Yuja peel hot water extract protects against dexamethasone-induced skeletal muscle atrophy through the PI3K-Akt-mTOR/FoxO3α signaling pathway.

Background/objectives: Yuja peel possesses anti-cancer, anti-inflammatory, and anti-diabetic properties. However, its potential anti-sarcopenic effects remain unclear. This study examined the effects of yuja peel hot water extract (YW) on dexamethasone (DEX)-induced muscle atrophy in C2C12 myotubes and sarcopenic mouse model.

Materials/methods: We measured grip strength, cross-sectional area of the muscle fiber, biochemical markers, and expression of muscle-specific messenger RNA and proteins in atrophied muscle cell/tissue after treatment with YW.

Results: In DEX-treated C2C12 cells, YW (100 and 200 µg/mL) increased the diameter of myotubes and reduced the gene and protein expression of muscle-specific F-box protein (atrogin-1) and muscle RING-finger protein-1 (MuRF-1) compared to the DEX (100 µM). In the mouse model with DEX (10 mg/kg)-induced muscle atrophy, treatment with YW (200 mg/kg/day) significantly increased grip strength and the cross-sectional area of the gastrocnemius muscle fibers, whereas it decreased serum lactate dehydrogenase and creatine phosphokinase levels compared to the DEX group. Treatment with YW downregulated the proteins related to muscle degradation, such as atrogin-1, MuRF-1, ubiquitin, and growth differentiation factor 8 (myostatin), by regulating the phosphatidylinositol 3-kinase (PI3K)-protein kinase B (Akt)-forkhead box O3 alpha (FoxO3α) pathway. Furthermore, treatment with YW upregulated the proteins associated with muscle protein synthesis, such as myogenic differentiation 1 (MyoD1), myogenin (MyoG), and myosin heavy chain (MHC), by regulating the PI3K-Akt-mammalian target of rapamycin (mTOR) pathway. A puromycin labeling assay in C2C12 myotube cells showed that YW treatment significantly increased protein synthesis compared to the cells treated with DEX alone. YW significantly upregulated the protein expression of phosphorylated PI3K and Akt in wortmannin (a PI3K inhibitor)-treated C2C12 cells.

Conclusion: YW suppressed DEX-induced muscle atrophy by regulating the PI3K-Akt-mTOR/FoxO3α signaling pathway. These results indicate that YW may serve as a potential agent for the treatment or prevention of muscle atrophy.