Link between Circulating CCL2 Levels and Sarcopenia: Evidence from a Cohort Study, the UK Biobank, and Human GTEx Transcriptomic Data.

<h4>Background</h4>Chronic inflammation is a hallmark of aging, but the role of inflammatory mediators such as C-C motif chemokine ligand 2 (CCL2) in skeletal muscle health remains unclear. Although CCL2 is often considered a detrimental pro-aging factor, it is also essential for myogenesis. This study aimed to clarify the complex role of CCL2 in human muscle metabolism.<h4>Methods</h4>We used a multimodal approach integrating clinical, proteomic, transcriptomic, and genetic analyses. The association between circulating CCL2 and sarcopenia-related parameters was examined in 323 community-dwelling older adults and validated using UK Biobank data (n=54,219). Genotype-Tissue Expression (GTEx) transcriptomic data (n=818) were used for tissue-level analysis, and Mendelian randomization (MR) was performed to assess causality.<h4>Results</h4>In the cohort study, serum CCL2 levels were significantly higher in participants with sarcopenia, weak muscle strength, or poor physical performance (P<0.001 to 0.042) and were inversely correlated with skeletal muscle index, grip strength, and gait speed (P<0.001 to 0.003). Each standard deviation increase in circulating CCL2 level was associated with 1.37-1.71-fold higher odds of sarcopenia-related outcomes (all P≤0.028). UK Biobank data also showed higher plasma CCL2 levels in participants with sarcopenia (P=0.005). In contrast to these observational findings, tissue-level analysis using GTEx data showed that higher skeletal muscle CCL2 expression was correlated with greater muscle cross-sectional area. MR further supported an inverse causal association between genetically predicted plasma CCL2 levels and sarcopenia risk (P=0.029).<h4>Conclusion</h4>These divergent findings raise the possibility that elevated circulating CCL2 levels in sarcopenia reflect a compensatory response to muscle deterioration rather than a direct pathogenic driver, highlighting the need for further mechanistic validation.