Melatonin Ameliorates Age-Related Sarcopenia via the Gut-Muscle Axis Mediated by Serum Lipopolysaccharide and Metabolites

Sarcopenia affects the quality of life and increases adverse outcomes in the elderly. However, as a potential safe and effective remedy to many age-related disorders, little is known about the protective effect of melatonin against sarcopenia, especially the underlying mechanisms of pathophysiology related to the gut-muscle axis. The young (4 months) and old-aged (24 months) wild-type C57BL/6J male mice were included in this study, of which the old-aged mice in the experimental group were treated with 10 mg/kg/day of melatonin for 16 weeks. After that, muscle strength, muscle mass and the cross-sectional area (CSA) of the gastrocnemius muscle fibres were measured. Then, the putative pathways, based on the data obtained from 16S rDNA sequencing of the gut microbiota, RNA sequencing of gastrocnemius muscle and serum untargeted metabolomics, were screened out by the integrated multiomics analysis and validated using immunohistochemistry, ELISA and TUNEL staining. C2C12 myoblasts were treated with LPS. Flow cytometric analysis and western blotting were applied to detect cell apoptosis and protein expressions of Tnfrsf12a and caspase8, respectively. In addition, the mediation analysis was carried out to infer the causal role of the microbiome in contributing to the skeletal muscle through metabolites. Melatonin treatment ameliorated age-related declines in muscle strength (p