Stem Cell Dysfunction in Aged Skeletal Muscle

摘要 衰老生物学中最大的谜团之一是理解为什么我们身体中的许多组织和器官， 包括骨骼肌，随着年龄的增长，功能会衰退吗？最近的研究表明，没有能力 肌肉干细胞(MuSCs)在创伤后开启修复程序是导致 观察老年人的肌肉质量和力量。然而，鉴于驱动MSC进入 再生状态仍然是一个谜，即使在年轻人，我们几乎没有治疗选择 在临床上增强老化的骨髓间充质干细胞的修复潜力。为了解决这一未得到满足的需求，我的实验室最近 在转录因子FBJ的驱动下，发现了一种新的“超级治愈”成人干细胞激活程序 骨肉瘤癌基因(FOS)，加速成人干细胞激活，增强肌肉修复。 有趣的是，在成年MuSCs中，fos的一个关键下游靶基因是消耗NAD的细胞表面 酶，ADP-核糖基转移酶1(Art1)，它附着着一个未被研究的翻译后修饰 (PTM)，单-ADP-核糖基化(MAR化)，到蛋白质底物。令人兴奋的是，我们的初步数据显示 在衰老的MUSCs中，Fos/Art1-MAR化途径被破坏，因此，代表了 降低衰老骨骼肌再生潜力的最早的分子改变。因此，在这方面 建议，我们将检验FOS/AP-1组织再生程序(包括Art1)的假设 途径)在衰老的骨骼肌中被错误调节，触发一连串的分子事件，抑制茎 细胞激活潜能，并导致骨骼肌随年龄增长而逐渐恶化；以及 最重要的是，这种分子功能障碍的逆转将纠正干细胞的激活和 在衰老的骨骼肌中出现的再生缺陷。在Aim1中，我们将确定表达模式和 Fos/AP-1基因靶点在成人和老年间充质干细胞中的功能意义在AIM2中，我们将确定 新发现的表达动力学、功能要求和MAR化蛋白底物 成人和老年间充质干细胞中NAD/Art1-MAR化干细胞激活途径的研究总体而言，这项工作将 重点介绍一条新的FOS/NAD/Art1-MAR化干细胞激活途径，该途径在很大程度上被 衰老生物学到目前为止，其进一步的研究将为改善肌肉开辟新的治疗途径 老年人口的健康状况。

Abstract One of the greatest mysteries in ageing biology is to understand why many tissues and organs in our body, including skeletal muscle, decline in function as we get older? Recent studies suggest that the inability of muscle stem cells (MuSCs) to turn on the repair program after trauma is a major factor leading to the loss of muscle mass and strength observed in the elderly. However, given that the signals driving MuSCs into the regenerative state remains a mystery even in young adults, we are left with virtually no therapeutic options for boosting the repair potential of aging MuSCs in the clinic. To address this unmet need, my laboratory recently discovered a new “Super-Healing” adult stem cell activation program, driven by the transcription factor, FBJ osteosarcoma oncogene (FOS), that speeds up adult stem cell activation and enhances muscle repair. Intriguingly, a key downstream target gene of FOS in adult MuSCs is the NAD-consuming, cell surface enzyme, ADP-Ribosyl-Transferase 1 (Art1), which attaches an understudied post-translational modification (PTM), mono-ADP-Ribosylation (MARylation), to protein substrates. Excitingly, our preliminary data suggests that the FOS/ART1-MARylation pathway is disrupted in aged MuSCs, and thus, representing one of the earliest molecular alterations that diminish the regenerative potential of aged skeletal muscle. Thus, in this proposal, we will test the hypothesis that the FOS/AP-1 tissue regenerative program (including the ART1 pathway) is mis-regulated in aged skeletal muscle, triggering a cascade of molecular events that dampen stem cell activation potential and lead to the progressive deterioration of skeletal muscle with increasing age; and most importantly, that reversal of this molecular dysfunction will correct the stem cell activation and regenerative deficits seen in aged skeletal muscle. In Aim1, we will determine the expression patterns and functional significance of FOS/AP-1 gene targets in adult and aged MuSCs. In Aim2, we will determine the expression dynamics, functional requirements, and MARylated protein substrates of the newly discovered NAD/ART1-MARylation stem cell activation pathway in adult and aged MuSCs. Collectively, this work will highlight a new FOS/NAD/ART1-MARylation stem cell activation pathway that has been largely ignored in aging biology until now and whose further study will open new therapeutic avenues for improving muscle health in the elderly population.