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

Department of Pharmacy

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

19 Citations (Scopus)

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
Journal	Nature communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-13889-6
Publication status	Published - 2020 Dec 1

Bibliographical note

Publisher Copyright:
© 2020, The Author(s).

All Science Journal Classification (ASJC) codes

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

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10.1038/s41467-019-13889-6

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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(1), [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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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, SM & De Bock, K 2020, 'PHD1 controls muscle mTORC1 in a hydroxylation-independent manner by stabilizing leucyl tRNA synthetase', Nature communications, vol. 11, no. 1, 174. https://doi.org/10.1038/s41467-019-13889-6

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AU - Veys, Koen

AU - Fitzgerald, Gillian

AU - Smeuninx, Benoit

AU - Kim, Sunghoon

AU - Deldicque, Louise

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

Bibliographical note

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