Satellite Cells Choreograph an Immune Cell-Fibrogenic Cell Circuit During Mechanical Loading in Geriatric Skeletal Muscle

Muscle stem cells, or satellite cells, decline in number with age and may become senescent. Whether and how satellite cells contribute to muscle adaptation in the oldest-old is unclear. Using short-term mechanical overload in geriatric satellite cell replete and depleted mice (28 months of age) combined with single cell RNA-sequencing, we show: 1) subsets of geriatric satellite cells show signs of senescence as well as normal fate progression during overload, 2) satellite cells express markers that may contribute to the regulation of innervation, 3) the presence of satellite cells during overload globally enhances intercellular communication and causes upregulation of the cell surface receptor gene Cd74 in immune cells, 4) Mif, the primary ligand for CD74, is produced by fibrogenic cells and is more pronounced in the absence of satellite cells - perhaps to help normalize dysregulated fibrotic signaling, and 5) satellite cells drive fate directive transcript splicing that promotes the canonical macrophage response to hypertrophic loading. Our findings expose the behavior of satellite cells in response to mechanical loading in the oldest-old and reveal a satellite cell-macrophage-fibrogenic cell circuit in geriatric muscle that may promote extracellular matrix remodeling 28-month-old Pax7-DTA mice with satelite cells depleted via tamoxifen treatment ("SC-" in study, "t" in file names) or satellite cells retained via sunflowerseed oil treatment vehicle ("SC+" in study, "v" in file names) 2-weeks prior to 96-hours of mechnical overlaod via removal of gastrocnemius and soleus muscles.