Abstract
Tendons are essential connective tissues that transmit mechanical forces from muscles to bones, enabling locomotion and maintaining joint stability. Proper mechanosensation is critical for preserving their extracellular matrix (ECM) integrity. PIEZO1, a mechanosensitive ion channel, has been implicated in regulating tendon architecture under increased mechanical loads, but its role under baseline physiological conditions remains unclear. Here, we generated tendon-targeted Piezo1 conditional knockout (Piezo1 p-t-ko ) mice using a tamoxifen-inducible Scx-CreERT2 system. All in vivo experiments were performed in female mice. PIEZO1 deficiency resulted in significantly reduced Achilles tendon thickness and smaller collagen fibril diameters by transmission electron microscopy. RNA sequencing and qPCR analyses demonstrated downregulation of key ECM-related genes, including Col1a1, Dcn and Fmod, as well as the tendon transcription factors Mkx. Immunostaining further showed reduced signals of MKX, COL1A1 and DCN. Adjacent muscle morphology and transcriptomes were unaltered, supporting the tendon-selective nature of the observed phenotype. Together, these findings suggest that PIEZO1 contributes to collagen fibril architecture and tendon-associated transcriptional programs in female mouse Achilles tendons under baseline physiological conditions.