Tonsil-Derived Mesenchymal Stem Cell-Derived Small Extracellular Vesicles (sEVs) Restore Myo-Inositol Production in LPS-Treated Skeletal Muscle

Background: Systemic inflammation, often induced by elevated circulating lipopolysaccharide (LPS) levels, is a common consequence of intestinal epithelial barrier damage and microbial translocation. This condition is particularly prevalent in menopausal women, who are at increased risk for chronic inflammation and metabolic syndrome due to physiological changes during menopause. Myo-inositol has been shown to improve metabolic profiles in menopausal women with metabolic syndrome. In this study, we investigated whether small extracellular vesicles (sEVs) from human palatine tonsil-derived mesenchymal stem cells (T-MSCs) can restore circulating myo-inositol levels and promote myo-inositol synthesis in skeletal muscle under repeated LPS exposure, mimicking the intestinal leakage seen in menopausal women. Methods: Over 2 weeks period, LPS was repeatedly administered to mice, along with a group that also received T-MSC-derived sEVs. After 15 days, the expression of proteins involved in inositol synthesis in skeletal muscle, and serum inositol levels were measured. Additionally, intracellular inositol expression was compared in LPS-treated skeletal muscle cells with and without T-MSC sEVs treatment in vitro. Lastly, the protein and microRNA composition of T-MSC sEVs was analyzed. Results: Our results demonstrated that T-MSC-derived sEVs significantly increased serum myo-inositol levels and enhanced the expression of myo-inositol synthesis proteins in mice exposed to LPS. Similarly, LPS-treated myotubes supplemented with T-MSC sEVs exhibited restored myo-inositol expression. Moreover, T-MSC sEVs were found to contain high levels of muscle-related proteins. Conclusion: These findings suggest that T-MSC sEVs may serve as a promising therapeutic strategy for mitigating the effects of intestinal leakage and chronic inflammation in menopausal women. By improving skeletal muscle mass and maintaining myo-inositol levels, T-MSC sEVs offer potential for addressing metabolic disturbances associated with menopause.