Integration of multiple omics reveals key targets and cellular mechanisms for intervention in sarcopenia

Area of Science:

• Genetics and Omics
• Aging Research
• Immunology

Background:

• Sarcopenia, characterized by age-related loss of muscle mass and function, poses a significant global health challenge with limited treatment options.
• Current therapeutic strategies for sarcopenia are insufficient, necessitating the identification of novel, mechanistically informed targets.

Purpose of the Study:

• To integrate genomic causality, multi-tissue omics, and cellular mediation analyses to identify and prioritize therapeutic targets for sarcopenia.
• To establish a causal framework linking plasma proteins to sarcopenia pathophysiology.

Main Methods:

• Two-sample Mendelian randomization (MR) was used to investigate causal relationships between 4907 plasma proteins and sarcopenia traits in a large cohort.
• Bayesian colocalization and transcriptomic validation in muscle biopsies were performed to prioritize potential therapeutic targets.
• Cellular mediation analysis quantified the role of immune and stromal cells in protein-trait pathways using transcriptomic deconvolution.

Main Results:

• Mendelian randomization identified 1237 plasma proteins causally associated with sarcopenia traits.
• Six proteins (HGFAC, GATM, HMOX2, F2, LMAN2L, HPGDS) were validated as potential targets through colocalization, expression data, and disease association.
• Cellular mediation highlighted immune mechanisms, with CD4+ regulatory T cells mediating a portion of HGFAC's effect on sarcopenia.

Conclusions:

• This study provides a causal map linking plasma proteins to sarcopenia, emphasizing immune-stromal interactions.
• Six prioritized proteins serve as actionable targets, suggesting repurposing of thrombin inhibitors and development of immunometabolic therapies.
• The integrated framework advances precision strategies for combating age-related muscle decline by connecting genomic insights to cellular mechanisms.