Advances in the Role of Leucine-Sensing in the Regulation of Protein Synthesis in Aging Skeletal Muscle.

Yan Zhao,Zhi Xia,Jason Cholewa,Qianjin Wang,Nelo Eidy Zanchi,Yueqin Yang,Quansheng Su,Xiaomin Ding,Huayu Shang

doi:10.3389/fcell.2021.646482

Abstract

Skeletal muscle anabolic resistance (i.e., the decrease in muscle protein synthesis (MPS) in response to anabolic stimuli such as amino acids and exercise) has been identified as a major cause of age-related sarcopenia, to which blunted nutrition-sensing contributes. In recent years, it has been suggested that a leucine sensor may function as a rate-limiting factor in skeletal MPS via small-molecule GTPase. Leucine-sensing and response may therefore have important therapeutic potential in the steady regulation of protein metabolism in aging skeletal muscle. This paper systematically summarizes the three critical processes involved in the leucine-sensing and response process: (1) How the coincidence detector mammalian target of rapamycin complex 1 localizes on the surface of lysosome and how its crucial upstream regulators Rheb and RagB/RagD interact to modulate the leucine response; (2) how complexes such as Ragulator, GATOR, FLCN, and TSC control the nucleotide loading state of Rheb and RagB/RagD to modulate their functional activity; and (3) how the identified leucine sensor leucyl-tRNA synthetase (LARS) and stress response protein 2 (Sestrin2) participate in the leucine-sensing process and the activation of RagB/RagD. Finally, we discuss the potential mechanistic role of exercise and its interactions with leucine-sensing and anabolic responses.

Highlights

In 2020, the population over 60 years old in China was in excess of 250 million and accounted for 18.1% of the total population, becoming the first country in the world with an elderly population in excess of 100 million
When amino acids are sufficiently present, RagA/B is bound to GTP, and RagC/D to GDP, which enhances the interaction between the heterodimeric Rag GTPase complex and Raptor and promotes mTORC1 translocation to the lysosome surface for subsequent activation
The GTP-/GDP-loading status of both RagB/RagD heterodimer and ras homolog enriched in brain (Rheb) GTPase may be the ratelimiting factor in mTORC1 activation induced by leucine stimulation, and a series of protein and/or complexes that are able to regulate their nucleotide state by working as their GTPase-activating protein (GAP) and/or guanine nucleotide exchange factor (GEF) may play the central role

Summary

Introduction

In 2020, the population over 60 years old in China was in excess of 250 million and accounted for 18.1% of the total population, becoming the first country in the world with an elderly population in excess of 100 million. When amino acids are sufficiently present, RagA/B is bound to GTP, and RagC/D to GDP, which enhances the interaction between the heterodimeric Rag GTPase complex and Raptor and promotes mTORC1 translocation to the lysosome surface for subsequent activation.

Results

Conclusion