Glucocorticoid-coordinated regulation of satellite cells and their microenvironment in skeletal muscle

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Muscle injury is a severe clinical burden. Muscle regeneration involves a tight regulation between various cell types, including satellite cells, immune cells, fibroadipogenic progenitors, as well as complex signaling pathways. Muscle healing usually occurs under conditions of hypothalamus-pituitary-adrenal (HPA) gland axis activation, which is associated with increased levels of glucocorticoids (GC). These hormones exert pleiotropic effects in mammals, including the control of immune response and metabolism. Their effects are mediated by the glucocorticoid receptor (GR), the activity of which can also be modulated by synthetic agonists and antagonists. GR therefore represents an important drug target for a number of diseases, including allergies, asthma and inflammatory myopathies. Despite intensive research of GR pathophysiological functions, how HPA-induced glucocorticoid-mediated GR activation acts on muscle repair remains poorly understood. The research groups of this consortium are studying for many years the pathophysiological functions of nuclear receptor signaling in various tissues and cell-types, including immune and stromal cells (Team 1), and skeletal muscle (Team 2). Their recent studies, using various genetically engineered mouse lines, revealed that GCs impact distinct cell types during muscle regeneration, thus providing the opportunity, by combining their efforts, to dissect the underlying complex cellular and molecular signaling pathways. In particular, Team 2 revealed that genetic GR ablation in satellite cells elevates the abundance of macrophages and impairs muscle healing. Furthermore, Team 1 found that the number of lipid containing cells was increased in mice with impaired GR function, indicating that GR regulates the proliferation and/or differentiation of fibro-adipogenic progenitor cells during muscle healing. In addition, their preliminary data show that GR loss in macrophages leads to altered muscle regenerative capabilities. Thus, these results indicate that GR regulates various functions in satellite, stromal cells and macrophages during muscle regeneration through cell-type-specific gene regulations. However, those promoting muscle regeneration and those leading to detrimental effects remain unknown. The German-French CorticoSat consortium will use an integrative approach based on genetics, genomic and cellular and molecular biology, to determine the target cells of endogenous GCs during muscle regeneration, the underlying molecular events, as well as the cross-talk between these cells. Thus, the results gained from this ambitious project might open innovative perspectives to develop therapeutic strategies to improve muscle regeneration after injury.