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Cited by 2,310Muscle metabolism and nutritionMuscle Physiology and DisordersPI3K/AKT/mTOR signaling in cancer

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

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D’Hulst, Gommaar, Soro-Arnaiz, Inés, Masschelein, Evi, Veys, Koen, Fitzgerald, Gillian, Smeuninx, Benoit, Kim, Sunghoon, Deldicque, Louise +6 more·2020·Nature Communications
DOI 10.1038/s41467-019-13889-6PMC PMC6954236
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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.

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  • Confounding in GWAS can cause biases in downstream applications, including estimation of heritability and genetic correlation, Mendelian Randomization analyses, and inferences of natural selection.

    “Confounding can cause biases in downstream applications, including: estimation of heritability and genetic correlation6,7, Mendelian Randomization analyses13, and inferences of natural selection4,5.”

    From Family-GWAS reveals effects of environment and mating on genetic associations (2024) · cites this paper as [13]

    The Introduction discusses leucine sensing and mTORC1 signaling, while the Methods and Results describe muscle experiments; no page numbers are available in our copy. Searches for GWAS confounding, heritability, genetic correlation, Mendelian randomization, and natural selection found no passage addressing the claimed downstream biases. (LLM, conf=0.79)

    Experimental — accuracy not yet measured

  • Polygenic indices based on direct genetic effects from FGWAS have favorable properties due to the removal of confounding from PGI weights, making them suited to applications that are sensitive to confounding.

    “Polygenic predictors (called polygenic indices, PGIs, or polygenic scores) based on DGE estimates from FGWAS – hereafter, DGE PGIs – have favorable properties due to the removal of confounding from PGI weights, making them suited to applications that are sensitive to confounding4,5,9,13,23.”

    From Family-GWAS reveals effects of environment and mating on genetic associations (2024) · cites this paper as [13]

    The Results section on Phd1-deficient mice concerns muscle mass and mTORC1 activation, not polygenic prediction. Searches for FGWAS, direct genetic effects, polygenic indices, and confounding returned no passage addressing the claim. The available passages have no page numbers. (LLM, conf=0.78)

    Experimental — accuracy not yet measured

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Authors
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.
Affiliations
  • ETH Zurich (CH)
  • VIB-KU Leuven Center for Cancer Biology (BE)
  • Arthritis Research UK (GB)
  • UCLouvain (BE)
  • University of Padua (IT)
  • University of Oulu (FI)
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2020-01-10
Volume
11
Issue
1
Pages
174-174
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-019-13889-6
PMC
PMC6954236
OpenAlex
W2999304916
Cited by
2,310
References
14
Citations by year
2026: 126 · 2025: 253 · 2024: 306 · 2023: 440 · 2022: 519 · 2021: 501 · 2020: 157 · 2019: 6 · 2018: 1 · 2017: 1
FWCI
201.56
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion, cc-by)
  • Lirias (KU Leuven) (submittedVersion, other-oa)
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  • DIAL (Catholic University of Leuven) (submittedVersion, other-oa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
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  • Padua Research Archive (University of Padova) (submittedVersion, cc-by)
  • ETH Zürich Research Collection (cc-by)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Muscle metabolism and nutrition
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
Keywords
PHD1, mTORC1, leucyl-tRNA synthetase, protein stabilization, muscle mass, leucine sensing, oxygen sensing, muscle protein synthesis, aging, protein degradation, amino acid starvation
MeSH terms
Mechanistic Target of Rapamycin Complex 1, Adult, Aged, Aging, Amino Acids, Animals, Disease Models, Animal, Female, Humans, Hydroxylation, Leucine, Leucine-tRNA Ligase, Male, Mice, Inbred C57BL, Muscles, Oxygen, Procollagen-Proline Dioxygenase, Signal Transduction, Mice, Knockout, Muscle Development, Mice, HEK293 Cells, Hypoxia-Inducible Factor-Proline Dioxygenases

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