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          Institute of Basic Medical Sciences Zhu Dahai and Professor Zhang Yong's team published an article in EMBO J, revealing the function and molecular mechanism of MyoD-mediated tissue metabolism microenvironment to regulate the heterogeneity of adult stem cells during aging

          Skeletal muscle is the body's largest endocrine and metabolic organ, and it plays an irreplaceable role in the body's normal movement, metabolism, homeostasis, and life span determination. Especially with the increasing aging of the population, the incidence of aging syndrome caused by skeletal muscle attenuation caused by aging and metabolic diseases has increased significantly, which has greatly reduced people's quality of life. So far, there is no effective treatment for most skeletal muscle diseases, and the pathogenesis of many skeletal muscle diseases is not clear.

          Skeletal muscle adult stem cells play a very important role in skeletal muscle development, regeneration, and aging. Skeletal muscle adult stem cells (Pax7 cells) have a certain heterogeneity, but little is known about its heterogeneous composition, molecular mechanism of establishment and maintenance, and its function in skeletal muscle regeneration and aging. Surrounding these scientific issues, Zhu Dahai and Professor Zhang Yong's team first reported the molecular mechanism of Pax7 Lo subpopulations in 2015 (Wu et al. Nature Communications, 2015). However, no studies have been reported on the establishment and maintenance of Pax7 cell heterogeneity by tissue metabolic microenvironment during development and aging. In recent years, life science research has gained a new understanding of the function of cell metabolism, that is, the function of body metabolism is not only to provide substances and energy for cell activities, but also more importantly, cell metabolism has a very important signal transduction function. Skeletal muscle tissue is composed of two types of muscle fibers, oxidized and fermented. It is interesting that Pax7 stem cells directly adhere to skeletal muscle fibers with different metabolic characteristics. Therefore, anatomically, skeletal muscle fibers provide a immediate niche for Pax7 cells. Based on this, the research team first proposed the concept hypothesis of “skeletal muscle fiber metabolism in regulating tissue metabolism microenvironment during the establishment and maintenance of Pax7 cell heterogeneity”. This research validated the hypothesis of "tissue metabolic microenvironment" using technologies such as scRNA-seq and various mouse genetic and aging models. Its research work "Muscle-secreted granulocyte colony-stimulating factor functions as metabolic niche factor ameliorating loss of muscle "Stem cells in aged mice" was published in the EMBO Journal on November 18, 2019.

          MyoD is a well-known Master transcription factor that determines the cell lineage. Previous studies have focused on the function and molecular mechanism of MyoD in skeletal muscle cell fate determination, while MyoD's function in mature skeletal muscle fibers has not been reported. The team's research work for the first time discovered the function of MyoD to regulate csf3 gene expression in a glycolytic metabolism-dependent manner in mature skeletal muscle fibers, providing new insights into the new function of Master transcription factors determined by classical cell lineages . Perspective . At the same time, the study also found that Pax7 Hi cell subsets play an important role in the aging process, and that G-CSF regulated by metabolism and MyoD is secreted by skeletal muscle fibers as a metabolic microenvironment factor to regulate Pax7 Hi and Pax7. Functional and molecular mechanisms of Mi cells asymmetric division in the process of establishing and maintaining Pax7 Hi subpopulation cells .

          In short, the study proved the concept of "tissue metabolism microenvironment" for adult stem cells at the in vivo level for the first time, discovered the new function of MyoD as a metabolic sensor on the molecular mechanism, established exercise on physiological functions and aging It plays an important role in maintaining Pax7 Hi and Pax7 Mi subpopulation cells. The research results provide a theoretical basis for strengthening the function of skeletal muscle stem cells, and also provide new ideas for exploring the application of different subgroups of stem cells to treat skeletal muscle atrophy and other related diseases.

          The first author of the paper is post-doctoral Li Hu of the Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, and Professor Zhu Dahai and Zhang Yong are the corresponding authors. This research work was supported by the National Major Scientific Research Program (973) Project (2015CB943103), the National Key R & D "Stem Cell and Transformation Research" Special Project (2016YFA0100703), the National Natural Science Foundation of China Major Research Project (91540206), and the Academy of Medical Sciences' Medical and Health Technology Innovation Project (2016-I2M-1-017) and other projects.

          Abstract

          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 decreases during aging. Here, we find Pax7 Hi cells are dramatically reduced in aged mice and this aged-dependent loss of Pax7 Hi cells is metabolically mediated by myofiber-secreted granulocyte-colony stimulating factor G-CSF 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 and the myofibers-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 a metabolic niche role of muscle metabolism in regulating Pax7 SC heterogeneity in mice.


          MyoD-mediated tissue metabolism microenvironment regulates adult stem cell heterogeneity during aging