Amelioration of diabetic myopathy by APMCG-1: A mountain-cultivated ginseng-derived glycopeptide evaluated in zebrafish and mouse models.

ETHNOPHARMACOLOGICAL RELEVANCE: Mountain-cultivated Panax ginseng C.A.Mey. (MCG) residues represent an underutilized resource with significant therapeutic potential. We previously isolated a potent glycopeptide, APMCG-1, from MCG residues using alkaline protease-assisted extraction.

AIM OF THE STUDY: This study comprehensively investigates the protective effects of APMCG-1 against diabetic myopathy in vitro (C2C12), in vivo (zebrafish), and mammalian (mouse) models.

MATERIALS AND

METHODS

In palmitic acid (PA)-induced C2C12 myoblasts, the effects of APMCG-1 on cell viability, creatine kinase release, and glucose consumption were evaluated. Mechanistic studies assessed mitochondrial function, apoptosis, mitochondrial membrane potential, and activation of the PI3K/AKT pathway. In type 2 diabetic (T2DM) zebrafish, skeletal muscle performance (swimming endurance), blood biochemical indices, antioxidant enzyme activities, inflammatory cytokines, and metabolomic profiles were examined. In T2DM mice, glucose tolerance, insulin sensitivity, glucolipid metabolism, muscle glycogen content, histopathology, and activation of the PI3K/AKT/GLUT4 pathway were assessed.

RESULTS

In palmitic acid (PA)-induced C2C12 skeletal myoblasts, APMCG-1 significantly increased cell viability, reduced creatine kinase levels, and enhanced glucose consumption in a time- and dose-dependent manner. Mechanistically, APMCG-1 activated the PI3K/AKT signaling pathway, while attenuating mitochondrial dysfunction, reducing apoptosis, and restoring mitochondrial membrane potential. In T2DM zebrafish models, APMCG-1 treatment markedly improved skeletal muscle function, evidenced by enhanced swimming endurance. It significantly reduced fasting blood glucose, insulin, triglycerides, total cholesterol, free fatty acids, malondialdehyde, TNF-α, and IL-6 levels, while increasing muscle glycogen, superoxide dismutase, glutathione peroxidase, and catalase activities. Metabolomic analysis further revealed that APMCG-1 modulated glucolipid metabolic disorders by regulating key pathways, including cysteine and methionine metabolism, arginine and proline metabolism, and steroid hormone biosynthesis. Critically, in T2DM mice, APMCG-1 improved glucose tolerance, enhanced insulin sensitivity, reduced hyperglycemia, and dyslipidemia, restored insulin-stimulated skeletal muscle glucose uptake. Moreover, it increased muscle glycogen content and attenuated histopathological muscle damage. These protective effects were mechanistically linked to the activation of the PI3K/AKT/GLUT4 pathway in skeletal muscle.

CONCLUSIONS

Our findings demonstrate that APMCG-1, derived from MCG residues, is a promising therapeutic candidate for preventing and treating diabetic myopathy by enhancing insulin sensitivity and reducing oxidative stress.