Muscle-secreted granulocyte colony-stimulating factor functions as metabolic niche factor ameliorating loss of muscle stem cells in aged mice

The function and number of muscle stem cells (satellite cells, SCs) decline with muscle aging. Although SCs are heterogeneous and different subpopulations have been identified, it remains unknown whether a specific subpopulation of muscle SCs selectively decreases during aging. Here, we find that the number of SCs expressing high level of transcription factor Pax7 (Pax7(Hi)) is dramatically reduced in aged mice. Myofiber-secreted granulocyte colony-stimulating factor (G-CSF) regulates age-dependent loss of Pax7(Hi) cells, as the Pax7(Hi) 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. Furthermore, myofiber-secreted G-CSF acts as a metabolic niche factor required for establishing and maintaining the Pax7(Hi) SC subpopulation in adult and physiological aged mice by promoting the asymmetric division of Pax7(Hi) and Pax7(Mi) SCs. Together, our findings uncover that muscles provide a metabolic niche regulating Pax7 SC heterogeneity in mice.