Shear sensor mechano-signaling determines tendon stiffness and human jumping performance

Abstract

Tendons enable movement by transferring muscle forces to the skeleton, and athletic performances critically rely on mechanically-optimized tendons. How load-bearing structures of tendon sense and adapt to physical demands is an open question of central importance to musculoskeletal medicine and human sports performance. Here, with calcium imaging in tendon explants and primary tendon cells we characterized how tenocytes detect mechanical forces and determined collagen fiber-sliding-induced shear stress as a key stimulus. CRISPR/Cas9 screening in human and rat tenocytes identified PIEZO1 as the crucial shear sensor. In rodents, elevated mechano-signaling increased tendon stiffness and strength both in vitro by pharmacological channel activation and in vivo by a Piezo1 gain-of-function mutation. Strikingly, humans carrying the PIEZO1 gain-of-function E756del mutation revealed a 16% average increase in normalized jumping height, with more effective storage of potential energy released during dynamic jumping maneuvers. We propose that PIEZO1-mediated mechano-signaling regulates tendon stiffness and impacts human athletic performance.

Intermittent Cyclic Stretch of Engineered Ligaments Drives Hierarchical Collagen Fiber Maturation in a Dose- and Organizational-Dependent Manner

“…LOX crosslinks are another critical element in providing mechanical strength and transferring load between fibrils [5,6,[70][71][72][73]. It is not well understood how mature LOX crosslinks form [74,75], but it is thought to be due to a cellular response to load [71,76,77]. In this study loading significantly increased LOX activity temporally throughout culture, with 10% load inducing a 2-fold higher activity at 0 and 6 weeks in comparison to 5% load (Fig.…”

“…6). It has been previously reported that cyclic loading of mature tendons stimulates or activates the cellular mechanical stretch ion channel PIEZO1 and it has been suggested this activation of PIEZO1 stimulates LOX synthesis, producing stronger tendons [77]. Further, it has been reported PIEZO1 is strain dependent in chondrocytes, with only strains higher than 8% triggering the channel [76,[78][79][80].…”

How subject-specific biomechanics influences tendon strains in Achilles tendinopathy patients: A finite element study

“…However, future development of FE models of Achilles tendinopathy patients will necessitate the incorporation of subject-specific frictional contact, to also take into account the alterations in non-uniform deformation within sub-tendons for estimation of the AT strains. In general, positive AT adaptation is not only dependent on strain magnitude but also time-and rate-dependent (Passini et al, 2021;T. Wang et al, 2015).…”

The role of mechanically sensitive ion channel Piezo1 in bone remodeling

“…Another gain-of-function mutation in Piezo1 gene, known as E756del has been linked to enhanced athletic performance and the ability of protection against severe malaria. When performing leaping actions requiring high tendon loading, energy storage, and return, carriers of the E756del mutation outperform non-carriers by a large margin (Passini et al, 2021). Recent case reports have highlighted skeletal manifestations associated with Piezo1 mutations, demonstrating the diverse impact of this gene on human health.…”