Mapping the genetically predicted associations of plasma metabolites with sarcopenia and aging traits: Evidence from bidirectional Mendelian randomization and transcriptome analysis

Observational studies have demonstrated associations between plasma metabolites and sarcopenia/aging. This study aimed to investigate the genetically predicted associations between plasma metabolites and sarcopenia/aging traits and to discover the regulating genes. A Mendelian randomization (MR) study was performed using metabolomic data obtained from the Canadian Longitudinal Study on Aging cohort. Data of sarcopenia/aging traits were obtained from genome-wide association studies for frailty index, telomere length, left- and right-hand grip strength, adjusted appendicular lean mass, anterior and posterior thigh muscle fat infiltration, total thigh muscle volume z-score and usual walking pace. Sensitivity analyses, reverse MR and Bayesian colocalization were employed to validate the genetically predicted associations. Replication analyses were performed in the metabolic syndrome in men cohort. The MR analysis identified 18 per-trait and two across-trait significant associations between plasma metabolites/metabolite ratios and sarcopenia/aging traits, five of which were successfully replicated in external validation. Using functional mapping and annotation analysis, protein tyrosine phosphatase receptor type D (PTPRD) was mapped to the genomic risk loci of multiple significant metabolites/metabolite ratios and was transcriptionally upregulated in the muscle of the (pre-)frail elderly. Single-cell analysis further showed that PTPRD was mainly expressed in adipogenic MME⁺ fibro-adipogenic progenitors in the skeletal muscle tissue, which could cause elevated levels of circulating lipid metabolites and fat infiltration in the skeletal muscle, triggering sarcopenia and aging of the muscle. In conclusion, this study revealed the role of PTPRD in regulating the genetically predicted associations between plasma metabolites/metabolite ratios and sarcopenia/aging traits, thereby contributing to the improved risk assessment and prevention strategies for aging and sarcopenia, meriting further investigation.