Asiatic acid alleviates dexamethasone-induced muscle atrophy through regulating the Sirt1/PGC-1α/FOXO3 pathway.

Abstract

Background: Skeletal muscle atrophy, which results in muscular dysfunction and weakness, is associated with various factors, including aging, sepsis, chronic diseases, and long-term glucocorticoid therapy. Although asiatic acid exhibits multiple biological activities and can activate the Sirt1 signaling pathway, an important regulator of skeletal muscle function,itsrole in muscle atrophy remains unclear.

Methods: C2C12 myotubes were treated with 10 μM dexamethasone,with or without designated concentrations of asiatic acid. Subsequently, cell viability, apoptosis, differentiation markers (MyHC and myogenin), levels of atrophy-related proteins (MAFbx, MuRF1), and the Sirt1/PGC-1α/FOXO3 pathway were analyzed. Moreover,the underlyingmechanismswere further explored through inhibition of Sirt1 using the selective inhibitor EX-527 or short hairpin RNA in vitro. In vivo, muscle atrophy was induced via intraperitoneal injections of 20 mg/kg dexamethasone, and 50 mg/kg asiatic acid was administered by oral gavage. Body weight, muscle strength, gastrocnemius muscle mass, histological changes, and atrophy- and Sirt1/PGC-1α/FOXO3 pathway-associated proteins were assessed.

Results: Asiatic acid elevated cellviability, inhibited apoptosis, increased MyHC and myogeninprotein contents, and suppressed MAFbx and MuRF1 proteinlevels in dexamethasone-treated C2C12 myotubes. Moreover, asiatic acid activated the Sirt1/PGC-1αp athwayand inactivated FOXO3. Inhibition of Sirt1 attenuated the influence of asiatic acid in a muscle atrophy cell model. In vivo, asiatic acid increased body weight and gastrocnemius muscle mass, improved muscle strength and structural damage of gastrocnemius muscles, suppressed MAFbx and MuRF1 protein contents, and regulated the Sirt1/PGC-1α/FOXO3 pathway.

Conclusions: Asiatic acid can improve dexamethasone-induced muscle atrophy via regulating the Sirt1/PGC-1α/FOXO3 pathway. Therefore, asiatic acid might be a potential therapeutic agent for muscle atrophy.