Supraspinatus Muscle Degeneration, Inflammation, and Regeneration Vary By Location in a Rat Model of Severe Rotator Cuff Tear.

Purpose: Degeneration of the human supraspinatus muscle after rotator cuff tendon tear varies by location within the muscle; however, the localization of changes to muscle fiber size, amount of regenerating fibers, and cellular immune response have not been previously characterized. Due to the proximity to the injured tendon, we hypothesized that these processes are more pronounced near the lateral myotendinous junction region of the muscle and the intramuscular tendon. Methods: Spatially-defined immunohistochemical analysis was used to evaluate lengthwise and radial differences within the supraspinatus muscle in a rat model of full supraspinatus and infraspinatus tendon transection and subscapular denervation. Muscle fiber diameter was quantified, regeneration was evaluated by myofiber central nuclei and embryonic myosin heavy chain, and the immune environment was assessed by the presence of macrophage subsets and T cells. Results: Degeneration (smaller fiber diameter), regeneration (embryonic myosin heavy chain-positive fibers), and macrophage infiltration are more substantial in the lateral muscle near the myotendinous junction and radially near the intramuscular tendon. The muscle adjacent to the myotendinous junction had a balanced M1-like and M2-like macrophage response up to 2 weeks post-injury followed by an M1-dominant inflammation. The medial muscle belly maintained an M1-dominant response throughout 3 weeks. T cells were not highly abundant, however, were most elevated one week after injury near the intramuscular tendon. Fibrous infiltration was observed 1-week post-injury throughout the muscle, while fatty infiltration was elevated after 3 weeks only in the lateral muscle region. Conclusions: Together, these findings suggest that the supraspinatus muscle undergoes regional changes (particularly muscle fiber size, markers of regeneration, and macrophage infiltration) after supraspinatus tendon injury. Lay Summary and Future Work: Rotator cuff tendon tear in the rat shoulder leads to a greater inflammatory response and a greater early pro-regenerative response in the supraspinatus muscle spatially near the muscle-tendon attachment compared with areas deeper in the muscle in the first two weeks after the tendon is injured. Both fatty and fibrous muscle degeneration were observed over three weeks throughout the muscle, with less spatial localization. Together, these data indicate that there are regional differences in damage and repair of the supraspinatus muscle early post-injury. These findings may help interpret results from clinical studies of muscle degeneration after rotator cuff tear and may lead to improved, spatially-targeted approaches for delivery of therapeutics to muscle after rotator cuff tendon tear. Supplementary Information: The online version contains supplementary material available at 10.1007/s40883-024-00343-3.