Transcriptional Adaptations to Muscle Loading in a Murine Model of Achilles Tendinopathy

Achilles tendinopathy limits mobility and decreases quality of life. Physical therapy (eccentric muscle loading) improves tendon function; however, the underlying mechanisms are unknown. This study investigated the effect of load magnitude and treatment duration in a mouse Achilles tendinopathy model. We hypothesized that loading would upregulate signaling and metabolic transcriptional networks associated with improved tendon healing. Mice were randomly assigned to muscle loading groups (50 or 100% body weight (BW)) or age-matched injured/untreated (IU) and naïve control groups. Following induction of Achilles tendinopathy via paired TGFB-β1 injections, loading was performed for 1, 2, or 4 weeks, mice euthanized, and Achilles tendons harvested for transcriptomics. The exercised groups exhibited relatively converging transcriptional patterns at 4 weeks, while the IU group was tightly associated with the naïve group over time, and diverging from both exercised groups at 2 and 4 weeks. Two weeks of exercise at either 50 or 100% BW load resulted in uniquely expressed gene networks not present in unexercised controls. Comparative assessment of the expression profile and functional annotation of networks across groups revealed that exercise differentially affected the innate immune response, sensory innervation and collagen biosynthesis during tendon repair. Ingenuity Pathway Analysis further suggests that 50% BW loading is associated with a shorter pro-inflammatory response and early matrix deposition in healing tendons compared to 100% BW loading. The transcriptional alterations seen in response to 50% BW eccentric muscle loading support the benefits of controlled loading exercises when treating Achilles tendinopathy.