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

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...

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Vydáno v:	Nature communications Ročník 11; číslo 1; s. 174 - 15
Hlavní autoři:	D’Hulst, Gommaar, Soro-Arnaiz, Inés, Masschelein, Evi, Veys, Koen, Fitzgerald, Gillian, Smeuninx, Benoit, Kim, Sunghoon, Deldicque, Louise, Blaauw, Bert, Carmeliet, Peter, Breen, Leigh, Koivunen, Peppi, Zhao, Shi-Min, De Bock, Katrien
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	London Nature Publishing Group UK 10.01.2020 Nature Publishing Group Nature Portfolio
Témata:	13/1 13/106 13/109 13/51 13/95 14/19 38/35 38/77 631/80/304 631/80/83/2359 64/60 692/308/2778 82/29 82/58 96/95 Activation Adult Aged Aging - metabolism Amino acids Amino Acids - metabolism Animals Degradation Depletion Disease Models, Animal Female Geriatrics Growth factors HEK293 Cells Humanities and Social Sciences Humans Hydroxylation Hypoxia-Inducible Factor-Proline Dioxygenases - metabolism Leucine Leucine - metabolism Leucine-tRNA Ligase - metabolism Male Mechanistic Target of Rapamycin Complex 1 - metabolism Mice Mice, Inbred C57BL Mice, Knockout multidisciplinary Muscle Development Muscles Muscles - metabolism Muscles - pathology Nutrient content Nutrients Oxygen Oxygen - metabolism Oxygen probes Procollagen-Proline Dioxygenase - genetics Procollagen-Proline Dioxygenase - metabolism Prolyl hydroxylase Science Science (multidisciplinary) Sensors Signal Transduction tRNA Leu
ISSN:	2041-1723, 2041-1723
On-line přístup:	Získat plný text
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Shrnutí:	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. mTORC1 is an important regulator of muscle mass. Here, the authors show that the PHD1 controls muscle mass in a hydroxylation-independent manner. PHD1 prevents the degradation of leucine sensor LRS during oxygen and amino acid depletion to ensure effective mTORC1 activation in response to leucine.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	2041-1723 2041-1723
DOI:	10.1038/s41467-019-13889-6