The role of mitochondrial redox stress in the impaired Nrf2 response to contraction in aged muscle

线粒体氧化还原应激在 Nrf2 对衰老肌肉收缩反应受损中的作用

• 批准号: 10544485
• 负责人: Ethan Lambert Ostrom
• 金额: $ 6.91万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10544485
• 关键词: Acceleration; Achievement; Acute; Affect; Age; Aging; Antioxidants; Attenuated; Automobile Driving; Binding; Cells; Cessation of life; Chemistry; Chronic; Chronic stress; Communication; Disease; Equilibrium; Exercise; Future; Gene Expression; Genetic Models; Glutathione Disulfide; Homeostasis; Human; Impairment; In Vitro; Individual; Intervention; Knowledge; Measures; Mitochondria; Modeling; Molecular; Mus; Muscle; Muscle Contraction; Muscle function; Organ; Organism; Oxidants; Oxidation-Reduction; Pathologic; Pathology; Pathway interactions; Performance; Pharmacologic Substance; Physiological; Process; Production; Proteins; Proteome; Proteomics; Quality of life; Reactive Oxygen Species; Research; Resolution; Response Elements; Rest; Risk; Role; SOD2 gene; Signal Pathway; Signal Transduction; Site; Skeletal Muscle; Source; Stress; Stress Response Signaling; Sulfhydryl Compounds; System; Testing; Training; Work; acute stress; age related; aged; biological adaptation to stress; cellular resilience; exercise training; functional improvement; habituation; healthspan; improved; in vivo; insight; knock-down; loss of function; mitochondrial dysfunction; muscle aging; oxidant stress; oxidation; physiologic stressor; poor health outcome; resilience; response; stress resilience; stressor; therapeutic target; transcription factor; treatment comparison; young adult

Abstract Aging is associated with impaired stress resilience defined as a loss of the ability of cells, organs, and organisms to adapt to physiological or pathological stressors. Evidence suggests that this loss of resilience arises before any overt pathology, and eventually contributes to the loss of function, disease, and death. However, the cellular mechanisms that drive this process are poorly understood. In order for cells to adapt to environmental and endogenous stressors they need to be able to communicate the stress signal through signal transduction mechanisms. However, in order for transient stress signals to be effective, they should be low under resting conditions. The Nrf2 antioxidant response element activates early changes in gene expression to enhance redox protective mechanisms in response to acute redox stress associated with muscle contraction. In healthy individuals this leads to an adaptive response to restore redox balance and increased cellular resilience to future stresses. We have found that Nrf2 is chronically activated under basal conditions and has an attenuated response to muscle contraction in human aged skeletal muscle. In addition, we have found that aging is associated with elevated reversible oxidation of the thiol proteome, a primary signal transduction mechanism driving redox adaptation, and that reducing mitochondrial redox stress restores the thiol proteome to that found in young adults. Here we hypothesize that mitochondrial redox stress in aging muscle is the chronic low-level stress that impairs the signal transduction communication in the cell underlying the impaired Nrf2 response to muscle contraction. Aim 1 tests whether decreasing mitochondrial redox stress in aged or increasing mitochondrial redox stress in young improves or impairs the Nrf2 activation to acute muscle contraction. Aim 2 tests whether the manipulation of mitochondrial redox stress and basal Nrf2 activation improves the adaptive responses to exercise training in aged mice. This research uses skeletal muscle contraction as a model to generate new insights into the molecular mechanisms underlying reduced resilience with age. A more complete mechanistic understanding of this phenomenon will provide therapeutic targets for aging and disease by identifying stressors that are necessary and sufficient to drive the aging process.

摘要 衰老与受损的压力恢复力有关，定义为细胞，器官和生物体能力的丧失 以适应生理或病理压力。有证据表明，这种恢复力的丧失发生在 任何明显的病理，并最终导致功能丧失、疾病和死亡。然而，Cellular 驱动这一过程的机制知之甚少。为了使细胞适应环境和 内源性应激源，它们需要能够通过信号转导传递应激信号 机制等然而，为了使瞬时压力信号有效，它们在休息时应该是低的 条件Nrf2抗氧化反应元件激活基因表达的早期变化以增强氧化还原 保护机制响应急性氧化还原应激与肌肉收缩。健康 这导致适应性反应，以恢复氧化还原平衡，并增加细胞对未来的适应能力。 压力我们已经发现Nrf2在基础条件下被慢性激活，并且具有减弱的 对人老年骨骼肌肌肉收缩的反应。此外，我们还发现， 与巯基蛋白质组的可逆氧化升高相关，这是一种主要的信号转导机制 驱动氧化还原适应，减少线粒体氧化还原应激使巯基蛋白质组恢复到发现的水平。 在年轻人中。在此，我们假设衰老肌肉中线粒体氧化还原应激是慢性低水平的 应激损害细胞中的信号转导通讯，该信号转导通讯是受损的Nrf2对 肌肉收缩。目的1检测是否降低老年人线粒体氧化还原应激或增加 年轻人的线粒体氧化还原应激改善或损害急性肌肉收缩的Nrf2活化。目的2 测试线粒体氧化还原应激和基础Nrf2激活的操纵是否改善了适应性 老年小鼠对运动训练的反应。这项研究使用骨骼肌收缩作为模型， 产生新的见解的分子机制的基础上减少弹性与年龄。更完整 对这一现象的机械理解将为衰老和疾病提供治疗靶点， 确定压力源是必要的和足够的驱动老化过程。