Muscle Loading Treatments for Achilles Tendinopathy

Tendinopathies are common, painful, and debilitating injuries that can be challenging to treat. Current treatment methods are limited to surgery, nonsteroidal anti-inflammatory drugs, dry needling, and injectable therapeutics, platelet rich plasma and corticosteroids. Unfortunately, these existing treatments display poor long-term outcomes and have an increased risk of reinjury. Additionally, the healing mechanism for injured tendons forms scar tissue which is characterized by disrupted extracellular matrix rather than complete injury resolution. These structural changes impact the mechanical properties of tendon, reducing their capacity to transfer and store energy, making them inferior to uninjured tendons. The reduced mechanical properties increase the risk of rupture, exacerbating this debilitating disease and decreasing quality of life. Physical therapy (eccentric loading) decreases the symptoms of tendinopathy and restores Achilles tendon functionality. However, the mechanism by which these mechanical stimulations induce healing is poorly understood. There is a clinically relevant motivation to better understand the healing cascade in response to eccentric exercises. We aim to identify and characterize the effects of eccentric rehabilitative muscle loading on the Achilles tendon and gastrocnemius muscle complex using our preclinical TGF-ß1-induced murine model of Achilles tendinopathy. To accomplish our objective, we tested three muscle loading magnitudes (50%, 75%, and 100% body weight), over three treatment durations (1, 2, and 4 weeks) to determine their effects on tendon healing. Age-matched injured/untreated and naïve groups accompanied each loading magnitude and duration period. The functional biomechanical properties, morphological adaptations, transcriptomic response, and muscle strength of the Achilles tendon were assessed. Injured/untreated tendons had a significantly increased cross-sectional area compared to naïve and all loading groups at 2 and 4 weeks. Maximum stress and elastic modulus of injured/untreated tendons were significantly lower compared to naïve and all loading groups after 4 weeks. Gastrocnemius muscle strength was maintained over time as loading magnitude increased. Force output was lower after 2 weeks at 100% body weight loading compared to the naïve group, then recovered to naïve levels after 4 weeks. Histological findings included increased cross-sectional area, matrix disorganization, and increased cellular density of injured/untreated tendons. The transcriptomic evaluation revealed several patterns of expression among exercised groups. Biological processes associated with exercised groups revealed genes responsible for inflammation, extracellular matrix organization, and cell to cell signaling. Overall, eccentric muscle loading improved tendon geometry and material properties compared to naïve levels and improved muscle strength over time. Morphological evaluation also showed improvements in cross-sectional area, and collagen orientation, and cell appearance after 2 and 4 weeks of eccentric loading. Similarly, the transcriptomic changes showed an effect from exercise and upregulation of genes essential for extracellular matrix organization, inflammatory regulation, and cell to cell signaling.