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

Author

Listed:
  • Michal Dudek

    (University of Manchester
    University of Manchester
    University of Manchester, Manchester Academic Health Science Centre)

  • Dharshika R. J. Pathiranage

    (University of Manchester
    University of Manchester
    University of Manchester, Manchester Academic Health Science Centre)

  • Beatriz Bano-Otalora

    (University of Manchester)

  • Anna Paszek

    (University of Manchester
    University of Manchester
    University of Manchester, Manchester Academic Health Science Centre)

  • Natalie Rogers

    (University of Manchester
    University of Manchester
    University of Manchester, Manchester Academic Health Science Centre)

  • Cátia F. Gonçalves

    (University of Manchester
    University of Manchester
    University of Manchester, Manchester Academic Health Science Centre)

  • Craig Lawless

    (University of Manchester
    University of Manchester, Manchester Academic Health Science Centre)

  • Dong Wang

    (Fourth Military Medical University)

  • Zhuojing Luo

    (Fourth Military Medical University)

  • Liu Yang

    (Fourth Military Medical University)

  • Farshid Guilak

    (Washington University
    Shriners Hospitals for Children – St. Louis)

  • Judith A. Hoyland

    (University of Manchester, Manchester Academic Health Science Centre
    Central Manchester Foundation Trust, Manchester Academic Health Science Centre)

  • Qing-Jun Meng

    (University of Manchester
    University of Manchester
    University of Manchester, Manchester Academic Health Science Centre)

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.

Suggested Citation

  • 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., 2023. "Mechanical loading and hyperosmolarity as a daily resetting cue for skeletal circadian clocks," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-42056-1
    DOI: 10.1038/s41467-023-42056-1
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    References listed on IDEAS

    as
    1. Steven M. Reppert & David R. Weaver, 2002. "Coordination of circadian timing in mammals," Nature, Nature, vol. 418(6901), pages 935-941, August.
    2. E. Nicholas Petersen & Hae-Won Chung & Arman Nayebosadri & Scott B. Hansen, 2016. "Kinetic disruption of lipid rafts is a mechanosensor for phospholipase D," Nature Communications, Nature, vol. 7(1), pages 1-8, December.
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