Mechanical loading and hyperosmolarity as a daily resetting cue for skeletal circadian clocks

Michal Dudek, Dharshika R. J. Pathiranage, Beatriz Bano-Otalora, Anna Paszek, Natalie Rogers, Cátia F. Gonçalves, Craig Lawless, Dong Wang, Zhuojing Luo, Liu Yang, Farshid Guilak, Judith A. Hoyland () and Qing-Jun Meng ()
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Michal Dudek: University of Manchester
Dharshika R. J. Pathiranage: University of Manchester
Beatriz Bano-Otalora: University of Manchester
Anna Paszek: University of Manchester
Natalie Rogers: University of Manchester
Cátia F. Gonçalves: University of Manchester
Craig Lawless: University of Manchester
Dong Wang: Fourth Military Medical University
Zhuojing Luo: Fourth Military Medical University
Liu Yang: Fourth Military Medical University
Farshid Guilak: Washington University
Judith A. Hoyland: University of Manchester, Manchester Academic Health Science Centre
Qing-Jun Meng: University of Manchester

Nature Communications, 2023, vol. 14, issue 1, 1-12

Abstract: Abstract Daily rhythms in mammalian behaviour and physiology are generated by a multi-oscillator circadian system entrained through environmental cues (e.g. light and feeding). The presence of tissue niche-dependent physiological time cues has been proposed, allowing tissues the ability of circadian phase adjustment based on local signals. However, to date, such stimuli have remained elusive. Here we show that daily patterns of mechanical loading and associated osmotic challenge within physiological ranges reset circadian clock phase and amplitude in cartilage and intervertebral disc tissues in vivo and in tissue explant cultures. Hyperosmolarity (but not hypo-osmolarity) resets clocks in young and ageing skeletal tissues and induce genome-wide expression of rhythmic genes in cells. Mechanistically, RNAseq and biochemical analysis revealed the PLD2-mTORC2-AKT-GSK3β axis as a convergent pathway for both in vivo loading and hyperosmolarity-induced clock changes. These results reveal diurnal patterns of mechanical loading and consequent daily oscillations in osmolarity as a bona fide tissue niche-specific time cue to maintain skeletal circadian rhythms in sync.

Date: 2023
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DOI: 10.1038/s41467-023-42056-1

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