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

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.

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.

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).

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.