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Shear-stress sensing by PIEZO1 regulates tendon stiffness in rodents and influences jumping performance in humans

Nature Biomedical Engineering volume 5, pages 1457–1471 (2021)Cite this article

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Abstract

Athletic performance relies on tendons, which enable movement by transferring forces from muscles to the skeleton. Yet, how load-bearing structures in tendons sense and adapt to physical demands is not understood. Here, by performing calcium (Ca2+) imaging in mechanically loaded tendon explants from rats and in primary tendon cells from rats and humans, we show that tenocytes detect mechanical forces through the mechanosensitive ion channel PIEZO1, which senses shear stresses induced by collagen-fibre sliding. Through tenocyte-targeted loss-of-function and gain-of-function experiments in rodents, we show that reduced PIEZO1 activity decreased tendon stiffness and that elevated PIEZO1 mechanosignalling increased tendon stiffness and strength, seemingly through upregulated collagen cross-linking. We also show that humans carrying the PIEZO1 E756del gain-of-function mutation display a 13.2% average increase in normalized jumping height, presumably due to a higher rate of force generation or to the release of a larger amount of stored elastic energy. Further understanding of the PIEZO1-mediated mechanoregulation of tendon stiffness should aid research on musculoskeletal medicine and on sports performance.

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Fig. 1: Mechanically induced Ca2+ elevations in tissue-resident tenocytes.
Fig. 2: Shear stress as a key stimulus driving Ca2+ signals in isolated tenocytes.
Fig. 3: PIEZO1-mediated shear-stress response in human tenocytes.
Fig. 4: Decreased stretch-induced Ca2+ response and stiffness in fascicles from tenocyte-targeted Piezo1-knockout mice.
Fig. 5: Stiffness and strength regulation of murine tendons by PIEZO1.
Fig. 6: Unchanged collagen fibrils but increased cross-link-associated thermal stability and autofluorescence in load-bearing tendons from Piezo1GOF mice.
Fig. 7: Human jumping performance is influenced by PIEZO1GOF E756 mutation with no effect on Achilles tendon morphology.
Fig. 8: Proposed mechanism of tendon mechanotransduction that adapts the tissue and influences physical performance.

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Data availability

The main data supporting the findings of this study are available within the paper and its Supplementary Information. The raw and analysed datasets generated during the study are too large to be publicly shared, yet they are available from the corresponding author on reasonable request.

Code availability

The software of the stretching device, as well as MATLAB, ImageJ and R codes, are all available from the corresponding author on request. The toolbox CHIPS is freely available65.

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Acknowledgements

We thank A. Ziegler for software assistance; N. Wili for support in chemistry; B. Rutishauser and E. Bachmann for engineering assistance; L. Gasser (Statistical Consulting Group, ETH Zurich) for statistical support; members of the Snedeker group for constructive discussions; A. Huang and R. Schweitzer for providing Scx-creERT2 mice; A. Patapoutian for providing Piezo1GOF mice and feedback; U. Lüthi and A. Käch from the Center for Microscopy and Image Analysis (University of Zurich) for help with transmission electron microscopy; R. Mezzenga and Y. Yao (ETH Zurich) for access to the differential scanning calorimeter and assistance during the experiments; and P. Aagaard for insights on the human jumping performance data. Funding was provided by the Swiss National Science Foundation (grant numbers 165670 and 185095).

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Authors and Affiliations

  1. University Hospital Balgrist, University of Zurich, Zurich, Switzerland

    Fabian S. Passini, Patrick K. Jaeger, Nicole A. Chittim, Matthias J. Arlt, Sebastiano Caprara, Maja Bollhalder, Barbara Niederöst, Aron N. Horvath, Tobias Götschi, Bettina Passini-Tall, Sandro F. Fucentese, Ulrich Blache, Unai Silván & Jess G. Snedeker

  2. Institute for Biomechanics, ETH Zurich, Zurich, Switzerland

    Fabian S. Passini, Patrick K. Jaeger, Nicole A. Chittim, Matthias J. Arlt, Sebastiano Caprara, Maja Bollhalder, Barbara Niederöst, Aron N. Horvath, Tobias Götschi, Ulrich Blache, Unai Silván & Jess G. Snedeker

  3. Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland

    Aiman S. Saab, Kim David Ferrari & Bruno Weber

  4. Neuroscience Center, University and ETH Zurich, Zurich, Switzerland

    Aiman S. Saab, Kim David Ferrari & Bruno Weber

  5. Department of Physical Therapy, University of Delaware, Newark, DE, USA

    Shawn Hanlon & Karin Grävare Silbernagel

  6. Center for Microscopy and Image Analysis, University of Zurich, Zurich, Switzerland

    Dominik Haenni

  7. Howard Hughes Medical Institute, Department of Neuroscience, Dorris Neuroscience Center, Scripps Research, La Jolla, CA, USA

    Shang Ma

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Contributions

F.S.P., P.K.J., A.S.S. and J.G.S. designed experiments and wrote the manuscript. F.S.P. performed the Ca2+-imaging experiments with tendon explants. F.S.P., K.D.F., D.H., S.C., A.N.H., U.S. and B.W. designed and analysed the Ca2+-imaging experiments. P.K.J. and F.S.P. carried out and analysed the shear-stress experiments. M.J.A., F.S.P., M.B. and B.P.-T. generated and analysed the knockout cells. S.F.F., M.B. and U.B. helped with human tendon tissues and isolation of primary cells. F.S.P. and S.M. performed mouse experiments. S.H., K.G.S., F.S.P. and J.G.S. designed and performed the human study. F.S.P. and B.P.-T. carried out human genotyping. F.S.P., S.H. and T.G. analysed the human data. All of the authors provided feedback on the manuscript.

Corresponding author

Correspondence to Jess G. Snedeker.

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The authors declare no competing interests.

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Peer review information Nature Biomedical Engineering thanks Michael Lavagnino and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Peer reviewer reports are available.

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Supplementary information

Supplementary Information

Supplementary Figs. 1–7 and Tables 1 and 2, and captions for Supplementary Videos 1–5.

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Supplementary Video 1

A tendon fascicle at baseline (unstretched condition), showing sparse spontaneous Ca2+ signals in tenocytes.

Supplementary Video 2

A tendon fascicle during tissue stretching from 0–10% strain, showing a tissue-wide Ca2+ response in tenocytes.

Supplementary Video 3

Propagation of Ca2+ signals to neighbouring cells, potentially through cell–cell communication.

Supplementary Video 4

Isolated human tenocytes showing Ca2+ signals on stimulation with 5 Pa shear stress.

Supplementary Video 5

A tendon fascicle stimulated with the PIEZO1-agonist Yoda1, showing a prompt Ca2+ response in tenocytes.

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Passini, F.S., Jaeger, P.K., Saab, A.S. et al. Shear-stress sensing by PIEZO1 regulates tendon stiffness in rodents and influences jumping performance in humans. Nat Biomed Eng 5, 1457–1471 (2021). https://doi.org/10.1038/s41551-021-00716-x

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