Summary
We identified the Mkx–Piezo1 axis as a key regulator of tendon differentiation and function, linking mechanosensation to enhanced locomotor performance and human athletic potential, thereby providing novel insights for tendon regeneration and functional optimization.
Abstract
Tendons and ligaments are essential connective tissues that anchor muscles to bones, yet their intrinsic regenerative capacity is limited—injuries often predispose individuals to osteoarthritis. A major challenge in tendon biology has been the lack of identified master transcription factors governing tendon development. To address this, we generated a comprehensive expression atlas of developmental transcription factors and identified Mohawk (Mkx) as a key regulator of tendon differentiation. We also explored the mechanosensitive function of Piezo1 in tendon cells. Mice engineered to express a constitutively active form of Piezo1 showed increased expression of Mkx and exhibited markedly improved locomotor abilities, including enhanced jumping power and maximum running speed. Moreover, genetic analysis of Jamaican elite sprinters revealed a significantly higher prevalence of the functional PIEZO1 E756del polymorphism compared to the general population. Together, these findings suggest that targeting the Mkx–Piezo1 axis may not only advance our understanding of tendon physiology but also provide new strategies to enhance musculoskeletal performance and develop tendon-focused therapies.