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. 2025 Feb;16(1):e13722.
doi: 10.1002/jcsm.13722.

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

Ling-Shan Zhou  1 , Yuan Yang  2 , Li Mou  3 , Xin Xia  4 , Min Liu  5 , Ling-Jie Xu  6 , Rong Liu  1 , Jun-Ping Liu  7 , Hai-Yan Zhang  8 , Xiao-Jun Ao  9 , Chang-Jiang Liu  3 , Qian Xiao  10 , Shi-Xiong Liu  1
Affiliations

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

Ling-Shan Zhou (V体育ios版) et al. J Cachexia Sarcopenia Muscle. 2025 Feb.

Abstract

Background: Sarcopenia affects the quality of life and increases adverse outcomes in the elderly VSports手机版. 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. .

Methods: 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 V体育安卓版. 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. .

Results: Melatonin treatment ameliorated age-related declines in muscle strength (p < 0. 05), muscle mass (p < 0 V体育ios版. 01) and CSA of the gastrocnemius muscle fibres (p < 0. 01), as well as changed the gut microbial composition (beta-diversity analysis; R = 0. 513, p = 0. 005). The integrated multiomics analysis implied two main mechanisms about the impact of melatonin-related modifications in the gut microbiota on sarcopenia. First, a lower serum lipopolysaccharide (LPS) level associated with the altered gut microbiota was observed in melatonin-treated mice (p < 0. 001) and was most relevant to the transcription level of Tnfrsf12a in skeletal muscle (R = 0. 926, p < 0. 001). Further bioinformatics analyses and in vitro experiments showed that LPS could contribute to skeletal muscle apoptosis by regulating the Tnfrsf12a/caspase-8 signalling pathway. Second, melatonin significantly altered serum metabolites (variable importance on projection (VIP) > 1. 5, p < 0. 05). Mediation models showed that changes in the gut microbiome also influenced skeletal muscle through these metabolites (27 linkages; BH-adjusted p < 0. 05). .

Conclusions: Our study revealed functional insights and a putative causality for the role of the gut-muscle axis in the mechanism of melatonin ameliorating age-related sarcopenia, namely, inhibition of the LPS-induced Tnfrsf12a/caspase-8 signalling pathway or serum metabolites as intermediates in the gut-muscle axis VSports最新版本. .

Keywords: LPS; gut–muscle axis; mediation analysis; melatonin; metabolites; sarcopenia. V体育平台登录.

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Conflict of interest statement

The authors declare no conflicts of interest.

"V体育ios版" Figures

FIGURE 1
FIGURE 1
Treatment with melatonin prevents the progression of sarcopenia in aged mice. (A) Treatment with melatonin ameliorates the age‐related loss of grip strength in aged mice. (B) Treatment with melatonin has no effect on weight in aged mice. (C) Treatment with melatonin alleviates the age‐related decrease in the ratio of gastrocnemius weight to body weight. (D) Treatment with melatonin relieves the age‐related decline in CSA of the muscle fibres. *p < 0.05, **p < 0.01, ***p < 0.001, and ns = nonsignificant, Y versus Con or Con versus Mel. n = 6.
FIGURE 2
FIGURE 2
Treatment with melatonin modifies the composition of the gut microbiome. (A) Principal component analysis (PCA) of intestinal microbiome; (B) analysis of similarities (ANOSIM) of intestinal microbiome; (C) intestinal microbe relative abundance at the phylum level; (D) the ratio of Firmicutes to Bacteroidetes in intestinal microbiome at the phylum level; (E) significant changes in abundance of intestinal microbe at the genus levels; (F) line discriminant analysis (LDA) effect size (LEfSe) analysis. *p < 0.05, **p < 0.01, and ns = nonsignificant, Con versus Mel. n = 6.
FIGURE 3
FIGURE 3
Treatment with melatonin has an effect on the transcriptomics of skeletal muscle in aged mice. (A) The volcano plot for differentially expressed genes (DEGs) in skeletal muscle; (B) significantly enriched biological processes and molecular function in GO; (C) significantly enriched pathways in Reactome. n = 6.
FIGURE 4
FIGURE 4
The LPS‐induced Tnfrsf12a/caspase‐8 signalling pathway is involved in the mechanism by which melatonin alleviates age‐associated sarcopenia via the gut–muscle axis. (A) The serum level of LPS; (B) the immunohistochemical staining of Tnfrsf12a in gastrocnemius of aged mice; (C) TUNEL analysis of apoptosis in gastrocnemius; (D) the immunohistochemical staining of caspase‐8 in gastrocnemius of aged mice; (E) the percentages of apoptotic C2C12 myoblasts; (F) the protein expression of Tnfrsf12a and caspase‐8 in C2C12 myoblasts. *p < 0.05, **p < 0.01, ***p < 0.001.
FIGURE 5
FIGURE 5
Melatonin intake affects serum metabolomic profiles in aged mice. (A) Principal component analysis (PCA) plots of Con and Mel groups; (B) partial least‐squares‐discriminant analysis (PLS‐DA) plots of Con and Mel groups; (C) the volcano plots of melatonin Con and Mel groups; (D) hierarchical cluster analysis of serum differential metabolites between Con and Mel groups. n = 6.
FIGURE 6
FIGURE 6
The mediation role of metabolites in the gut microbiota–skeletal muscle axis. (A) The correlations among the gut microbiome, serum metabolites and muscle genes; (B) Sankey diagram showing the significant mediation effects of serum metabolites in the gut microbiota–skeletal muscle axis.
FIGURE 7
FIGURE 7
The mechanism diagram of this study for explaining the effect of melatonin on age‐related sarcopenia through the gut–muscle axis.
See this image and copyright information in PMC

V体育安卓版 - References

    1. Tieland M., Trouwborst I., and Clark B. C., “Skeletal Muscle Performance and Ageing,” Journal of Cachexia, Sarcopenia and Muscle 9, no. 1 (2018): 3–19. - V体育ios版 - PMC - PubMed
    1. Yeung S. S. Y., Reijnierse E. M., Pham V. K., et al., “Sarcopenia and Its Association With Falls and Fractures in Older Adults: A Systematic Review and Meta‐Analysis,” Journal of Cachexia, Sarcopenia and Muscle 10, no. 3 (2019): 485–500. - PMC - PubMed
    1. Kelley G. A. and Kelley K. S., “Is Sarcopenia Associated With an Increased Risk of All‐Cause Mortality and Functional Disability?,” Experimental Gerontology 96 (2017): 100–103. - PMC - PubMed
    1. Minich D. M., Henning M., Darley C., Fahoum M., Schuler C. B., and Frame J., “Is Melatonin the “Next Vitamin D”?: A Review of Emerging Science, Clinical Uses, Safety, and Dietary Supplements,” Nutrients 14, no. 19 (2022): 3934. - PMC - PubMed
    1. Lee J. Y., Kim J. H., and Lee D. C., “Urine Melatonin Levels Are Inversely Associated With Sarcopenia in Postmenopausal Women,” Menopause (New York, NY) 21, no. 1 (2014): 39–44. - PubMed

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