PHD1 controls muscle mTORC1 in a hydroxylation-independent manner by stabilizing leucyl tRNA synthetase

Gommaar D’Hulst,Katrien De Bock,Shi-Min Zhao,Peppi Koivunen,Bert Blaauw,Louise Deldicque,Benoit Smeuninx,Peter Carmeliet,Koen Veys,Leigh Breen,Sunghoon Kim,Inés Soro-Arnaiz,Gillian Fitzgerald,Evi Masschelein

doi:10.1038/s41467-019-13889-6

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 (PHD1KO) reduces muscle mass. PHD1KO 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.

Highlights

MTORC1 is an important regulator of muscle mass but how it is modulated by oxygen and nutrients is not completely understood
Mechanisms that allow protein synthesis during hypoxia have been described as stabilization of HIF2α promotes mechanistic target of rapamycin complex 1 (mTORC1) activation during low amino acid availability by increasing the expression of the amino acid carrier Lat[129]
In vivo data in lung and liver during hypoxia have indicated that HIF2α mediated activation of mTORC1 can prevail over HIF1α dependent mTORC1 inhibition[29]

Summary

Introduction

MTORC1 is an important regulator of muscle mass but how it is modulated by oxygen and nutrients is not completely understood. Skeletal muscle mass is defined by a fine balance between protein synthesis and breakdown[8,9], processes which are governed by mechanistic target of rapamycin complex 1 (mTORC1), a master regulator of cellular metabolism[10]. LRS, an aminoacyl tRNA synthetase that catalyzes the ligation of leucine to its cognate tRNA20, exerts a noncanonical role and activates mTORC1 upon leucine binding by functioning as a GAP toward RagD and by ensuring the leucylation of RagA/B18,21 Besides their sensing activities, it is plausible that alterations in protein levels of leucine sensors can impose an additional level of control on mTORC1 activity[22]. Protein synthesis and mTORC1 activity need to be tightly controlled upon metabolic stress such as hypoxia and nutrient deprivation, to ensure cell survival. Whether PHDs can directly control protein synthesis, is not known

Methods

Results

Conclusion