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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Experimental & Molecular Medicine Open Access 14 June 2022
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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.
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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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).
The authors declare no competing interests.
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.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Figs. 1–7 and Tables 1 and 2, and captions for Supplementary Videos 1–5.
A tendon fascicle at baseline (unstretched condition), showing sparse spontaneous Ca2+ signals in tenocytes.
A tendon fascicle during tissue stretching from 0–10% strain, showing a tissue-wide Ca2+ response in tenocytes.
Propagation of Ca2+ signals to neighbouring cells, potentially through cell–cell communication.
Isolated human tenocytes showing Ca2+ signals on stimulation with 5 Pa shear stress.
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