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: 10311399
• 负责人: Ethan Lambert Ostrom
• 金额: $ 6.56万
• 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/10311399
• 关键词: role; mitochondrial; redox; stress; impaired

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.

抽象的 衰老与压力弹性受损相关，定义为细胞，器官和生物的能力的丧失 适应生理或病理压力。有证据表明，这种弹性丧失之前出现 任何明显的病理，最终导致功能，疾病和死亡的丧失。但是，细胞 推动这一过程的机制知之甚少。为了使细胞适应环境和 内源性应力源，他们需要能够通过信号转导传达应力信号 机制。但是，为了使瞬态应力信号有效，应在休息下较低 状况。 NRF2抗氧化剂反应元件激活基因表达的早期变化，以增强氧化还原 响应与肌肉收缩相关的急性氧化还原应激的保护机制。健康 个体这会导致对恢复氧化还原平衡和对未来的蜂窝弹性提高的自适应反应 压力。我们发现NRF2在基础条件下长期激活，并且衰减 对人老年骨骼肌的肌肉收缩的反应。此外，我们发现衰老是 与硫醇蛋白质组的可逆氧化升高有关，这是一种主要信号转导机制 驱动氧化还原适应，减少线粒体氧化还原应力将硫醇蛋白质组恢复到发现的硫醇蛋白质组 在年轻人中。在这里，我们假设衰老肌肉中的线粒体氧化还原应激是慢性低级 损害NRF2响应受损的细胞中信号转导通信的压力 肌肉收缩。 AIM 1测试是减少老化或增加的线粒体氧化还原应激 幼年中的线粒体氧化还原应激改善或损害NRF2激活急性肌肉收缩。目标2 测试线粒体氧化还原应力和基础NRF2激活的操纵是否改善了自适应 对老年小鼠运动训练的反应。这项研究使用骨骼肌收缩作为模型 对降低弹性随着年龄的弹性的分子机制产生新的见解。更完整 对这种现象的机械理解将为衰老和疾病提供治疗靶标 识别所需和足够的压力源以推动衰老过程。