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

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.

Energy stress modulation of AMPK/FoxO3 signaling inhibits mitochondria-associated ferroptosis

“…FoxO3a is involved in the regulation of mitochondrial function and energy homeostasis [ 20 , 21 ]. Previous studies found that mitochondrial dysfunction resulted in insufficient ATP supply and activation of the AMPK/FoxO3a pathway [ 22 , 23 ]. However, whether FoxO3a mediates mitochondrial activity in regulating ferroptosis remains unknown.…”

Potential of Lycii Radicis Cortex as an Ameliorative Agent for Skeletal Muscle Atrophy

“…BAX, acting as a pro-apoptotic protein, mediates cell death through mitochondrial permeability transition induction, while Bcl-2, an anti-apoptotic protein, suppresses apoptosis by inhibiting BAX activity [ 56 ]. Several studies have shown increased apoptosis in DEX-treated C2C12 myotubes or mice, with co-treatment with natural compounds like quercetin, myricanol, fucoxanthin, and 20( S )-ginseonside-Rg3 preventing apoptosis by reducing BAX expression and increasing Bcl-2 expression [ 37 , 38 , 39 , 57 ]. Our current study confirmed these findings by observing increased BAX expression and decreased Bcl-2 expression in DEX-treated C2C12 myotubes, both of which were significantly inhibited by LRCE treatment ( Figure 5 ).…”

Polyamines and Physical Activity in Musculoskeletal Diseases: A Potential Therapeutic Challenge

“…On the contrary, if AMPK is activated, as in the response to low glucose levels or to energetic stress, it induces autophagy [ 99 ]. Indeed, when activated, AMPK inhibits mTORC1, stimulates ULK1 kinase through phosphorylation of ULK1Ser317 and Sr777 [ 98 ] and Ser555 [ 100 ], as well as triggers FOXO3, upregulating the expression of muscle specific atrophy-induced genes [ 101 , 102 ]. In particular, this excessive dysregulated event in skeletal muscle can culminate in protein degradation, and thus determines atrophy [ 103 ].…”