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

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

Sport, Exercise and Rehabilitation Sciences

Research output: Contribution to journal › Article › peer-review

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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.

Original language	English
Article number	174
Number of pages	15
Journal	Nature Communications
Volume	11
DOIs	https://doi.org/10.1038/s41467-019-13889-6
Publication status	Published - 10 Jan 2020

Keywords

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

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D'Hulst, G., Soro-Arnaiz, I., Masschelein, E., Veys, K., Fitzgerald, G., Smeuninx, B., Kim, S., Deldicque, L., Blaauw, B., Carmeliet, P., Breen, L., Koivunen, P., Zhao, S.-M., & De Bock, K. (2020). PHD1 controls muscle mTORC1 in a hydroxylation-independent manner by stabilizing leucyl tRNA synthetase. Nature Communications, 11, Article 174. https://doi.org/10.1038/s41467-019-13889-6

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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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AU - Blaauw, Bert

AU - Carmeliet, Peter

AU - Breen, Leigh

AU - Koivunen, Peppi

AU - Zhao, Shi-Min

AU - De Bock, Katrien

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

Abstract

Keywords

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