Muscle atrophy occurs in patients with sepsis and increases mortality and disability. Remission of muscle atrophy may improve the quality of life in patients with sepsis. Astragaloside IV (ASIV) has been shown to have excellent anti-inflammatory and anti-fibrotic effects and to reduce organ damage caused by sepsis. However, the effect of ASIV on sepsis-induced muscle atrophy has not been reported. Therefore, this study explored the pharmacological effects and mechanisms of ASIV in sepsis-induced muscle atrophy.Cecal ligation and puncture (CLP) was used to establish a mouse model of sepsis and lipopolysaccharide (LPS)-stimulated C2C12 myotubes. After administration of ASIV, the body weight, tibialis anterior (TA) and gastrocnemius muscle weight and fiber cross-sectional area of the mice were measured. The diameter of myotubes was observed by immunofluorescence staining. ELISA was used to assess inflammatory factors in plasma and cell culture supernatants. RT-PCR and Western blotting were used to detect the expression of MuRF1, Atrogin-1 and TGF-β1/Smad signaling pathway components in TA and C2C12 myotubes.Our study found that ASIV reduced serum inflammatory factors and improved survival in septic mice. ASIV alleviated muscle mass reduction, myofiber cross-sectional area reduction, and C2C12 myotube atrophy by inhibiting the expression of the E3 ubiquitin ligases MuRF1 and atrogin-1. In addition, we observed that ASIV inhibited TGF-β1/Smad signaling. Inhibition of the TGF-β1/Smad signaling pathway partly blocked the anti-muscle atrophy effect of ASIV.ASIV can alleviate sepsis-induced muscle atrophy, which may be related to the inhibition of the TGF-β1/Smad signaling pathway.Copyright © 2022 Elsevier B.V. All rights reserved.