

“…Similar to humans [46], Drosophila undergo an agerelated decline in physical health that can be slowed with exercise, but not stopped [21]. Climbing speed, endurance, flight performance, cardiac performance, and mitochondrial health all decline with age [21,28,41,[47][48][49]. In addition to slowing the rate of age-related decline in climbing ability, chronic exercise training using the Power Tower can preserve endurance and flight performance, improve resistance to cardiac stress that declines with age, and maintain mitochondrial health in trained flies [18,21,22,29,33,47,50], though the magnitude of the training response differs between wild-type strains [21,50].…”

Variation in mobility and exercise adaptations between Drosophila species

“…The authors also found similar expression patterns of AMPK in D. simulans from latitudes of similar temperatures as their experimental conditions. Sestrin is a critical mediator of exercise adaptations, as it activates AMPK and downregulates TORC1, which collectively increases fatty acid oxidation, mitochondrial biogenesis, and autophagy (Richter and Ruderman 2009;Kim et al 2020;Ho et al 2016). Drosophila found in different latitudes may, therefore, be at a genetic predisposition to respond differently to exercise training.…”

Sestrin2 Phosphorylation by ULK1 Induces Autophagic Degradation of Mitochondria Damaged by Copper-Induced Oxidative Stress

“…In mammals, the Sestrin family is comprised of three closely related members, Sestrin1 (Sesn1 or PA26), Sestrin2 (Sesn2 or Hi95), and Sestrin3 (Sesn3) [ 3 , 4 ]. Sestrin1 is predominantly expressed in cardiac and skeletal muscles, whereas Sestrin2/3 are more commonly expressed in the liver, adipose tissue, and the brain [ 2 , 5 , 6 ]. Drosophila melanogaster (Drosophila) and Caenorhabditis elegans (C. elegans) have single Sestrin in their genomes, namely dSesn and cSesn , respectively.…”