PGC-1α介导运动抗抑郁的“肌脑Crosstalk”机制研究

Exercise represents a major challenge to whole-body homeostasis provoking widespread perturbations in numerous cells, tissues, and organs that are caused by or are a response to the increased metabolic activity of contracting skeletal muscles. Recently, integrative biology of exercise has been established as a research hypothesis to explain the pathways by which multiple organ systems communicate their fitness to meet the challenge of exercise and promote the whole-body health. Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) is known as the master regulator of skeletal muscle in response to exercise. PGC-1α not only regulates metabolic and functional adaptation in skeletal muscle, but also targets brain and mediates neural resilience to stress-induced depression by modulating kynurenine metabolism and myokine secretion. In this proposal, the key scientific question is to identify whether PGC-1α mediates muscle/brain crosstalk in antidepressant effects of exercise. Based on depression models induced by chronic unpredictable mild stress (CUMS) and acute tryptophan depletion (ATD), the current project aims to compare and explore: 1) effects of skeletal muscle PGC-1α on depression-like behaviors in the CUMS/ATD-induced mice; 2) mechanisms by which PGC-1α regulates tryptophan metabolism (KYN), proinflammatory cytokines (CK), and brain-derived neurotrophic factor (BDNF) in pathogenesis of depression; 3) effects of skeletal muscle PGC-1α on antidepressant actions of exercise and potential mechanisms. Further, we will explore the effects of muscle-derived PGC-1α on hippocampal neurogenesis and synaptic plasticity in the condition of co-cultured with C2C12 cells. The findings are supposed to better understand the beneficial effects of exercise on brain function, and suggest new targets for different types of depression such as CUMS/ATD-induced disorders and personalized exercise intervention of depression.

过氧化物酶体增殖物激活受体γ共激活因子1α（PGC-1α）是骨骼肌最重要的运动应答基因。PGC-1α表达不仅调控骨骼肌本身的代谢与功能适应，也能通过肌肉代谢物与活性分子的释放，作用于脑组织参与神经保护机制。本项目的核心问题是：骨骼肌PGC-1α是否作为运动敏感基因通过某种途径作用于脑，介导运动的抗抑郁作用？拟通过慢性不可预见性温和应激和急性色氨酸耗竭两种抑郁动物模型，比较：1）骨骼肌PGC-1α对抑郁行为的影响；2）骨骼肌PGC-1α对犬尿氨酸代谢、促炎性细胞因子、脑源性神经营养因子的调控作用，及其介导抑郁行为的可能机制；3）骨骼肌PGC-1α缺失对运动抗抑郁的行为学影响及机制。通过C2C12细胞共培养，探讨肌源性PGC-1α对海马神经元发生与突触可塑性的影响，辅证骨骼肌PGC-1α介导运动抗抑郁的“肌脑Crosstalk”机制。旨在针对不同病因所致的抑郁症提出运动干预策略和科学理论。

运动整合生物学认为，为应对运动挑战，多层次的整合和应答为机体建立一个新的动态平衡以提高肌肉能量和氧气供应，这种系统稳态的扰乱及其重塑不仅惠及骨骼肌本身，还给人体多个器官和系统带来了积极效应。基于整合生物学研究视角，本项目通过采用慢性不可预见性温和应激（CUMS）模型、基因敲除小鼠模型及快速色氨酸衰竭模型（SATD）探究不同的分子信号通路在运动的抗抑郁机制中的作用，这可为“运动健脑”有关研究提供一种具有启发性的探索思路和阐释方法。具体包括：.1）建立SATD模型，探究骨骼肌PGC-1α介导的运动抗抑郁效应及分子信号通路。本部分主要采取运动预适应的干预方式，利用PGC-1α激动剂和拮抗剂检验PGC-1α及下游分子（NF-κB、FNDC5/CREB/BDNF）表达情况，进一步阐明PGC-1α介导的信号通路在运动预适应抵抗抑郁行为中的分子机制。.2）探究运动干预CUMS模型和ASMT基因敲除模型小鼠抑郁行为的生物学机制。利用CUMS模型发现了胰高血糖素样肽-1（GLP-1）可能是介导运动联合二甲双胍药物干预抑郁行为小鼠的重要靶点。基于ASMT基因多态性与人类抑郁症的相关性，本项目还构建了ASMT基因敲除小鼠模型，发现了ASMT基因缺失造成小鼠的抑郁倾向且能被运动所改善的表型。.3）通过组学技术初步构建“肌脑 Crosstalk”的分子网络。为了系统地阐述运动对抑郁行为的干预机制，利用目前较成熟的各类组学技术挖掘运动在mRNA、miRNA、蛋白质组、代谢层面的信号靶点和信号通路，初步阐释了“肌脑 Crosstalk”的介导分子及调节网络。