Targeting Oxidative Stress to Prevent Vascular and Skeletal Muscle Dysfunction during Disuse

在急性住院期间停用与功能缺陷、再次住院、康复受损、 并增加了死亡率。老年人在功能性(血管和骨骼肌)方面特别脆弱 线粒体功能障碍)和结构性(肌肉质量和力量丧失)缺陷表现为 老化过程的后果。在老年人中，在废用进一步耗尽的过程中会出现加速下降 已经减弱的生理和功能储备能力。目前，骨骼肌以肌肉为中心 预防萎缩和力量丧失的策略无效，机制(S)促成 加速的损失是未知的，但似乎与氧化应激有关。因此，确定 机制(S)和制定有效的策略来减轻血管和骨骼肌功能的损失， 与机动性、疾病进展和健康有着千丝万缕联系的系统，对于延缓 残疾人权利和保护老年人的健康。我们的中心假设是氧化应激触发了 在停用期间血管和骨骼肌功能加速下降。两个新颖而根本的 提出了减少氧化应激的独特方法，包括：1)线粒体靶向抗氧化剂 (Mito-AO；目标1)和2)核因子红系2(NRF2)激活剂PB125(目标2)。共有72名健康人 年龄较大的男性和女性(65岁)将随机分成3组：对照组、Mito-AO组和PB125组。五 卧床休息的天数，一种模仿急性住院的废用模式，将被用来唤起氧化应激和 血管和骨骼肌功能丧失。在具体目标1中，参与者将获得Mito-AO(由 在卧床休息5天期间)。预计Mito-AO将减缓氧化应激的增加 通过限制线粒体衍生的活性氧(ROS)的产生，从而保护血管和 骨骼肌功能，从而揭示了线粒体来源的ROS的关键作用。在具体目标2中， 新型NRF2激活剂PB125将在卧床休息5天内使用。预计NRF2的激活 用PB125将修复衰老相关的Nrf2信号通路功能障碍所致的诱导 内源性抗氧化酶，反过来，将保持氧化还原平衡诱导的停用。初级阶段 这两个目标的结果衡量标准是通过腿部被动运动来评估血管功能。 (PLM)。次级结果衡量标准将评估氧化应激对观察到的变化的贡献 在卧床前和卧床后血管和骨骼肌功能，将包括直接测量游离 自由基，线粒体功能和过氧化氢的产生，细胞氧化应激的标志， 组织和系统水平，肌肉质量和力量的变化，以及肌肉蛋白质和基因的变化 在停用过程中可能与蛋白质分解和萎缩有机械联系的表达。

Disuse during acute hospitalization is linked to functional deficiencies, hospital readmission, impaired recovery, and increased mortality. Older adults are particularly vulnerable as functional (vascular and skeletal muscle mitochondrial dysfunction) and structural (loss in muscle mass and strength) deficits are present as a consequence of the aging process. In older adults, accelerated declines occur during disuse further depleting an already diminished physiological and functional reserve capacity. Currently, skeletal muscle-centered strategies to prevent atrophy and losses in strength are ineffective and the mechanism(s) contributing to accelerated losses are unknown, but appear to be linked to oxidative stress. Therefore, identifying the mechanism(s) and developing effective strategies to mitigate losses in vascular and skeletal muscle function, systems that are inextricably linked to mobility, disease progression, and health, is critical to delay the onset of disability and preserve the health of older adults. It is our central hypothesis that oxidative stress triggers the accelerated declines in vascular and skeletal muscle function during disuse. Two novel and fundamentally unique approaches to diminish oxidative stress are proposed including; 1) mitochondrial targeted antioxidants (MITO-AO; Aim 1) and 2) the nuclear factor erythroid-2-like 2 (Nrf2) activator, PB125 (Aim 2). A total of 72 healthy older men and women (> 65 yrs.) will be block randomized to 3 groups; CONTROL, MITO-AO, and PB125. Five days of bed rest, a model of disuse mimicking acute hospitalization, will be used to evoke oxidative stress and losses in vascular and skeletal muscle function. In Specific Aim 1, participants will receive MITO-AO (consisting of mitoquinone) during 5 days of bed rest. It is expected that MITO-AO will blunt the increase in oxidative stress by limiting mitochondrial-derived reactive oxygen species (ROS) production leading to preserved vascular and skeletal muscle function, thereby revealing a critical role of mitochondrial-derived ROS. In Specific Aim 2, the novel Nrf2 activator, PB125, will be administered during 5 days of bed rest. It is expected that activation of Nrf2 with PB125 will restore the age-related dysfunction of the Nrf2 signaling pathway resulting in the induction endogenous antioxidant enzymes that will, in turn, maintain redox balance induced by disuse. The primary outcome measure for both aims is the assessment of vascular function as measured by passive leg movement (PLM). Secondary outcomes measures will assess the contributions of oxidative stress to the observed changes in vascular and skeletal muscle function before and after bed rest and will include direct measurements of free radicals, mitochondrial function and hydrogen peroxide production, markers of oxidative stress at the cellular, tissue, and systemic levels, changes in muscle mass and strength, and changes in muscle protein and gene expression that may be mechanistically linked to proteolysis and atrophy during disuse.