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; Katrien De Bock

doi:10.1038/s41467-019-13889-6

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

Nat Commun. 2020 Jan 10;11(1):174. doi: 10.1038/s41467-019-13889-6.

Authors

Gommaar D'Hulst¹, Inés Soro-Arnaiz¹, Evi Masschelein¹, Koen Veys^{2

3}, Gillian Fitzgerald¹, Benoit Smeuninx^{4

5}, Sunghoon Kim⁶, Louise Deldicque⁷, Bert Blaauw⁸, Peter Carmeliet^{2

3}, Leigh Breen^{4

5}, Peppi Koivunen⁹, Shi-Min Zhao^{10

11

12}, Katrien De Bock¹³

Affiliations

¹ Department Health Sciences and Technology, Laboratory of Exercise and Health, Swiss Federal Institute of Technology (ETH) Zurich, Zurich, Switzerland.
² Laboratory of Angiogenesis and Vascular Metabolism, VIB Center for Cancer Biology (CCB), VIB, Leuven, Belgium.
³ Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, KU Leuven, Leuven, Belgium.
⁴ School of Sport, Exercise and Rehabilitation Sciences, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK.
⁵ MRC Arthritis Research UK Centre for Musculoskeletal Ageing Research, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK.
⁶ Medicinal Bioconvergence Research Center, College of Pharmacy, Seoul National University, Gwanak-gu, Seoul, South Korea.
⁷ Institute of Neuroscience, Université catholique de Louvain, Louvain-La-Neuve, Belgium.
⁸ Department of Biomedical Sciences, Venetian Institute of Molecular Medicine, University of Padova, Padova, Italy.
⁹ Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, Oulu Center for Cell-Matrix Research, University of Oulu, Oulu, Finland.
¹⁰ Obstetrics and Gynaecology Hospital of Fudan University, State Key Lab of Genetic Engineering, School of Life Sciences and Institutes of Biomedical Sciences, Shanghai, P. R. China.
¹¹ Institute of Biomedical Science, Fudan University, Shanghai, P. R. China.
¹² Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, P. R. China.
¹³ Department Health Sciences and Technology, Laboratory of Exercise and Health, Swiss Federal Institute of Technology (ETH) Zurich, Zurich, Switzerland. katrien-debock@ethz.ch.

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.

MeSH terms

Adult
Aged
Aging / metabolism
Amino Acids / metabolism
Animals
Disease Models, Animal
Female
HEK293 Cells
Humans
Hydroxylation
Hypoxia-Inducible Factor-Proline Dioxygenases / metabolism
Leucine / metabolism
Leucine-tRNA Ligase / metabolism*
Male
Mechanistic Target of Rapamycin Complex 1 / metabolism*
Mice
Mice, Inbred C57BL
Mice, Knockout
Muscle Development
Muscles / metabolism*
Muscles / pathology
Oxygen / metabolism
Procollagen-Proline Dioxygenase / genetics
Procollagen-Proline Dioxygenase / metabolism*
Signal Transduction

Substances

Amino Acids
PHD1 protein, mouse
Procollagen-Proline Dioxygenase
EGLN2 protein, human
Hypoxia-Inducible Factor-Proline Dioxygenases
Mechanistic Target of Rapamycin Complex 1
Leucine-tRNA Ligase
Leucine
Oxygen