Tissue-resident macrophage activation orchestrates CXCL10-mediated CD8⁺ T-cell recruitment to drive ageing-related loss of skeletal muscle regenerative capacity
June 21
Ageing is the dominant risk factor for regenerative failure and is accompanied by pronounced structural and functional deterioration of skeletal muscle. The basal lamina enveloping myofibres is especially susceptible to age-related damage, triggering activation of tissue-resident macrophages within the satellite-cell niche. Here we use complementary pharmacological and genetic strategies to interrogate macrophage contributions to ageing-associated decline in myofibre integrity in mice. Our data show that maladaptive macrophage activation fosters the accrual of cytotoxic CD8⁺ T cells, culminating in sarcolemma degeneration and consequent deficits in muscle force production and locomotor performance.
We delineate stromal heterogeneity and age-dependent transcriptional shifts in muscle using single-cell and spatial transcriptomics, uncovering intricate macrophage–lymphocyte crosstalk. Mechanistically, we demonstrate that the CXCL10–CXCR3 axis is indispensable for recruitment and retention of CD8⁺ T cells in aged muscle, where they execute pathogenic effector programs. These findings establish that basal-lamina-linked macrophage dysfunction licenses adaptive immune responses during ageing and highlight candidate therapeutic targets for preserving musculoskeletal regeneration.