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

TLDR

mTORC1 regulates muscle mass, yet its modulation by oxygen and nutrients remains incompletely understood. PHD1 enhances mTORC1 activity by binding to and stabilizing leucyl tRNA synthetase, a process that is upregulated during oxygen or amino‑acid depletion and protects LRS from degradation. Loss of PHD1 in mice decreases muscle mass and blunts leucine‑stimulated mTORC1 activation, while PHD1 levels and LRS activity are reduced in aged human muscle, indicating PHD1 is essential for a robust leucine‑dependent mTORC1 response after metabolic stress.

Abstract

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 KO ) reduces muscle mass. PHD1 KO 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.