<scp><i>Poncirus trifoliata</i></scp> Extract and Its Active Coumarins Alleviate Dexamethasone‐Induced Skeletal Muscle Atrophy by Regulating Protein Synthesis, Mitochondrial Biogenesis, and Gut Microbiota

Sarcopenia, an age-related decline in skeletal muscle mass and function, contributes to frailty and increased morbidity in the elderly. This necessitates the development of effective interventions to combat muscle atrophy. This study investigated the therapeutic potential of Poncirus trifoliata ethanol extract (PT) and its coumarin derivatives against dexamethasone (DEX)-induced muscle atrophy. We employed in vitro and in vivo models of DEX-induced muscle atrophy. C2C12 myotubes were used for mechanistic studies. C57BL/6J mice received DEX injections and oral PT supplementation (50 mg/kg/day) to evaluate effects on muscle mass, function, gene expression, and gut microbiota composition. In vitro, PT enhanced protein synthesis, mitochondrial biogenesis, and myogenic differentiation in DEX-exposed myotubes, with auraptene, ponciol, and triphasiol identified as key bioactive coumarins. In vivo, PT significantly attenuated DEX-induced muscle atrophy, increasing tibialis anterior muscle mass by 36% (p < 0.01), grip strength by 31% (p < 0.001), and maximal running speed by 18% (p < 0.05). Mechanistically, PT upregulated genes associated with muscle function and mitochondrial health. Furthermore, PT modulated gut microbiota composition, notably increasing Phocaeicola vulgatus abundance 2.2-fold, which correlated with improved muscle performance (R = 0.58, p < 0.01). These findings suggest that PT and its coumarin derivatives, particularly auraptene, ponciol, and triphasiol, hold promise as therapeutic agents for combating muscle atrophy. The observed benefits may be mediated through enhanced protein synthesis, improved mitochondrial function, and modulation of the gut-muscle axis.