TY - JOUR
T1 - The mechanosensitive ion channel PIEZO1 is expressed in tendons and regulates physical performance
AU - Nakamichi, Ryo
AU - Ma, Shang
AU - Nonoyama, Takayuki
AU - Chiba, Tomoki
AU - Kurimoto, Ryota
AU - Ohzono, Hiroki
AU - Olmer, Merissa
AU - Shukunami, Chisa
AU - Fuku, Noriyuki
AU - Wang, Guan
AU - Morrison, Errol
AU - Pitsiladis, Yannis
AU - Ozaki, Toshifumi
AU - D'Lima, Darryl
AU - Lotz, Martin
AU - Patapoutian, Ardem
AU - Asahara, Hiroshi
PY - 2022/6/1
Y1 - 2022/6/1
N2 - 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 co-hort, 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 byPIEZO1 in tenocytes.
AB - 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 co-hort, 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 byPIEZO1 in tenocytes.
KW - Animals
KW - Ion Channels - genetics
KW - Mice
KW - Physical Functional Performance
KW - Stress, Mechanical
KW - Tendons - metabolism
KW - Transcription Factors
U2 - 10.1126/scitranslmed.abj5557
DO - 10.1126/scitranslmed.abj5557
M3 - Article
VL - 14
JO - Science Translational Medicine
JF - Science Translational Medicine
IS - 647
M1 - eabj5557
ER -