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

• Published in: The EMBO journal Vol. 38; no. 24; pp. e102154 - n/a
• Main Authors: Li, Hu, Chen, Qian, Li, Changyin, Zhong, Ran, Zhao, Yixia, Zhang, Qianying, Tong, Weimin, Zhu, Dahai, Zhang, Yong
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 16.12.2019; Blackwell Publishing Ltd; John Wiley and Sons Inc
• Subjects: aged mice; Aging; Animals; asymmetric division; Asymmetry; Cell Line; Colonies; EMBO01; EMBO21; EMBO34; Glycolysis; Granulocyte Colony-Stimulating Factor - genetics; Granulocyte Colony-Stimulating Factor - metabolism; Granulocytes; G‐CSF; Heterogeneity; Leukocytes (granulocytic); metabolic niche; Metabolism; Mice; Muscle, Skeletal - cytology; Muscle, Skeletal - metabolism; Muscles; MyoD protein; MyoD Protein - metabolism; Pax7 satellite cells; PAX7 Transcription Factor - metabolism; Regeneration; Ribonucleic acid; RNA; Satellite cells; Satellite Cells, Skeletal Muscle - cytology; Satellite Cells, Skeletal Muscle - metabolism; Skeletal muscle; Stem cell transplantation; Stem cells; Stem Cells - metabolism; Subpopulations; Transcription factors; G‐CSF; asymmetric division; metabolic niche; Pax7 satellite cells; aged mice; G-CSF
• ISSN: 0261-4189; 1460-2075
• DOI: 10.15252/embj.2019102154

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. Synopsis Transcription factor Pax7 regulates the function of adult muscle stem cells (satellite cells, SCs) and Pax7‐positive SCs are essential for skeletal muscle regeneration. Myofiber‐secreted G‐CSF promotes age‐related dynamic heterogeneity of Pax7‐positive SCs in mice by stimulating their asymmetric division. Single‐cell RNA‐seq unveils that Pax7 Hi and Pax7 Lo cells are two distinct subpopulations. Pax7 Hi SCs are enriched in glycolytic fibers and undergo progressive reduction in aging muscle. Metabolic niche factor G‐CSF regulates the dynamic change of Pax7‐positive SCs. G‐CSF replenishes Pax7 Hi cell population by stimulating asymmetric division of a subpopulation of SCs with high and intermediate level of Pax7. Graphical Abstract Myofiber‐secreted G‐CSF promotes the dynamic heterogeneity of Pax7‐positive satellite cells in vivo by stimulating their asymmetric division.