Exosome Reporter Mice Reveal Age-Dependent Shifts in Satellite Cell Communication at Rest and During Skeletal Muscle Hypertrophy

Skeletal muscle hypertrophy in response to mechanical loading is blunted with aging, but the mechanisms underlying this decline remain unclear. Satellite cells (SCs), essential for muscle growth, communicate with diverse mononuclear cell populations to coordinate tissue remodeling. We hypothesize that SC-derived exosome signaling is a key regulator of this process and that age-related disruptions contribute to reduced hypertrophic growth. Using Pax7-CD63-GFPf/f exosome reporter mice and single-cell RNA sequencing, we mapped SC exosome recipient cells and evaluated their functional responses at rest and during the early phase of hypertrophic adaptation induced by 4 days of synergist ablation-induced mechanical overload (MOV) in young (5–6 months) and aged (24 months) mice. At rest, SC exosomes predominantly target endothelial cells (ECs) and anti-inflammatory macrophages. In young mice, exosome signaling promotes EC maturation and vascular stability. In aged mice, however, SC-derived exosomes induce the upregulation of apoptosis-related genes in ECs and oxidative stress-related genes in anti-inflammatory macrophages, potentially impairing their reparative roles. During MOV, SC exosome signaling shifts toward macrophages in both age groups. In aged macrophages, this signaling induces chronic inflammation-associated gene expression, which may exacerbate the attenuated hypertrophic response. Notably, SC exosomes downregulate collagen-associated transcripts in macrophages during early MOV, a conserved response across age groups. Overall, we show that SC-derived exosomes orchestrate age-dependent intercellular communication networks that regulate inflammation, oxidative stress, and extracellular matrix remodeling. This communication is critical for muscle growth and may underlie the impaired hypertrophic adaptation observed with aging. This research was supported by the National Institutes of Health (AG069909) This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.