Mitochondrial ROS dyshomeostasis: a key driver of accelerated supraspinatus atrophy after rotator cuff injury

Rotator cuff injuries are common musculoskeletal disorders and are frequently accompanied by progressive supraspinatus muscle atrophy, which severely compromises functional recovery and surgical outcomes. Accumulating evidence indicates that mitochondrial reactive oxygen species (mtROS) dyshomeostasis is a central pathological driver of post-injury muscle degeneration. This review synthesizes current knowledge on the anatomical and histopathological changes following rotator cuff tears and focuses on the mechanisms governing mitochondrial ROS production, clearance, and dysregulation in the supraspinatus muscle. We highlight how excessive mtROS contribute to oxidative damage, mitochondrial dysfunction, impaired energy metabolism, and activation of key atrophy-related signaling pathways, including FOXO, NF-κB, MAPK, the ubiquitin-proteasome system, and the autophagy-lysosome pathway. Particular emphasis is placed on the unique biomechanical unloading, ischemic stress, and metabolic vulnerability of the supraspinatus following rotator cuff injury, which predispose this muscle to ROS-driven degeneration. Finally, we critically evaluate emerging therapeutic strategies targeting mtROS, including mitochondria-targeted antioxidants and conventional redox-modulating interventions, and discuss their translational potential and current limitations.