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

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.

SUBMITTER: Passini FS

PROVIDER: S-EPMC7612848 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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

Passini Fabian S FS Jaeger Patrick K PK Saab Aiman S AS Hanlon Shawn S Chittim Nicole A NA Arlt Matthias J MJ Ferrari Kim David KD Haenni Dominik D Caprara Sebastiano S Bollhalder Maja M Niederöst Barbara B Horvath Aron N AN Götschi Tobias T Ma Shang S Passini-Tall Bettina B Fucentese Sandro F SF Blache Ulrich U Silván Unai U Weber Bruno B Silbernagel Karin Grävare KG Snedeker Jess G JG

Nature biomedical engineering 20210524 12

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 (Ca<sup>2+</sup>) 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 ...[more]

PMID: 34031557

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Project description:Prolonged periods of increased physical demands can elicit anabolic tendon adaptations that increase stiffness and mechanical resilience or conversely can lead to pathological processes that deteriorate tendon structural quality with ensuing pain and potential rupture. Although the mechanisms by which tendon mechanical loads regulate tissue adaptation are largely unknown, the ion channel PIEZO1 has been implicated in tendon mechanotransduction, with human carriers of the PIEZO1 gain-of-function variant E756del displaying improved dynamic vertical jump performance compared with noncarriers. Here, we sought to examine whether increased tendon stiffness in humans could explain this increased performance. We assessed tendon morphological and mechanical properties with ultrasound-based techniques in 77 participants of Middle- and West-African descent, and we measured their vertical jumping performance to assess potential functional consequences in the context of high tendon strain-rate loading. Carrying the E756del gene variant (n = 30) was associated with 46.3 ± 68.3% (P = 0.002) and 45.6 ± 69.2% (P < 0.001) higher patellar tendon stiffness and Young's modulus compared with noncarrying controls, respectively. Although these tissue level measures strongly corroborate the initial postulate that PIEZO1 plays an integral part in regulating tendon material properties and stiffness in humans, we found no detectable correlation between tendon stiffness and jumping performance in the tested population that comprised individuals of highly diverse physical fitness level, dexterity, and jumping ability.NEW & NOTEWORTHY The E756del gene variant causes overactivity of the mechanosensitive membrane channel PIEZO1 and is suspected to upregulate tendon collagen cross linking. In human carriers of E756del, we found increased patellar tendon stiffness but similar tendon lengths and cross-sectional areas, directly supporting the premise that PIEZO1 regulates human tendon stiffness at the level of tissue material properties.

Project description:BackgroundWe sought to utilize a noninvasive technology to assess the effects of activity on Achilles tendon stiffness and define baseline Achilles tendon stiffness in female college athletes compared with nonathletes using tendon shear wave velocity as a marker for tendon stiffness.HypothesisTraining status and exercise may affect Achilles tendon stiffness.Study designLevel of evidenceLevel 4.MethodsA total of 32 college-age female athletes were prospectively enrolled (n = 17 varsity athletes and n = 15 nonathletes). Demographic characteristics, activity level, and previous injuries were recorded. Sonographic shear wave elastography (SWE) was used to assess Achilles tendon shear wave velocity bilaterally for all subjects, both at baseline and after 2 minutes of exercise. Student t tests were used to compare the mean elastography measurements between participants stratified by athlete status and pre/postexercise stimulus. Analysis of variance (ANOVA) was used to compare the mean proximal, middle, and distal Achilles tendon elastography measurements.ResultsAs seen by a greater mean shear wave velocity (8.60 ± 1.58 m/s vs 8.25 ± 1.89 m/s; P = 0.02), athletes had stiffer tendons than nonathletes. Exercise stimulus decreased average tendon shear wave velocity (8.57 ± 1.74 m/s vs 8.28 ± 1.72 m/s; P = 0.05). Tendon shear wave velocity was greatest proximally and least distally with significant differences between each region (P < 0.001). In addition, there was a significant 2-way interaction between weekly training status and foot dominance (P = 0.01). Post hoc analysis showed that this result was due to differences in tendon shear wave velocity between the dominant and nondominant lower extremity in nonathletes (7.73 ± 2.00 m/s vs 8.76 ± 1.62 m/s; P < 0.001).ConclusionFemale varsity collegiate athletes have higher baseline Achilles tendon stiffness as measured by SWE compared with nonathletes. Mean tendon stiffness varies based on Achilles measurement location. SWE is a quick, cost-effective, and noninvasive imaging modality that can be used to evaluate tendon stiffness and elasticity.Clinical relevanceSWE is an efficient and noninvasive imaging modality that can evaluate dynamic tendon stiffness and elasticity. SWE may be helpful to assess injuries in female college athletes and may play a role in risk stratification or clinical follow-up. In theory, SWE could be used to identify athletes with increased elasticity as a marker for potential risk for rupture in this population.

Project description:Objectives(1) To determine the association between patellar tendon stiffness and the presence of patellar tendinopathy (PT). (2) To evaluate the reliability of shear-wave elastography (SWE).MethodsParticipants were consecutively enrolled between January 2017 and June 2019. PT was diagnosed clinically and confirmed by either grayscale US or power Doppler US, or both. Controls had no history of anterior knee pain and no clinical signs of PT. Patellar tendon stiffness (kilopascal, kPa) was assessed using SWE. Logistic regression was used to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs). Reliability analyses included coefficients-of-variation (CV), coefficients-of-repeatability (CR), intraclass correlation coefficient (ICC) for intraobserver and interobserver reliability, and Bland-Altman analysis.ResultsIn total, 76 participants with PT (58 men, mean age 24.4 ± 3.8 years) and 35 asymptomatic controls (16 men, mean age 21.5 ± 3.8 years) were included. Univariate analyses (OR 1.094, 95% CI 1.061-1.128, p < .001) and adjusted multivariate analyses (OR 1.294, 95% CI 1.044-1.605, p = .018) showed that athletes with PT had significantly increased patellar tendon stiffness. ICC for intraobserver reliability was 0.95 (95% CI 0.92-0.97), CR (CV) 12 kPa (10%) and 0.79 (95% CI 0.65-0.88), CR (CV) 18 kPa (21%) for interobserver reliability. Mean differences from Bland-Altman analysis were 5.6 kPa (95% CI 3.1-8.1, p < .001) for intraobserver reliability and 4.6 kPa (95% CI 1.9-7.2, p < .001) for interobserver reliability.ConclusionsPT is associated with significantly higher patellar tendon stiffness. SWE measurements demonstrate excellent intraobserver reliability and good interobserver reliability. Therefore, SWE is a promising tool to implement in longitudinal studies and future studies should evaluate its prognostic value and utility as a monitoring tool in athletes with PT.Key points• Patellar tendon stiffness measured with shear-wave elastography (SWE) is higher in athletes with patellar tendinopathy than in healthy controls, also after adjusting for potential confounders. • Excellent intraobserver reliability and good interobserver reliability were found for the quantitative assessment of patellar tendon stiffness using SWE.

Project description:Adhesion formation after flexor tendon repair remains a clinical problem. Early postoperative motion after tendon repair has been demonstrated to reduce adhesion formation while increasing tendon strength. It is hypothesized that during mobilization, tendon cells experience mechanical shear forces that alter their biology in a fashion that reduces scar formation but also activates key genes involved in tendon healing. To test this hypothesis, primary intrinsic tenocyte cultures were established from flexor tendons of 20 Sprague-Dawley rats and sheared at 50 rpm (0.41 Pa) using a cone viscometer for 6 and 12 hours. Total RNA was harvested and compared with time-matched unsheared controls using cDNA microarrays and Northern blot analysis. Microarray analysis demonstrated that mechanical shear stress induced an overall "antifibrotic" expression pattern with decreased transcription of collagen type I and collagen type III. Shear stress down-regulated profibrotic molecules in the platelet-derived growth factor, insulin-like growth factor, and fibroblast growth factor signaling pathways. In addition, shear stress induced an overall decrease in transforming growth factor (TGF)-beta signaling pathway molecules with down-regulation of TGF-beta2, TGF-beta3, TGF-RI, and TGF-RII expression. Moreover, sheared tendon cells increased expression of matrix metalloproteinases and decreased expression of tissue inhibitors of metalloproteinase, an expression pattern consistent with an antifibrotic increase in extracellular matrix degradation. However, up-regulation of genes implicated in tendon healing, specifically, vascular endothelial growth factor-A and several bone morphogenetic proteins. Interestingly, the known mechanoresponsive gene, TGF-beta1, also implicated in tendon healing, was differentially up-regulated by shear stress. Northern blot validation of our results for TGF-beta1, TGF-beta2, TGF-beta3, and collagen type I demonstrated direct correlation with microarray data. Groups of assays that are related as part of a time series. Computed

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

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

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