Irisin Mediates Sirtuin 1 to Improve Glucocorticoid-Induced Sarcopenia and Mitochondrial Dysfunction

Background: Sarcopenia is characterised by the progressive and accelerated loss of skeletal muscle mass, strength, and function,h. Irisin, a cleavage product of fibronectin type III domain-containing protein 5 (FNDC5), serves as an exercise- induced myokine critical for preserving muscle health and functionality. Methods: Western blotting and ELISA were employed to quantify FNDC5/irisin protein levels in skeletal muscle and plasma of glucocorticoid-induced sarcopenic mice. Following irisin administration (2.5 mg/kg body weight, i.p., 14 days) to dexamethasone-treated mice (25 mg/kg body weight, i.p., 14 days), comprehensive phenotypic analyses were performed, encompassing body weight tracking, functional muscle assessments (grip strength, treadmill endurance), histopathological evaluation, and mitochondrial morphology/function characterization. Results: In glucocorticoid-induced sarcopenic mice, FNDC5/irisin protein expression was downregulated (FNDC5: -37.9%, P < 0.05; irisin: -33.9%, P < 0.001). Exogenous irisin supplementation effectively rescued skeletal muscle mass and functional losses, evidenced by improvements in body weight (+10%, P < 0.05), muscle mass (+22%, P < 0.05), grip strength (+25%, P < 0.05), grid-hanging performance (+50.2%, P < 0.001), and treadmill endurance (+52%, P < 0.01). Irisin exerted its effects through SIRT1-dependent deacetylation-mediated inhibition of forkhead box O3a (FoxO3a) transcriptional activity, thereby reducing muscle protein degradation (MuRF1: -35.9%, P < 0.001; atrogin-1: -25.9%, P < 0.01) and promoting protein synthesis (p-mTOR/mTOR: +60.7%, P < 0.01; p-AKT/AKT: +70.7%, P < 0.05; puromycin: +60.9%, P < 0.001). Additionally, irisin enhanced peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) activity (+77.7%, P < 0.001), significantly improving mitochondrial function (ATP synthesis: +66.5%, P < 0.01; citrate synthase activity: +93.2%, P < 0.01; aconitase activity: +74.6%, P < 0.01). Conclusion: This study demonstrates that irisin alleviates glucocorticoid-induced muscle atrophy and dysfunction through SIRT1-mediated pathways, thereby restoring the balance between muscle physiology and systemic energy homeostasis. These findings suggest that irisin-based therapeutic agents may serve as a promising exercise surrogate strategy for combating sarcopenia, offering new avenues for the clinical management of sarcopenia.