Ganoderic Acids Alleviate Dexamethasone-Induced Muscle Atrophy Potentially via Regulating Protein Synthesis/Degradation, Attenuating Oxidative Stress, and Antagonizing Glucocorticoid Receptor.

Abstract

Ganoderic acids (GA), a class of specific triterpenoids found exclusively in Ganoderma lucidum, have broad pharmacological activities. The purpose of this study was to determine whether GA attenuates dexamethasone (DEX)-induced muscle atrophy and to explore the underlying mechanisms. The therapeutic effect of GA (at intraperitoneal doses of 3.125, 12.5, and 50 mg/kg) and its active monomers were assessed in DEX-treated C57BL/6 mice and C2C12 myotubes. Experimental results showed that GA significantly protected muscle function and mass and reduced muscle damage. Interestingly, GA significantly inhibited protein degradation by suppressing muscle atrophy F-box protein (Atrogin-1)/muscle RING finger protein 1 (MuRF1) expression and promoted protein synthesis by enhancing protein kinase B (AKT)/ribosomal S6 kinase (S6K) phosphorylation in the gastrocnemius muscle. GA also significantly reduced oxidative stress by decreasing 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA), enhancing activities of superoxide dismutase (SOD) and catalase (CAT), and upregulating nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1)/NAD(P)H dehydrogenase quinone 1 (NQO1) pathway. In DEX-induced C2C12 cells, both GA and ganoderic acid-A (GA-A) markedly attenuated myotube atrophy, with GA-A further regulating protein synthesis/degradation and reducing oxidative stress in vitro. Moreover, the binding of GA-A to the glucocorticoid receptor (GR) was supported by molecular docking, dynamics simulation, surface plasmon resonance (SPR), microscale thermophoresis (MST), and cellular thermal shift assays (CETSA). A glucocorticoid response element (GRE)-driven luciferase reporter assay further revealed that GA-A suppressed DEX-induced GR transcriptional activity, suggesting functional antagonism of GR signaling. In conclusion, our study found that GA alleviated DEX-induced muscle atrophy, potentially via regulating protein synthesis/degradation, attenuating oxidative stress, and functionally antagonizing GR.