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

摘要 衰老与应激韧性受损有关，其定义为细胞、器官和生物体能力的丧失 适应生理或病理应激源。有证据表明，这种韧性的丧失出现在 任何明显的病理，并最终导致功能丧失、疾病和死亡。然而，蜂窝 人们对推动这一过程的机制知之甚少。为了让细胞适应环境和 内源性应激源需要能够通过信号转导传递应激信号 机械装置。然而，为了使瞬时应力信号有效，它们在静止状态下应该是低的 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 与肌肉收缩相关的急性氧化还原应激反应的保护机制。在健康中 这会导致适应性反应，以恢复氧化还原平衡并提高细胞对未来的适应能力 压力。我们发现，Nrf2在基础条件下被长期激活，并具有减弱的 人类老年骨骼肌对肌肉收缩的反应。此外，我们还发现，衰老是 与硫醇蛋白质组的可逆氧化增加有关，这是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压力使硫醇蛋白质组恢复到已发现的水平 在年轻人身上。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水平的。 损害NRF2反应受损的细胞内的信号转导通讯的应激 肌肉收缩。Aim 1测试老年或增龄者线粒体氧化还原应激程度是否降低 年轻时线粒体氧化还原应激可促进或削弱Nrf2对急性肌肉收缩的激活。目标2 测试线粒体氧化还原应激和基础Nrf2激活的操作是否改善了适应性 老年小鼠对运动训练的反应。这项研究以骨骼肌收缩为模型， 对随年龄增长弹性降低的分子机制产生新的见解。一个更完整的 从机制上理解这种现象将通过以下方式为衰老和疾病提供治疗靶点 找出推动衰老过程的必要和充分的压力源。

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.