Redox stress resilience in aging skeletal muscle

项目总结/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机制传递应激信号。 然而，为了使瞬时应力信号有效，它们在静息条件下应该是低的。的 转录因子Nrf 2激活基因表达的早期变化以增强氧化还原和能量适应 对与肌肉收缩相关的急性氧化还原应激的反应。在健康的个体中，这导致 适应性反应，以恢复氧化还原平衡和增加细胞对未来压力的恢复力。nrf 2是 在基础条件下被长期激活，对人体肌肉收缩的反应减弱 老化的骨骼肌此外，衰老与巯基蛋白质组的可逆氧化升高有关， 驱动氧化还原适应的主要信号传导机制，以及减少线粒体氧化还原应激 将巯基蛋白质组恢复到年轻时的水平。在这里，我们测试的假设，线粒体氧化还原应激 在老化的肌肉是慢性低水平的压力，损害了细胞中的信号转导通讯 导致对肌肉收缩的氧化还原应激反应受损。这项研究使用骨骼肌 收缩作为一个模型，以产生新的见解的分子机制降低弹性 随年龄目的1测试增加线粒体氧化还原应激是否足以驱动肌肉功能下降 通过表征新的SOD 2敲低来表达急性肌肉收缩的适应性应激反应信号 小鼠模型并将该敲低分层以测量氧化还原应激反应信号传导。目标2测试是否 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传导 通过用以下药物治疗年轻和年老的野生型小鼠以及小鼠iSOD 2 KD小鼠， mitoTEMPO或克里思作为线粒体靶向抗氧化剂对比非靶向抗氧化剂。结果 拟议的实验将通过阐明衰老中的氧化还原应激反应信号来显著影响该领域。 和年龄相关的肌肉/线粒体功能障碍。这些结果将具有明确的临床意义，因为 已经有几种具有氧化还原活性的靶向药物化合物， 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.