Sestrins are evolutionarily conserved mediators of exercise benefits

Nat Commun. 2020 Jan 13;11(1):190. doi: 10.1038/s41467-019-13442-5.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism*
  • Cell Differentiation
  • Drosophila
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism*
  • Energy Metabolism
  • Exercise / physiology*
  • Gene Expression
  • Heat-Shock Proteins / genetics
  • Heat-Shock Proteins / metabolism*
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Muscle Fibers, Skeletal / cytology
  • Muscle, Skeletal / metabolism
  • Muscle, Skeletal / physiology
  • Organelle Biogenesis
  • Oxidoreductases / genetics
  • Oxidoreductases / metabolism*
  • Peroxidases / genetics
  • Peroxidases / metabolism*
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / metabolism
  • Physical Endurance / genetics
  • Physical Endurance / physiology
  • Proto-Oncogene Proteins c-akt / metabolism
  • Signal Transduction
  • TOR Serine-Threonine Kinases / metabolism

Substances

  • Cell Cycle Proteins
  • Drosophila Proteins
  • Heat-Shock Proteins
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Ppargc1a protein, mouse
  • SESN3 protein, mouse
  • sestrin 1 protein, mouse
  • Oxidoreductases
  • sesn protein, Drosophila
  • Peroxidases
  • sestrin 2 protein, mouse
  • TOR Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt