Redox stress resilience in aging skeletal muscle

衰老骨骼肌的氧化还原应激恢复能力

• 批准号: 10722970
• 负责人: David J. Marcinek
• 金额: $ 48.54万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10722970
• 关键词: Ablation; Acute; Age; Aging; Animal Feed; Antioxidants; Attenuated; Automobile Driving; Binding; Biological; Cells; Cessation of life; Chronic; Communication; Cytoplasm; Development; Diet; Disease; Doxycycline; Equilibrium; Exercise; Functional disorder; Future; Gene Expression; Genetic Models; Homeostasis; Human; Impairment; Individual; Knowledge; MAP Kinase Gene; Measures; Messenger RNA; Mitochondria; Modeling; Molecular; Mus; Muscle; Muscle Contraction; Muscle function; Organ; Organism; Oxidants; Oxidation-Reduction; Pathologic; Pathology; Pathway interactions; Phosphotransferases; Physiological; Process; Production; Proteins; Proteome; Quality of life; Reactive Oxygen Species; Research; Resolution; Resources; Rest; Risk; Role; SOD2 gene; Signal Induction; Signal Transduction; Skeletal Muscle; Source; Stress; Stress Response Signaling; Sulfhydryl Compounds; Testing; Time; Tissues; Transgenic Organisms; Wild Type Mouse; Work; acute stress; age related; aged; biological adaptation to stress; cellular resilience; clinically significant; experimental study; functional decline; functional improvement; habituation; healthspan; improved; in vivo; insight; knock-down; loss of function; mitochondrial dysfunction; mouse model; muscle aging; novel; oxidant stress; oxidation; p38 Mitogen Activated Protein Kinase; pharmacologic; physiologic stressor; poor health outcome; protein expression; resilience; response; small hairpin RNA; stress resilience; stressor; tool; transcription factor

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.

项目摘要/摘要 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。细胞适应环境和内源性 他们需要能够通过信号转导机制传达应力信号。 但是，为了使瞬态应力信号有效，它们在静止条件下应较低。这 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 响应与肌肉收缩有关的急性氧化还原应激。在健康的个体中，这导致了 对恢复氧化还原平衡的适应性反应，并增加了对未来应力的细胞弹性。 NRF2是 长期在基础条件下激活，对人的肌肉收缩有衰减的反应 老化的骨骼肌。此外，衰老与硫醇蛋白质组的可逆氧化升高有关 主要信号转导机制驱动氧化还原适应，并减少线粒体氧化还原应激 将硫醇蛋白质组恢复到年轻人中发现的硫醇蛋白质组。在这里，我们测试了线粒体氧化还原应激的假设 在衰老的肌肉中是慢性低水平应力，会损害细胞中信号转导通信 氧化还原应力反应对肌肉收缩的基础。该研究使用骨骼肌肉 收缩作为模型，以产生对降低弹性的分子机制的新见解 随着年龄的增长。 AIM 1测试线粒体氧化还原胁迫是否足以驱动肌肉功能下降 通过表征新的SOD2敲低，以及对急性肌肉收缩的自适应应力反应信号传导 小鼠模型并分层此敲低以测量氧化还原应力响应信号传导。 AIM 2测试是否 线粒体或细胞质氧化还原应激的减小足以恢复适应性应力响应信号传导 通过治疗年轻和老年野生型小鼠以及ISOD2 kD小鼠的急性肌肉收缩 线粒体靶向抗氧化剂与非靶向抗氧化剂作为线粒体靶向抗氧化剂。结果 提出的实验将通过阐明衰老中的氧化还原应力响应信号来显着影响该领域 和与年龄有关的肌肉/线粒体功能障碍。这些结果将具有明显的临床意义 已经有几种具有氧化还原活性的线粒体靶向药理学化合物，可以在 人类。