Redox stress resilience in aging skeletal muscle

项目摘要/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。使细胞适应环境和内源性 压力源他们需要能够通过信号转导机制传达压力信号。 然而，为了使瞬时应力信号有效，它们在静止条件下应该是低的。这个 转录因子Nrf2激活基因表达的早期变化以增强氧化还原和能量适应 以应对与肌肉收缩相关的急性氧化还原应激。对于健康的人来说，这会导致 适应性反应，以恢复氧化还原平衡和提高细胞对未来压力的弹性。NRF2是 在基础条件下慢性激活，对肌肉收缩的反应减弱 衰老的骨骼肌。此外，衰老与硫醇蛋白质组的可逆氧化有关，a 驱动氧化还原适应的主要信号转导机制，以及减少线粒体氧化还原应激的信号转导机制 将硫醇蛋白质组恢复到在Young中发现的蛋白质组。在这里，我们检验了线粒体氧化还原应激的假设 在衰老的肌肉是慢性低水平的应激，它损害了细胞内的信号转导通讯 肌肉收缩导致氧化还原应激反应受损。这项研究使用了骨骼肌 收缩作为一种模型，对导致弹性降低的分子机制产生新的见解 随着年龄的增长。Aim 1测试增加线粒体氧化还原应激是否足以导致肌肉功能下降 以及通过表征一种新的SOD2基因敲除来对急性肌肉收缩发出适应性应激反应信号 小鼠模型和分层这种敲除来测量氧化还原应激反应信号。AIM 2测试 减少线粒体或细胞质氧化还原应激足以恢复适应性应激反应信号 对幼龄和老年野生型小鼠以及iSOD2KD小鼠的急性肌肉收缩作用 MitoTEMPO或TEMPO作为线粒体靶向抗氧化剂与非靶向抗氧化剂。调查结果： 拟议中的实验将通过阐明衰老中的氧化还原应激反应信号对该领域产生重大影响 以及与年龄相关的肌肉/线粒体功能障碍。这些结果将具有明确的临床意义，因为有 已经有几种线粒体靶向的药理化合物具有氧化还原活性，可以在 人类。

PROJECT SUMMARY/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. For cells to adapt to environmental and endogenous stressors they need to be able to communicate the stress signal through signal transduction mechanisms. However, for transient stress signals to be effective, they should be low under resting conditions. The transcription factor Nrf2 activates early changes in gene expression to enhance redox and energetic adaptations 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. Nrf2 is chronically activated under basal conditions and has an attenuated response to muscle contraction in human aged skeletal muscle. In addition, 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. Here we test the hypothesis 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 redox stress response to muscle contraction. This research uses skeletal muscle contraction as a model to generate new insights into the molecular mechanisms underlying reduced resilience with age. Aim 1 tests whether increasing mitochondrial redox stress is sufficient to drive declining muscle function and adaptive stress response signaling to acute muscle contraction by characterizing a novel SOD2 Knockdown mouse model and layering this knockdown to measure redox stress response signaling. Aim 2 tests whether decreasing mitochondrial or cytoplasmic redox stress is sufficient to restore adaptive stress response signaling to acute muscle contraction by treating young and old wild type mice as well as mice iSOD2 KD mice with mitoTEMPO or TEMPO as mitochondrial targeted antioxidant vs a non targeted antioxidant. Results from the proposed experiments will significantly impact the field by elucidating redox stress response signaling in aging and age-related muscle/mitochondrial dysfunction. These results will have clear clinical significance as there are already several mitochondrially targeted pharmacological compounds that are redox active and can be tested in humans.