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

糖皮质激素对骨骼肌卫星细胞及其微环境的协调调节

• 批准号: 505870049
• 负责人: Professor Dr. Jan Tuckermann
• 金额: --
• 依托单位: Institut für Molekulare Endokrinologie der Tiere
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/505870049?language=en
• 关键词: Glucocorticoid; coordinated; regulation; satellite; cells

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.

肌肉损伤是一个严重的临床负担。肌肉再生涉及多种细胞类型之间的紧密调节，包括卫星细胞、免疫细胞、纤维脂肪祖细胞，以及复杂的信号通路。肌肉愈合通常发生在下丘脑-垂体-肾上腺（HPA）腺轴激活的情况下，这与糖皮质激素（GC）水平升高有关。这些激素在哺乳动物中发挥多效作用，包括控制免疫反应和代谢。它们的作用是由糖皮质激素受体（GR）介导的，其活性也可以通过合成激动剂和拮抗剂调节。因此，GR是包括过敏、哮喘和炎症性肌病在内的许多疾病的重要药物靶点。尽管对GR的病理生理功能有深入的研究，但hpa诱导的糖皮质激素介导的GR激活如何作用于肌肉修复仍知之甚少。该联盟的研究小组多年来一直在研究各种组织和细胞类型中的核受体信号的病理生理功能，包括免疫和基质细胞（小组1）和骨骼肌（小组2）。他们最近的研究使用了各种基因工程小鼠系，揭示了GCs在肌肉再生过程中影响不同的细胞类型，从而提供了机会，通过结合他们的努力，剖析潜在的复杂细胞和分子信号通路。特别是，Team 2揭示了卫星细胞的遗传GR消融会增加巨噬细胞的丰度并损害肌肉愈合。此外，Team 1发现，在GR功能受损的小鼠中，含脂细胞的数量增加，这表明GR在肌肉愈合过程中调节了纤维脂肪祖细胞的增殖和/或分化。此外，他们的初步数据显示巨噬细胞GR的丧失导致肌肉再生能力的改变。因此，这些结果表明，GR通过细胞类型特异性基因调控肌肉再生过程中卫星细胞、基质细胞和巨噬细胞的各种功能。然而，那些促进肌肉再生的和那些导致有害影响的仍然未知。德国-法国corcosat联盟将采用基于遗传学、基因组学、细胞和分子生物学的综合方法，确定肌肉再生过程中内源性GCs的靶细胞、潜在的分子事件以及这些细胞之间的相互作用。因此，从这个雄心勃勃的项目中获得的结果可能为开发改善损伤后肌肉再生的治疗策略开辟了创新的视角。