Hormonal
Loss of the oxygen sensor PHD1 reduces muscle mass by impairing the stability of the leucine sensor LRS, thereby blunting mTORC1 activation specifically in response to leucine.
Maintaining healthy cellular oxygen sensing and nutrient sensor stability (specifically PHD1 and LRS) is crucial for your muscles to respond to protein/leucine intake. This mechanism explains why older adults often experience 'anabolic resistance'—their muscles struggle to build mass from protein because these specific sensors degrade. While you cannot directly 'dose' PHD1, ensuring adequate oxygenation and avoiding chronic metabolic stress may help preserve these sensors.
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.
Why this rating
Strong mechanistic evidence from multiple models (global KO, muscle-specific KO, cell culture) and human observational data, but lacks direct interventional trials in humans.
Source
PHD1 controls muscle mTORC1 in a hydroxylation-independent manner by stabilizing leucyl tRNA synthetase
Gommaar D’Hulst et al. · Nature Communications · 2020
DOI 10.1038/s41467-019-13889-6
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