20(s)‑ginseonside‑Rg3 modulation of AMPK/FoxO3 signaling to attenuate mitochondrial dysfunction in a dexamethasone‑injured C2C12 myotube‑based model of skeletal atrophy invitro.

Abstract

Muscle atrophy, a side effect from administration of the anti-inflammatory medication dexamethasone (DEX), is preventable by concomitant administration of the major monomeric constituent of Panax ginseng C.A. Meyer, 20(S)-ginsenoside Rg3 (S-Rg3). Putative S-Rg3-associated prevention of DEX-induced muscle atrophy may involve S-Rg3 mitigation of DEX-induced mitochondrial dysfunction. In the present study, MTT assays revealed enhanced cell viability following S-Rg3 treatment of DEX-injured C2C12 myotubes. Subsequent PCR and western blotting results demonstrated S-Rg3-induced reduction of expression of muscle atrophy F-box protein (atrogin-1) and muscle RING-finger protein-1, proteins previously linked to muscle atrophy. Additionally, S-Rg3 treatment of DEX-injured myotubes led to aggregation of Rg3 monomers in cells and dose-dependent increases in cellular mitochondrial basal respiratory oxygen consumption rate and intracellular ATP levels compared with their levels in untreated DEX-injured myotubes. In addition, S-Rg3 treatment significantly reversed DEX-induced reductions of expression of key mitochondrial respiratory electron transport chain subunits of protein complexes II, III and V in DEX-injured myotube cells. Furthermore, S-Rg3 alleviation of mitochondrial dysfunction associated with DEX-induced injury of C2C12 myotubes was linked to S-Rg3-associated decreases in both forkhead box O3 (FoxO3) protein expression and phosphorylation of AMP-activated protein kinase (AMPK). Collectively, these results implicate S-Rg3 modulation of signaling within the AMPK-FoxO3 pathway as a putative mechanism underlying S-Rg3 alleviation of DEX-induced muscle atrophy.