Muscle-secreted G-CSF as a metabolic niche factor ameliorates loss of muscle stem cell in aged mice

Summary Function and number of muscle stem cells (satellite cells, SCs) declines with muscle aging. Although SCs are heterogeneous and different subpopulations have been identified, it remains unknown if a specific subpopulation of muscle SCs selectively decreases during aging. Here, we find Pax7Hi cells are dramatically reduced in aged mice and this aged-dependent loss of Pax7Hi cells is metabolically mediated by myofiber-secreted granulocyte-colony stimulating factor G-CSF as the Pax7Hi SCs are replenished by exercise-induced G-CSF in aged mice. Mechanistically, we show that transcription of G-CSF (Csf3) gene in myofibers is regulated by MyoD in a metabolism-dependent manner and the myofibers-secreted G-CSF acts as a metabolic niche factor required for establishing and maintaining the Pax7Hi SC subpopulation in adult and physiological aged mice by promoting the asymmetric division of Pax7Hi and Pax7Mi SCs. Together, our findings uncover a metabolic niche role of muscle metabolism in regulating Pax7 SC heterogeneity in mice. Highlights Single cell RNA-seq unveils Pax7Hi and Pax7Lo cells are two distinct subpopulations. Pax7Hi SCs are enriched in glycolytic fibers and reduced in aging muscle. Metabolic niche factor G-CSF is required for regulating dynamic change of Pax7 SCs. G-CSF replenishes Pax7Hi cells by stimulating asymmetric division of Pax7Mi cells.