Co-regulation of endothelial and myogenic cell fates through intercellular crosstalk in skeletal muscle

Skeletal muscle is one of the most dynamic organs in the human body, which has a vigorous potential to regenerate and adapt to environmental changes. Depending on environments, skeletal muscle enables essential life activities to survive by controlling movement and metabolism. The functional and structural adaptations of skeletal muscle crosstalk with other physiological systems enabling nutrition and oxygen delivery, and the elimination of metabolic waste products. The work in this dissertation focuses on the intercellular signals produced by myogenic cells to dynamically remodel skeletal muscle during exercise or muscle repair, and the reciprocal signals from the local niche and the systemic environment that regulate myogenic cell fate and metabolism according to physiological needs. This complex crosstalk is dissected in three specific chapters where we study the crosstalk of myogenic cells with endothelial cells and the vasculature to coordinate local niche interactions and systemic crosstalks. First, we demonstrate that an exercise-induced myokine called apelin is produced by muscle fiber and mediates intercellular signaling to endothelial cells through the apelin receptor. In addition, through a yeast one-hybrid screen of transcription factor binding to the apelin promoter, we identified the myogenic transcription factor TEA domain family member 1 (Tead1) as a regulator of Apln transcription. We observed via single-cell transcriptomic analysis of regenerating skeletal muscle that Aplnr (Apelin receptor) is enriched in muscle endothelial cells, whereas Tead1 is enriched in myogenic cells. Myofiber-specific over-expression of Tead1 suppresses apelin secretion at the whole-body level, and apelin secretion via Tead1 knock-down in muscle cells stimulates endothelial cell proliferation in co-cultures. By showing that apelin peptide supplementation in vivo enhances endothelial cell expansion following muscle injury, we conclude that paracrine crosstalk in which apelin secretion controlled by Tead1 in myogenic cells influences endothelial remodeling during skeletal muscle repair. Secondly, we show how tissue-resident support cells affect muscle progenitor activation in different metabolic environments. Skeletal muscle progenitors (SKMP) reside in close proximity to supportive cell types in the stem cell niche and dynamically interact with each other to adapt to environmental changes. Here, we studied how different niche cell types affect SKMPs in response to glycemic levels. Using co-cultures of SKMPs and niche cells, we discovered that endothelial cells synergistically enhance SKMP proliferation in a low glycemic environment, while fibroblasts and macrophages had no effect. We observed that the crosstalk between SKMPs and endothelial cells was mediated by direct cell-cell contacts independent of soluble paracrine signals. Transcriptomic analysis revealed that the endothelial alpha/beta hydrolase N-Myc Downstream Regulated1 (NDRG1) is induced by a low glycemic environment and is associated with biological adhesion. SKMPs co-cultured with Ndrg1 knock-down endothelial cells lose their synergistic functional relationship in response to glucose levels. Therefore, our findings suggest that Ndrg1 is a key mediator of endothelial cell-mediated glycemic control of SKMPs and provides a link between systemic energy levels and the skeletal muscle stem cell niche. Lastly, I developed intravital imaging to monitor muscle stem cells and vasculature.

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