Muscle atrophy is a pathological condition characterized by the excessive degradation of muscle proteins, leading to impaired physical performance. Isoliquiritigenin (ISL) is a promising extract known for its medical effects
however, its impact on muscle atrophy remains unclear. We investigated the effects of ISL on muscle atrophy both in vitro and in vivo. The results showed that 5-µM ISL exhibited no significant cytotoxicity on C2C12 cells, as reflected by cell count kit-8 and 5-ethynyl-2'-deoxyuridine (EdU) tests. ISL increased the diameter of myotubes and downregulated forkhead box O proteins, muscle-specific RING finger protein 1 (MuRF-1), and Atrogin-1 induced by Dexamethasone (Dex). ISL could also enhance the phosphorylation of Akt, the mammalian target of rapamycin (mTOR), eIF4E-binding protein 1, and p70 S6 kinase in C2C12 myotubes. In animal experiments, ISL increased the muscle mass, improved the cross-sectional area of muscles, and inhibited the expression of MuRF-1 and Atrogin-1 in muscle tissues. For physical performance, ISL enhanced grip strength and running endurance. ISL ameliorated Dex-induced muscle atrophy both in vitro and in vivo, associated with increased diameter of myotubes and decreased Atrogin-1 and MuRF-1 expression via the Akt/mTOR signaling pathway. This suggested that ISL could be used as a natural drug for muscle atrophy.