Satellite cells choreograph an immune cell-fibrogenic cell circuit during mechanical loading in geriatric skeletal...

Muscle stem cells, or satellite cells (SCs), decline in number throughout the lifespan and may become senescent in very old age. Whether and how remaining SCs contribute to muscle adaptation in the oldest-old is unclear. Using acute mechanical overload in geriatric SC replete and depleted mice (28-month-old) combined with single-cell RNA-sequencing, we show: (i) subsets of geriatric SCs display signs of senescence as well as normal fate progression during overload, (ii) SCs express markers that may contribute to the regulation of innervation, (iii) the presence of SCs during overload enhances global intercellular communication and increases mRNA levels of the cell surface receptor Cd74 in immune cells, (iv) macrophage migration inhibitory factor (Mif), the primary ligand for CD74, is enriched in fibrogenic cells and is more pronounced in the absence of SCs-perhaps to normalize dysregulated fibrotic signaling and migration in macrophages, and (v) SCs influence cell fate dynamics to promote the canonical macrophage response to hypertrophic loading. Our findings expose the behavior of SCs in response to mechanical loading in the oldest-old in vivo and reveal a SC-macrophage-fibrogenic cell circuit in geriatric muscle that could support an early proadaptive inflammatory environment.