Lysine degradation-related metabolic remodeling in sarcopenia: Mendelian randomization prioritization and multi-omics-based characterization
Abstract
BACKGROUND AND AIMS
Previous metabolomic studies have implicated mitochondrial energy metabolism, lipid remodeling, and carnitine-related pathways in sarcopenia, but broader metabolic pathways linking these abnormalities remain unclear. We aimed to identify sarcopenia-related metabolic pathways by integrating metabolome-wide Mendelian Randomization (MR) with patient-derived serum and skeletal muscle multi-omics analysis.
METHODS
Two-sample MR analyses were performed using genome-wide association study summary statistics for 1400 circulating metabolite-related traits and three sarcopenia-related traits, appendicular lean mass (ALM), handgrip strength, and walking speed. Candidate metabolites retained after MR sensitivity filtering were subjected to Kyoto Encyclopedia of Genes and Genomes (KEGG)-based pathway enrichment. The MR-prioritized pathway was then examined in an independent cohort of 40 postmenopausal women with or without sarcopenia using untargeted serum and skeletal muscle metabolomics. Patient-derived and the external public skeletal muscle transcriptomic datasets were analyzed to evaluate pathway-related transcriptomic patterns.
RESULTS
Lysine degradation was the only pathway meeting the predefined pathway-level FDR criterion in the ALM-negative direction. Lysine, carnitine, and N6,N6,N6-trimethyllysine contributed nominal negative MR associations to this pathway. Colocalization identified strong evidence of a shared causal signal for one carnitine locus…
How strong is the evidence?
Evidence Hub reads this as a cohort study, done in people. Its evidence level is 3 of 5 (Moderate · trial / cohort / secondary analysis). Trials without a large randomized design, cohorts and secondary analyses give moderate evidence. Reported size: 40 participants or records.
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