TY - JOUR
T1 - Shear-stress sensing by PIEZO1 regulates tendon stiffness in rodents and influences jumping performance in humans
AU - Passini, Fabian S.
AU - Jaeger, Patrick K.
AU - Saab, Aiman S.
AU - Hanlon, Shawn
AU - Chittim, Nicole A.
AU - Arlt, Matthias J.
AU - Ferrari, Kim David
AU - Haenni, Dominik
AU - Caprara, Sebastiano
AU - Bollhalder, Maja
AU - Niederöst, Barbara
AU - Horvath, Aron N.
AU - Götschi, Tobias
AU - Ma, Shang
AU - Passini-Tall, Bettina
AU - Fucentese, Sandro F.
AU - Blache, Ulrich
AU - Silván, Unai
AU - Weber, Bruno
AU - Silbernagel, Karin Grävare
AU - Snedeker, Jess G.
N1 - Funding Information:
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).
Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2021/12
Y1 - 2021/12
N2 - 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.
AB - 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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U2 - 10.1038/s41551-021-00716-x
DO - 10.1038/s41551-021-00716-x
M3 - Article
C2 - 34031557
AN - SCOPUS:85106289573
SN - 2157-846X
VL - 5
SP - 1457
EP - 1471
JO - Nature Biomedical Engineering
JF - Nature Biomedical Engineering
IS - 12
ER -