Dehydroandrographolide succinate attenuates dexamethasone-induced skeletal muscle atrophy by regulating Akt/GSK3β and MuRF-1 pathways

Andrographis paniculata (AGPA) is known for its wide-ranging biological activities, including antiviral, antipyretic, and anticancer properties. However, its effects on muscle atrophy have not been well understood. This study investigates the impact of andrographolide (AD) and dehydroandrographolide succinate (DAS), key components of AGPA, on skeletal muscle atrophy using in vitro and in vivo models. We employed dexamethasone (DEX)-treated mice and C2C12 myotubes as models of skeletal muscle atrophy. While DAS and AD did not reverse the DEX-induced reduction in body weight, both compounds significantly restored grip strength in DEXtreated mice. Notably, DAS treatment, but not AD, markedly improved running speed, endurance time, and distance. Both DAS and AD enhanced lean muscle mass in the whole body, tibialis anterior (TA), and gastrocnemius (GS) muscles, as well as increased TA thickness, with DAS demonstrating superior efficacy compared to AD. In C2C12 myotubes treated with DEX, DAS and AD increased ATP production and myotube diameter. Mechanistically, both compounds upregulated phosphorylation of Akt and GSK3(3 and downregulated MuRF-1 expression. These results indicate that DAS and AD mitigate muscle atrophy via the Akt/GSK3(3 and MuRF-1 pathways, with DAS showing greater anti-atrophy efficiency. Thus, DAS emerges as a promising therapeutic candidate for the prevention of skeletal muscle atrophy.