Gymnemantoside A Ameliorates Steroid‐Induced Skeletal Muscle Atrophy via Bridging Glucocorticoid and Insulin Receptor Signalling

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BACKGROUND: Skeletal muscle atrophy is a common condition caused by numerous factors, such as aging (termed sarcopenia), disease (e.g., cancer cachexia) or specific medications (such as glucocorticoids). There is no FDA-approved drug for treating skeletal muscle atrophy. Previously, clinical studies had highlighted the anti-diabetic properties of Gymnema inodorum extract, an indigenous medicinal plant and functional food in Thailand. However, these studies did not identify the active compound(s) responsible for its therapeutic effects. This research aimed to identify safe natural product-derived compounds from clinically relevant plants such as Gymnema inodorum that bridge the connection between metabolic diseases and skeletal muscle atrophy. METHODS: Utilizing the dexamethasone (Dex) induced skeletal muscle atrophy model, the major active compounds were isolated using bioactivity-guided screening. The chemical structure of active compound(s) was elucidated using various spectroscopic methods, including HRESIMS, 1D and 2D NMR. Active compound(s) were tested in cell-based and murine models of skeletal muscle atrophy. Insulin signaling and autophagy activity were assessed by western blotting and the mRFP-GFP-LC3 (ptf-LC3) probe. Docking studies determined the binding affinities of active compound(s) for the insulin and glucocorticoid receptors. RESULTS: We determined a new, previously undescribed methyl anthranilate-conjugated oleanane bioactive compound, termed gymnemantoside A. Treatment with gymnemantoside A recovered myotube diameter and skeletal muscle fibre CSA in atrophy models and downregulated expression of the atrogenes, atrogin-1 and MuRF-1 (myotube diameter: +33.82%, p < 0.05, CSA: +128%, p < 0.01; atrogin-1: -58.70%, MuRF-1: -57.32%, p < 0.05). Gymnemantoside A also reduced autophagy levels both in vitro and in vivo (-65.56%, p < 0.01), increased expression of insulin growth factor-1 (+78.05%, p < 0.05) and the insulin receptor (+56.42%, p < 0.05), and recovered activity of the downstream Akt/mTOR-mediated insulin signalling pathway. Molecular docking analysis with gymnemantoside A and standard receptor ligands revealed that gymnemantoside A could interact with the insulin receptor tyrosine kinase and prevent Dex binding with the glucocorticoid receptor. In the murine atrophy model, gymnemantoside A treatment enhanced exercise endurance in the rotarod test (+260%, p < 0.05) and the mass of the predominantly fast fibre type TA muscle (+116%, p < 0.05). CONCLUSIONS: A newly identified bioactive compound gymnemantoside A, isolated from Gymnema inodorum, was structurally characterized and showed efficacy in Dex-induced muscle atrophy models. Gymnemantoside A produces anti-muscle atrophy effects by a hitherto unreported mechanism: modulation of the insulin receptor kinase domain and activation of downstream signalling, alongside competitive inhibition of the glucocorticoid receptor, which has been implicated in multiple forms of skeletal muscle wasting.

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