Exercise-Associated Signaling Against CNS Aging and Alzheimer's Disease

摘要 近年来，骨骼肌作为中枢神经系统(CNS)功能的一种新的调节因子而兴起 衰老，分泌生物活性分子，即具有蛋白平衡和新陈代谢调节功能的肌动蛋白 在靶组织中，包括中枢神经系统。肌肉细胞因子的分泌被运动严重改变，这表明 外周的肌动因子信号可能是运动对大脑的保护作用的有力证据 大脑。以下研究针对肌肉蛋白平衡，这是一种在运动中高度激活的途径，作为 运动对神经认知益处的潜在新调节作用。我们最近创作了一部小说 转录因子E-B适度过表达增强肌肉蛋白稳定的转基因小鼠 (TFEB)，一个强大的细胞清除和蛋白平衡的主调节器。我们发现， 由此产生的增强的骨骼肌蛋白稳定功能可以显著改善衰老过程中的蛋白毒性 还能改善衰老小鼠的认知和记忆能力。增强肌肉蛋白质平衡的作用也降低了 斑块和tau斑块中AD相关病理标志的神经炎症和积聚 基于AD的模型。我们还发现了以前未报道的骨骼转录组的变化。 AD患者的肌肉，以及潜在的独特的骨骼肌因子群体，可能是 推动了这些中枢神经系统的好处。在这个项目中，我们将确定增强的骨骼肌蛋白平衡 促进对AD相关表型的神经保护，并使用强大的迁移学习和 计算建模方法，将允许识别和使用运动相关的循环 因素作为AD期间保护中枢神经系统功能的新的治疗干预措施。

ABSTRACT Skeletal muscle has recently arisen as a novel regulators of Central Nervous System (CNS) function and aging, secreting bioactive molecules known as myokines with proteostasis and metabolism-modifying functions in targeted tissues, including the CNS. Myokine secretion is heavily modified by exercise, suggesting that myokine signaling in the periphery may underlie the well document geroprotective benefits of exercise on the brain. The following studies address muscle proteostasis, a pathway highly activated during exercise, as a potential new regulator of the neurocognitive benefits of exercise. We have recently generated a novel transgenic mouse with enhanced muscle proteostasis via moderate overexpression of Transcription Factor E-B (TFEB), a powerful master regulator of cellular clearance and proteostasis. We have discovered that the resulting enhanced skeletal muscle proteostasis function can significantly ameliorate proteotoxicity in the aging CNS and also improve cognition and memory in aging mice. Enhancing muscle proteostasis also reduced neuroinflammation and accumulation of AD-associated pathological hallmarks in plaque based and a tau- based models of AD. We have also identified previously unreported alterations in the transcriptome of skeletal muscle from patients with AD, as well as potential unique populations of skeletal muscle factors that may be driving these CNS benefits. In this project, we will determine if enhanced skeletal muscle proteostasis promotes neuroprotection against AD-associated phenotypes, and using powerful transfer learning and computational modeling approaches, will allow for the identification and use of exercise-associated circulating factors as new therapeutic interventions for the preservation of CNS function during AD.