Effects of Leucine Ingestion and Contraction on the Sestrin/GATOR2 Pathway and mTORC1 Activation in Rat Fast-Twitch muscle.

Abstract

BACKGROUND:

Leucine activates the mechanistic/mammalian target of rapamycin complex 1 (mTORC1) in mammalian skeletal muscle. Recent studies have shown that Sestrin, a leucine sensor, might play a role in this process. However, it remains unknown whether Sestrin dissociates from GATOR2 in a dose- and time-dependent manner and whether an acute bout of muscle contraction augments this dissociation.

OBJECTIVE:

This study aimed to examine the effects of leucine ingestion and muscle contraction on the interaction between Sestrin1/2 and GATOR2 and on mTORC1 activation.

METHODS:

Male Wistar rats were randomly assigned to control (C), leucine 3 (L3), or leucine 10 (L10) groups. Intact gastrocnemius muscles were subjected to 30 repetitive unilateral contractions. The L3 and L10 groups were then orally administered 3 and 10 mmol/kg body weight of L-leucine 2 h after the end of the contractions, respectively. Blood and muscle samples were collected 30, 60, or 120 min after the administration.

RESULTS:

The blood and muscle leucine concentrations increased in a dose-dependent manner. The ratio of phosphorylated ribosomal protein S6 kinase (S6K) to total S6K (which indicates mTORC1 signaling activation) was markedly increased by muscle contraction and increased in a dose-dependent manner only in rested muscle. Leucine ingestion but not muscle contraction increased Sestrin1 dissociation from GATOR2 and Sestrin2 association with GATOR2. A negative relationship was observed between the blood and muscle leucine concentrations and the Sestrin1 association with GATOR2.

CONCLUSIONS:

The results suggest that Sestrin1, but not Sestrin2, regulates leucine-related mTORC1 activation via its dissociation from GATOR2 and that acute exercise-induced mTORC1 activation involves pathways other than the leucine-related Sestrin1/GATOR2 pathway.

• Authors: Keita Kanzaki, Masanobu Wada
• Journal: The Journal of nutrition (J Nutr) Vol. 153 Issue 8 Pg. 2228-2236 (08 2023) ISSN: 1541-6100 [Electronic] United States
• PMID: 37328110 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2023 American Society for Nutrition. Published by Elsevier Inc. All rights reserved.

Chemical References

• Mechanistic Target of Rapamycin Complex 1
• Leucine
• Sestrins
• TOR Serine-Threonine Kinases
• Nuclear Proteins

Topics

• Rats
• Male
• Animals
• Mechanistic Target of Rapamycin Complex 1 (metabolism)
• Leucine (pharmacology, metabolism)
• Sestrins (metabolism)
• TOR Serine-Threonine Kinases (metabolism)
• Nuclear Proteins (metabolism)
• Rats, Wistar
• Muscle, Skeletal
• Eating
• Mammals (metabolism)