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

Gommaar D’Hulst, Inés 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 and Katrien De Bock ()
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Gommaar D’Hulst: Swiss Federal Institute of Technology (ETH) Zurich
Inés Soro-Arnaiz: Swiss Federal Institute of Technology (ETH) Zurich
Evi Masschelein: Swiss Federal Institute of Technology (ETH) Zurich
Koen Veys: VIB Center for Cancer Biology (CCB), VIB
Gillian Fitzgerald: Swiss Federal Institute of Technology (ETH) Zurich
Benoit Smeuninx: University of Birmingham, Edgbaston
Sunghoon Kim: Seoul National University, Gwanak-gu
Louise Deldicque: Institute of Neuroscience, Université catholique de Louvain
Bert Blaauw: Venetian Institute of Molecular Medicine, University of Padova
Peter Carmeliet: VIB Center for Cancer Biology (CCB), VIB
Leigh Breen: University of Birmingham, Edgbaston
Peppi Koivunen: University of Oulu
Shi-Min Zhao: Obstetrics and Gynaecology Hospital of Fudan University, State Key Lab of Genetic Engineering, School of Life Sciences and Institutes of Biomedical Sciences
Katrien De Bock: Swiss Federal Institute of Technology (ETH) Zurich

Nature Communications, 2020, vol. 11, issue 1, 1-15

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 (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.

Date: 2020
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DOI: 10.1038/s41467-019-13889-6

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