Apelin Signaling in Muscle Regeneration

摘要：Apelin信号通路在肌肉再生和恢复活力中的作用 少年派：玛德兰·罗曼 细胞外信号和细胞间通讯失调如何影响衰老过程中的组织稳态 人们对此仍然知之甚少。年龄相关的肌肉疾病--骨质疏松症--影响着超过60%的人 80岁以上，导致行动不便，死亡风险显著增加。识别 骨质疏松症病因学中涉及的失调生物机制是开发治疗方法的关键 限制肌肉萎缩的治疗方法。最近，apelin多肽的表达已经显示出下降。 随着年龄的增长，与肌肉组织的炎症、衰老和退化增加相关。 有趣的是，使用apelin多肽治疗可以改善老年人的肌肉再生和肌肉功能。 动物，表明在肌肉再生和恢复活力中发挥作用。然而，分子和细胞 Apelin功能的潜在机制很大程度上是未知的，并且依赖于Apelin的细胞串扰 肌肉干细胞(MUSC)、内皮细胞和免疫细胞之间的相互作用 再生是没有特征的。以斑马鱼为模型系统，我们将结合新颖的 进行APELIN功能研究和使用的最新药物遗传学方法 单细胞RNA测序以确定限制衰老影响的apelin下游效应器。我们 建议测试apelin作为抗衰老和促进再生的信号肽和解密细胞的功能 Apelin在肌肉老化和再生过程中的特定功能类型。这个Cobre项目包括两个 明确的目标。在第一个目标中，我们将使用最近发现的apelin受体的化学激动剂 和新产生的Cre/Lox斑马鱼转基因株系以确定慢性和遗传诱导 肌源性APELIN影响肌肉老化的特征(萎缩、衰老、炎症…)。小说 CRISPR/Cas-9斑马鱼突变体还将允许测试apelin受体激活在 MUSC、内皮细胞和巨噬细胞在肌肉过程中破译细胞类型特异性apelin的功能 老化和再生。使用最先进的单细胞rna测序技术，Aim 2将揭示一组基因 调节损伤后骨髓间充质干细胞向增殖的转化。利用apelin受体突变鱼， 这一转录分析也应该有助于鉴定apelin的再生因子。 在MUSC依赖的再生反应中的作用。成功完成这些目标将定义角色 在肌肉衰老过程中多种不同细胞类型的apelin信号，揭示了分子和细胞 治疗目标是缓解或逆转与年龄相关的石棺减少症。

Abstract: Apelin Signaling Pathway In Muscle Regeneration And Rejuvenation PI: Madelaine Romain How extracellular signals and cell-to-cell communication dysregulation affect tissue homeostasis during aging are still poorly understood. The age associated muscle disease, sarcopenia, affects more than 60% of people over 80 years of age and results in mobility disorders and a significantly increased risk of mortality. Identifying dysregulated biological mechanisms involved in the etiology of sarcopenia is critical to develop therapeutic treatments to limit muscle atrophy. Recently, the expression of the apelin peptide has been shown to decline with age, correlating with an increased inflammation, senescence, and degeneration of the muscle tissue. Interestingly, treatments with the apelin peptide improve muscle regeneration and muscular function in aged animals, indicating a role in muscle regeneration and rejuvenation. However, the molecular and cellular mechanisms underlying apelin function are largely unknown, and the apelin dependent cellular crosstalk between muscle stem cells (MuSC), endothelial cells, and immune cells contributing to enhanced muscle regeneration are uncharacterized. Using the zebrafish as a model system, we will combine novel pharmacological genetic approaches to perform state of the art apelin loss and gain of function studies and use single cell RNA sequencing to identify downstream effectors of apelin that limit the impacts of aging. We propose to test the function of apelin as an anti-aging and pro-regenerative signaling peptide and decipher cell type specific functions of apelin during muscle aging and regeneration. This COBRE project includes two specific aims. During the first aim, we will use a recently discovered chemical agonist of the apelin receptors and newly generated Cre/Lox zebrafish transgenic lines to determine how chronic and genetically-induced muscle-derived apelin affects the hallmarks of muscle aging (atrophy, senescence, inflammation…). Novel CRISPR/Cas-9 zebrafish mutants will also us allow to test the function of the apelin receptor activation in MuSC, endothelial cells and macrophages to decipher the cell type-specific apelin functions during muscle aging and regeneration. Using state of the art single cell RNA-sequencing, aim 2 will reveal a set of genes regulating MuSC transition into proliferation after injury. Taking advantage of the apelin receptors mutant fish, this transcriptomic analysis should also lead to the identification of regenerative factors underlying apelin functions in MuSC-dependent regenerative response. Successful completion of these aims will define the role of the apelin signaling in multiple different cell types during muscle aging and reveal molecular and cellular therapeutic targets to alleviate or reverse age-associated sarcopenia.