Dissecting Immune Mechanisms Underlying Sarcopenia Using Multi-omics Approaches

Area of Science:

• Genetics
• Immunology
• Gerontology

Background:

• Sarcopenia is an age-related muscle disease with poorly understood gene regulation in immune cells.
• Investigating immune cell gene expression is crucial for understanding sarcopenia pathogenesis.

Purpose of the Study:

• To systematically explore the causal roles of immune cell-specific gene expression in sarcopenia.
• To identify potential therapeutic targets and mechanistic insights for sarcopenia.

Main Methods:

• Integrated immune cell-specific expression quantitative trait loci (sc-eQTLs), genome-wide association studies (GWAS), and multi-omics data.
• Employed Mendelian randomization (MR), Bayesian colocalization, and genetic structural equation modeling (GSEM) across 14 immune cell types, whole blood, and skeletal muscle.
• Utilized two-step MR to investigate mediation pathways through common diseases and carnitine metabolites.

Main Results:

• Identified 14 genes, including HLA-DRB1, HLA-C, and SLC22A5, with significant causal effects on sarcopenia phenotypes in immune cells.
• Discovered mediation of causal effects by heart failure, rheumatoid arthritis, and chronic kidney disease for specific genes.
• Found that isovalerylcarnitine (C5) mediates the causal effect of SLC22A5 in skeletal muscle on sarcopenia, with a substantial mediation proportion.

Conclusions:

• Immune cell-specific gene expression of HLA-DRB1, HLA-C, SLC22A5, and FNBP4 contributes to sarcopenia development.
• These genes represent potential therapeutic targets for combating age-related muscle loss.
• The study provides novel mechanistic insights into sarcopenia pathogenesis involving immune and metabolic pathways.