The mTOR pathway drives daily physiology
- 1MRC Laboratory of Molecular Biology
Abstract
Daily rhythms in mammalian physiology are widely attributed to rhythmic transcription of "clock-controlled genes" driven by the circadian transcriptional/translational feedback loop (TTFL). Here we show that daily physiology can be uncoupled from the TTFL: inhibiting the mechanistic target of rapamycin (mTOR) abolishes most daily variation in cellular and organismal physiology, whilst clock protein rhythms persist. In cultured cells and mouse liver, functional rhythms are lost, including the proteome, RNA abundance, substrate utilisation and drug metabolism. In forebrain, most daily variation in protein abundance and phosphorylation is lost, yet locomotor activity and sleep-wake architecture are largely preserved in mice and zebrafish. PERIOD2 binds mTORC1 and limits its activity, providing a route by which clock proteins shape daily mTOR signalling. mTOR inhibition preferentially suppresses output over clock gene rhythms in Arabidopsis and Neurospora. We conclude that mTOR is a conserved conduit through which circadian and environmental timing impose daily organisation on physiology.
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BibTeX
@misc{zeng2026mtor,
title = {{The mTOR pathway drives daily physiology}},
author = {A. Zeng and A. Mihut and M. Anandapadamanaban and A. Goity and L. L. de Barros Dantas and S.-Y. Peak Chew and E. A. Hayter and L. C. Andersson and T. Smith and E. Seinkmane and A. Stangherlin and N. R. James and C. Beresford and J. Farnsworth and J. Menzies and A. al-Rawi and L. J. Holt and E. Derivery and R. S. Edgar and R. R. Madsen and D. A. Bechtold and L. F. Larrondo and A. N. Dodd and J. Rihel and G. M. Ratto and J. Williams and P. Newham and C. Hilgendorf and A. D. Beale and C. Lodovichi and J. S. O'Neill},
howpublished = {bioRxiv},
year = {2026},
month = aug,
doi = {10.64898/2026.08.28.747564},
url = {https://www.biorxiv.org/content/10.64898/2026.08.28.747564v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - The mTOR pathway drives daily physiology
AU - A. Zeng
AU - A. Mihut
AU - M. Anandapadamanaban
AU - A. Goity
AU - L. L. de Barros Dantas
AU - S.-Y. Peak Chew
AU - E. A. Hayter
AU - L. C. Andersson
AU - T. Smith
AU - E. Seinkmane
AU - A. Stangherlin
AU - N. R. James
AU - C. Beresford
AU - J. Farnsworth
AU - J. Menzies
AU - A. al-Rawi
AU - L. J. Holt
AU - E. Derivery
AU - R. S. Edgar
AU - R. R. Madsen
AU - D. A. Bechtold
AU - L. F. Larrondo
AU - A. N. Dodd
AU - J. Rihel
AU - G. M. Ratto
AU - J. Williams
AU - P. Newham
AU - C. Hilgendorf
AU - A. D. Beale
AU - C. Lodovichi
AU - J. S. O'Neill
PY - 2026
DA - 2026/08/28
PB - bioRxiv
DO - 10.64898/2026.08.28.747564
UR - https://www.biorxiv.org/content/10.64898/2026.08.28.747564v1
AB - Daily rhythms in mammalian physiology are widely attributed to rhythmic transcription of "clock-controlled genes" driven by the circadian transcriptional/translational feedback loop (TTFL). Here we show that daily physiology can be uncoupled from the TTFL: inhibiting the mechanistic target of rapamycin (mTOR) abolishes most daily variation in cellular and organismal physiology, whilst clock protein rhythms persist. In cultured cells and mouse liver, functional rhythms are lost, including the proteome, RNA abundance, substrate utilisation and drug metabolism. In forebrain, most daily variation in protein abundance and phosphorylation is lost, yet locomotor activity and sleep-wake architecture are largely preserved in mice and zebrafish. PERIOD2 binds mTORC1 and limits its activity, providing a route by which clock proteins shape daily mTOR signalling. mTOR inhibition preferentially suppresses output over clock gene rhythms in Arabidopsis and Neurospora. We conclude that mTOR is a conserved conduit through which circadian and environmental timing impose daily organisation on physiology.
ER -