Early adaptive and late degenerative tendon response to overload in rat model of synergist ablation.

Abstract

Mechanical loading is essential for tendon homeostasis. Increases in the duration and magnitude of load can promote tendon adaptation; however, excessive or prolonged overloading can surpass the tendon's adaptive capacity, leading to pathological degeneration. While the adaptive and degenerative responses of tendons to mechanical loading are well accepted, the threshold and mechanisms that distinguish adaptation from degeneration remain unknown. This study evaluated longitudinal mechanical, structural and cellular responses due to plantaris tendon overload using the synergistic ablation model (SynAb). Female Long-Evans rats either received bilateral SynAb surgery (Achilles tendon resected), or bilateral sham surgery, or were age-matched intact control. Animal activity was measured before surgery and then bi-weekly. Rats were euthanized at either 3 days, 8 weeks, or 16 weeks post-intervention. Each leg was randomly assigned for mechanical tests, histology, or gene expression. A subset of legs was also assessed for 3D tissue structure using magnetic resonance imaging. We observed time-dependent mechanical, structural, and cellular responses. While overload initially induced adaptive remodelling evidenced by increased tendon cross-sectional area and ultimate load, prolonged overload led to degenerative changes, including reduced mechanical properties (modulus and ultimate stress) and a transcriptomic profile showing elevated inflammatory and matrix degradation markers. These findings suggest that between 8 and 16 weeks, an adaptive-to-degenerative threshold was crossed, where repair mechanisms could no longer keep up with accumulated overload, triggering extracellular matrix breakdown. KEY POINTS: Mechanical loading is essential for tendon homeostasis and adaptive remodelling. However prolonged overload can lead to degeneration. The mechanisms driving adaptive remodelling or pathological degeneration in response to mechanical loading remain unknown. This study evaluated the longitudinal response to plantaris tendon overload using the synergist ablation model (SynAb). We observed time-dependent mechanical, structural and cellular changes to overload. Overload initially produced an adaptive response; however, prolonged overload eventually led to degeneration. These findings highlight a critical transition from adaptation to degeneration, opening important new opportunities to investigate mechanisms driving this progression. Understanding early changes is essential for identifying key factors that determine whether tendons adapt or develop pathology in response to increased loading.