Phenolic Profiling of Cornus controversa Hemsl. Extract and Its Protective Effects Against Dexamethasone-Induced Skeletal Muscle Atrophy

Plant-derived phenolic compounds have attracted considerable attention for their potential protective effects on skeletal muscle. However, the phenolic composition and muscle-protective potential of Cornus controversa Hemsl. leaf extract remain poorly understood. In this study, we characterized the phenolic constituents of C. controversa leaf extract (CCE) and investigated its protective effects against dexamethasone (DEX)-induced skeletal muscle atrophy. The total polyphenol content of CCE was 20 ± 1.41 μg GAE/mg extract, and LC–Q-TOF/MS analysis resulted in the putative annotation of nine phenolic features, primarily comprising galloyl hexoses, flavonol glycosides, and flavonol aglycones quercetin and kaempferol. Molecular docking analysis was subsequently performed using quercetin and kaempferol as representative structurally defined flavonol aglycones to investigate their potential interactions with mTOR, a key regulator of skeletal muscle protein synthesis. The calculated binding energies of kaempferol and quercetin were −204.518 and −109.629 kcal/mol, respectively, suggesting potential interactions within the mTOR ATP-binding pocket. The protective effects of CCE as a whole extract were further evaluated in DEX-induced skeletal muscle atrophy models. In DEX-treated C2C12 cells, CCE improved cell viability and attenuated reductions in myotube thickness and length. Furthermore, CCE enhanced Akt/mTOR-related anabolic signaling while suppressing proteins associated with muscle protein degradation. In zebrafish, CCE significantly improved DEX-induced locomotor impairment, indicating partial restoration of swimming activity. Collectively, these findings suggest that CCE may attenuate DEX-induced skeletal muscle dysfunction, potentially through the regulation of muscle protein homeostasis, and highlight its potential as a natural material for further investigation in skeletal muscle health applications.