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.

项目概要/摘要 衰老与应激恢复能力受损有关，应激恢复能力被定义为细胞、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，这种弹性丧失发生在 任何明显的病理，并最终导致功能丧失、疾病和死亡。然而，蜂窝 人们对驱动这一过程的机制知之甚少。使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压力信号。 然而，为了使瞬态压力信号有效，它们在休息条件下应该很低。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 响应与肌肉收缩相关的急性氧化还原应激。在健康个体中，这会导致 恢复氧化还原平衡并增强细胞对未来压力的适应能力的适应性反应。 Nrf2 是 在基础条件下长期激活，对人体肌肉收缩的反应减弱 老化的骨骼肌。此外，衰老与硫醇蛋白质组的可逆氧化升高有关，硫醇蛋白质组是一种 驱动氧化还原适应并减少线粒体氧化还原应激的主要信号转导机制 将硫醇蛋白质组恢复到年轻人的水平。在这里我们检验线粒体氧化还原应激的假设 老化肌肉中的慢性低水平压力会损害细胞内的信号转导通讯 肌肉收缩的氧化还原应激反应受损。这项研究使用骨骼肌 收缩作为模型，可以对弹性降低的分子机制产生新的见解 随着年龄的增长。目标 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 通过表征新型 SOD2 敲低来向急性肌肉收缩发出适应性应激反应信号 小鼠模型并对这种敲低进行分层以测量氧化还原应激反应信号。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 通过治疗年轻和年老的野生型小鼠以及 iSOD2 KD 小鼠来治疗急性肌肉收缩 mitoTEMPO 或 TEMPO 作为线粒体靶向抗氧化剂与非靶向抗氧化剂。结果来自 拟议的实验将通过阐明衰老过程中的氧化还原应激反应信号来对该领域产生重大影响 和与年龄相关的肌肉/线粒体功能障碍。这些结果将具有明确的临床意义，因为 已经有几种靶向线粒体的药理化合物具有氧化还原活性，可以在 人类。