ginsenoside-rg3 and Muscular-Atrophy

Ginsenoside Rg3 (Rg3), amplified by iterative heating processing with fresh ginseng, has a broad range of pharmacological activities and improves mitochondrial biogenesis in skeletal muscle. However, thus far no study has examined how Rg3 affects myotube growth or muscle atrophy, to the best of the authors' knowledge. The present study was conducted to examine the myogenic effect of Rg3 on dexamethasone (DEX)‑induced myotube atrophy and the underlying molecular mechanisms. Rg3 activated Akt/mammalian target of rapamycin signaling to prevent DEX‑induced myotube atrophy thereby stimulating the expression of muscle‑specific genes, including myosin heavy chain and myogenin, and suppressing muscle‑specific ubiquitin ligases as demonstrated by immunoblotting and immunostaining assays. Furthermore, Rg3 efficiently prevented DEX‑triggered mitochondrial dysfunction of myotubes through peroxisome proliferator‑activated receptor‑γ coactivator1α activities and its mitochondrial biogenetic transcription factors, nuclear respiratory factor‑1 and mitochondrial transcription factor A. These were confirmed by immunoblotting, luciferase assays, RT‑qPCR and mitochondrial analysis measuring the levels of ROS, ATP and membrane potential. By providing a mechanistic insight into the effect of Rg3 on myotube atrophy, the present study suggested that Rg3 has potential as a therapeutic or nutraceutical remedy to intervene in muscle aging or diseases including cancer cachexia.

Topics: Animals; Blotting, Western; Cell Line; Dexamethasone; DNA-Binding Proteins; Ginsenosides; Glucocorticoids; High Mobility Group Proteins; Mice; Mitochondria, Muscle; Muscle Fibers, Skeletal; Muscular Atrophy; Myoblasts; Nuclear Respiratory Factor 1; Organelle Biogenesis; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Protective Agents; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction

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

Topics: Adenosine Triphosphate; AMP-Activated Protein Kinases; Animals; Cell Line; Cell Survival; Dexamethasone; Electron Transport Chain Complex Proteins; Forkhead Box Protein O3; Gene Expression Regulation; Ginsenosides; Glucocorticoids; Mice; Mitochondria, Muscle; Models, Biological; Muscle Fibers, Skeletal; Muscle Proteins; Muscular Atrophy; Signal Transduction; SKP Cullin F-Box Protein Ligases; Tripartite Motif Proteins; Ubiquitin-Protein Ligases

We previously found that 20(S)-ginsenoside Rg3 (S-Rg3) promotes myoblast differentiation via an unknown mechanism. Here we measured levels of myosin heavy chain (MHC) and myogenin, markers of myoblast differentiation, using Western blot analysis and immunofluorescence staining. Notably, S-Rg3 treatment of C2C12 myoblasts led to increased muscle differentiation and protection from muscle atrophy in a dexamethasone (DEX)-treated C2C12 myotube-based muscle atrophy model. This effect was likely caused by S-Rg3 treatment-induced promotion of Akt/mTOR phosphorylation and inhibition of FoxO3 nuclear transcription. Additionally, S-Rg3 treatment also led to increased fruit fly climbing distances (Drosophila melanogaster) and prevented muscle atrophy in aged fruit flies. Our study provides a mechanistic framework for understanding how S-Rg3 enhances myoblast differentiation and inhibits myotube atrophy through activation of the Akt/mTOR/FoxO3 signaling pathway, as demonstrated in vitro in C2C12 cells and in vivo in fruit flies.

Topics: Animals; Cell Differentiation; Cell Line; Dose-Response Relationship, Drug; Drosophila melanogaster; Drosophila Proteins; Forkhead Box Protein O3; Ginsenosides; Mice; Muscle Fibers, Skeletal; Muscular Atrophy; Myoblasts; Nuclear Matrix-Associated Proteins; Proto-Oncogene Proteins c-akt; Signal Transduction

Ginsenoside Rg3 from Panax ginseng has reported to have multiple pharmacological activities including anti-diabetics, anti-inflammation and anti-cancer. However, the effect of ginsenoside Rg3 on myogenic differentiation and muscle atrophy is unknown.. In this study, we investigated the myogenic effect and underlying molecular mechanisms of ginsenoside Rg3 on myotube atrophy induced by tumor necrosis factor-α (TNF-α).. C2C12 myoblasts were induced to differentiate for one day followed by the treatment of TNF-α along with vehicle or ginsenoside Rg3 for additional 2 days and subjected to immunoblotting, immunocytochemistry, quantitative RT-PCR and biochemical analysis for mitochondrial function.. Ginsenoside Rg3 promotes myogenic differentiation and multinucleated myotube formation through Akt activation in a dose-dependent manner, without any cytotoxicity. Ginsenoside Rg3 treatment restores myotube formation and increases myotube diameters under TNF-α-treated conditions. Ginsenoside Rg3 enhances Akt/mTOR (mammalian target of rapamycin) signaling that in turn stimulates muscle-specific gene expression such as myosin heavy chain (MHC) and Myogenin, and suppresses the expression of muscle-specific ubiquitin ligases. In addition, ginsenoside Rg3 in TNF-α-treated myotubes significantly inhibits the production of mitochondrial ROS and restores mitochondrial membrane potential (MMP) and ATP contents. Furthermore, ginsenoside Rg3 upregulates the activities and expression of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1α) and the mitochondrial biogenetic transcription factors, nuclear respiratory factor-1 (NRF1) and mitochondrial transcription factor A (Tfam) in TNF-α-induced myotube atrophy.. This study provides a mechanistic insight into the effect of ginsenoside Rg3 on myogenic differentiation and myotube atrophy, suggesting that ginsenoside Rg3 has a promising potential as a therapeutic or neutraceutical remedy to intervene muscle weakness and atrophy.

Topics: Animals; Cell Differentiation; Cell Line; Ginsenosides; Membrane Potential, Mitochondrial; Mice; Mitochondria, Muscle; Muscle Fibers, Skeletal; Muscular Atrophy; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Proto-Oncogene Proteins c-akt; Reactive Oxygen Species; Tumor Necrosis Factor-alpha