University of Oulu

D’Hulst, G., Soro-Arnaiz, I., Masschelein, E. et al. PHD1 controls muscle mTORC1 in a hydroxylation-independent manner by stabilizing leucyl tRNA synthetase. Nat Commun 11, 174 (2020). https://doi.org/10.1038/s41467-019-13889-6

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

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Author: D’Hulst, Gommaar1; Soro-Arnaiz, Inés1; Masschelein, Evi1;
Organizations: 1Department Health Sciences and Technology, Laboratory of Exercise and Health, Swiss Federal Institute of Technology (ETH) Zurich, Zurich, Switzerland
2Laboratory of Angiogenesis and Vascular Metabolism, VIB Center for Cancer Biology (CCB), VIB, Leuven, Belgium
3Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, KU Leuven, Leuven, Belgium
4School of Sport, Exercise and Rehabilitation Sciences, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK
5MRC Arthritis Research UK Centre for Musculoskeletal Ageing Research, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK
6Medicinal Bioconvergence Research Center, College of Pharmacy, Seoul National University, Gwanak-gu, Seoul, South Korea
7Institute of Neuroscience, Université catholique de Louvain, Louvain-La-Neuve, Belgium
8Department of Biomedical Sciences, Venetian Institute of Molecular Medicine, University of Padova, Padova, Italy
9Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, Oulu Center for Cell-Matrix Research, University of Oulu, Oulu, Finland
10Obstetrics 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
11Institute of Biomedical Science, Fudan University, Shanghai, P. R. China
12Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, P. R. China
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 2.5 MB)
Persistent link: http://urn.fi/urn:nbn:fi-fe2020051126001
Language: English
Published: Springer Nature, 2020
Publish Date: 2020-05-11
Description:

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.

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Series: Nature communications
ISSN: 2041-1723
ISSN-E: 2041-1723
ISSN-L: 2041-1723
Volume: 11
Issue: 1
Article number: 174
DOI: 10.1038/s41467-019-13889-6
OADOI: https://oadoi.org/10.1038/s41467-019-13889-6
Type of Publication: A1 Journal article – refereed
Field of Science: 1182 Biochemistry, cell and molecular biology
Subjects:
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