IFNγ-CXCL9-CXCR3 axis links T cell recruitment to skeletal muscle remodelling in human physical frailty

Physical frailty in two human ageing cohorts is linked to an IFN{gamma}/CXCR3 module, with plasma CXCL9 as the strongest correlate and CD8-TEMRA cells most responsive.

• Why it matters: Mechanisms connecting the ageing immune system to skeletal muscle remodelling and physical function are unclear, limiting targeted therapeutics for human physical frailty.
• What they did: The study analyzed discovery (n=22) and validation (n=33) cohorts using plasma OLINK proteomics, spectral immunophenotyping, and PBMC single-cell RNA-seq with TCR profiling, then tested axis steps in primary human co-cultures and transwell migration with anti-CXCL9 and CXCR3 antagonism (AMG487).
• The result: In human skeletal muscle (n=340), CXCL9 is positively associated with a T-cell module and, via this, fibrosis; in vitro, IFN{gamma}-conditioned myotube-fibroblast cultures drive CD8-TEMRA migration reduced by anti-CXCL9/CXCR3 antagonism and promote fibrosis mediators.