Circulating immunometabolic markers associated with sarcopenia and muscle strength at high altitude: An integrated multi-omics study.

<h4>Objectives</h4>To characterize circulating immunabolic profiles associated with sarcopenia and muscle strength in middle-aged and older adults living at high altitude using an integrated multi-omics approach.<h4>Design</h4>Case-control study including 120 middle-aged and older adults, comprising 60 participants with sarcopenia and 60 matched controls. The control groups consisted of a positive control group comprising 35 patients with osteoporosis, and a negative control group of 25 healthy individuals.<h4>Setting</h4>A high-altitude region of Kunming, Yunnan, China (2000 m).<h4>Measurements</h4>Integrated transcriptomic, proteomic, and metabolomic analyses were performed on blood samples. Differentially expressed genes, proteins, and metabolites were identified, followed by pathway enrichment and protein-protein interaction analyses. Candidate markers were further evaluated by ELISA, correlation analyses with handgrip strength, and complementary in vitro and in vivo experiments.<h4>Results</h4>Participants with sarcopenia had significantly lower body weight, body mass index, and waist circumference than those in both control groups. Their ASMI was significantly lower than that in the positive control group and among female participants in the negative control group, and a significant reduction in handgrip strength was observed only in female participants (P < 0.05). Multi-omics analyses identified dysregulated pathways mainly related to inflammation, immune responses, and metabolism. Integrated analysis highlighted CD14, Fc-gamma receptor II-a (FCGR2A), and leucine-rich alpha-2-glycoprotein 1 (LRG1) as key molecules associated with sarcopenia (P < 0.05). Metabolomic profiles were mainly linked to sphingolipid, glycerophospholipid, and amino acid metabolism. Serum LRG1 and CD14 concentrations were significantly elevated in sarcopenia, with no significant sex interaction (P > 0.05). LRG1 and CD14 were positively correlated with handgrip strength in male participants (P < 0.05). Experimental models further supported upregulation of CD14, FCGR2A, and LRG1 in sarcopenia-related conditions.<h4>Conclusion</h4>Sarcopenia in middle-aged and older adults living at high altitude was associated with distinct circulating immunometabolic profiles. CD14, FCGR2A, and LRG1 may serve as candidate circulating markers, and the associations of CD14 and LRG1 with muscle strength suggest potential clinical relevance. Further validation in larger cohorts is warranted.