PHD1 controls muscle mTORC1 in a hydroxylation-independent manner by stabilizing leucyl tRNA synthetase
Research output: Contribution to journal › Article
Colleges, School and Institutes
- Swiss Federal Institute of Technology (ETH-Zurich)
- Laboratory of Angiogenesis and Vascular Metabolism
- Seoul National University, Seoul, Korea.
- Netherlands Institute for Neuroscience
- Padova University Hospital
- Department of Paediatrics, University of Oulu, Oulu, Finland.
- School of Manufacturing Science and Engineering, Sichuan University, Sichuan 610065
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.
|Number of pages||15|
|Publication status||Published - 10 Jan 2020|
- 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, Oxygen/metabolism, Procollagen-Proline Dioxygenase/genetics, Signal Transduction