PHD1 Controls Muscle MTORC1 in a Hydroxylation-independent Manner by Stabilizing Leucyl TRNA Synthetase

Overview

Journal Nat Commun

Specialty Biology

Date 2020 Jan 12

PMID 31924757

Citations 18

Authors

Gommaar DHulst

Ines Soro-Arnaiz

Evi Masschelein

Koen Veys

Gillian Fitzgerald

Benoit Smeuninx

Sunghoon Kim

Louise Deldicque

Bert Blaauw

Peter Carmeliet

Leigh Breen

Peppi Koivunen

Shi-Min Zhao

Katrien De Bock

Affiliations

Soon will be listed here.

Abstract

mTORC1 is an important regulator of muscle mass but how it is modulated by oxygen and nutrients is not completely understood. We show that loss of the prolyl hydroxylase domain isoform 1 oxygen sensor in mice (PHD1) reduces muscle mass. PHD1 muscles show impaired mTORC1 activation in response to leucine whereas mTORC1 activation by growth factors or eccentric contractions was preserved. The ability of PHD1 to promote mTORC1 activity is independent of its hydroxylation activity but is caused by decreased protein content of the leucyl tRNA synthetase (LRS) leucine sensor. Mechanistically, PHD1 interacts with and stabilizes LRS. This interaction is promoted during oxygen and amino acid depletion and protects LRS from degradation. Finally, elderly subjects have lower PHD1 levels and LRS activity in muscle from aged versus young human subjects. In conclusion, PHD1 ensures an optimal mTORC1 response to leucine after episodes of metabolic scarcity.

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