Plasma Extracellular Vesicles-Derived Complement Proteins as Biomarkers of Sarcopenia Progression in Longitudinal Cohorts

초록

Background Sarcopenia is characterized by progressive loss of muscle mass, strength and physical performance, yet current diagnostic tools are limited for practical and longitudinal monitoring. Extracellular vesicles (EVs) encapsulate various biomolecules, including proteins, nucleic acids, lipids and metabolites and have emerged as promising carriers of circulating biomarkers. In this study, we investigated longitudinal biomarkers of sarcopenia using plasma-derived EVs.Methods Plasma EVs were isolated by density gradient ultracentrifugation from participants in the community-based Korean Frailty and Aging Cohort Study (KFACS, n = 90) and performed quantitative proteomic profiling of EVs derived from plasma. Candidate proteins were validated in an independent hospital-based Osteoporosis Sarcopenia (OsteoSarc, n = 93) cohort at Seoul National University Bundang Hospital using MRM-based LC-MS/MS. Multivariate models were adjusted for age, sex, body mass index (BMI) and relevant covariates: metabolic comorbidities (hypertension, myocardial infarction, peripheral artery disease, cerebrovascular disease, and diabetes mellitus) in the KFACS cohort and femoral neck bone mineral density in the OsteoSarc cohort.Results In the KFACS cohort (mean age, 77.7 +/- 4.1 years; range, 70.0-84.7; 50.0% women), EV-associated complement proteins, particularly C2 and C4B, were strongly associated with declines in gait speed (beta = -0.302, p = 0.006; beta = -0.231, p = 0.028, respectively) and were elevated in individuals with worsened outcomes over 2 years (p = 0.002 and p = 0.034, respectively). Complement pathway enrichment analysis further supported associations with inflammatory and aging-related signatures. Independent validation in the hospital-based OsteoSarc cohort (mean age, 74.3 +/- 12.0 years; range, 52.0-96.0; 88.2% women) confirmed the predictive value of C2 and C1R for gait speed and SPPB decline, with AUC values exceeding 0.7 for clinically relevant measures.Conclusion Our findings demonstrate that several EV-associated complement proteins, including C2, C4B and C1R, are strongly associated with longitudinal decline in gait speed, highlighting their potential as promising circulating biomarkers for sarcopenia progression.

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