LAUSR

How mechanical stress affects physical performance via tendons is not fully understood. Piezo1 is a mechanosensitive ion channel, and E756del PIEZO1 was recently found as a gain-of-function variant that is common in individuals of African descent. We generated tendon-specific knock-in mice using R2482H Piezo1, a mouse gain-of-function variant, and found that they had higher jumping abilities and faster running speeds than wild-type or muscle-specific knock-in mice. These phenotypes were associated with enhanced tendon anabolism via an increase in tendon-specific transcription factors, Mohawk and Scleraxis, but there was no evidence of changes in muscle. Biomechanical analysis showed that the tendons of R2482H Piezo1 mice were more compliant and stored more elastic energy, consistent with the enhancement of jumping ability. These phenotypes were replicated in mice with tendon-specific R2482H Piezo1 replacement after tendon maturation, indicating that PIEZO1 could be a target for promoting physical performance by enhancing function in mature tendon. The frequency of E756del PIEZO1 was higher in sprinters than in population-matched nonathletic controls in a small Jamaican cohort, suggesting a similar function in humans. Together, this human and mouse genetic and physiological evidence revealed a critical function of tendons in physical performance, which is tightly and robustly regulated by PIEZO1 in tenocytes. Description PIEZO1 acts as a critical mechanosensor in tenocytes, promoting tendon-specific gene expression, tendon function, and physical performance. Potentiating physical performance Tendons connect muscle to bone and are important for musculoskeletal function, including athletic performance. Here, Nakamichi et al. used a mouse model to study the effects of a gain-of-function variant in Piezo1, a mechanosensitive ion channel, in tendon. Mutant tendons were wider, with larger collagen fibril cross-sectional diameter, and had increased compliance and greater storage of elastic energy. Tendon-specific mutant mice demonstrated greater jumping ability and faster running. The authors also observed increased frequency of a gain-of-function PIEZO1 deletion in a cohort of Jamaican sprinters, supporting a role for tendon expression of PIEZO1 in potentiating physical performance.