MitoQ treatment of claudication: myofiber and micro-vessel pathology

摘要 跛行是外周动脉疾病（PAD）患者最常见的临床表现， 下肢严重功能受限，被确定为步行引起的腿部肌肉疼痛， 休息许多研究已经确定了这些患者的小腿肌病。人们普遍同意 这种肌病的近因是线粒体功能失调， 对步行诱导的缺血/缺氧反复发作的反应。这些患者很少有治疗 选择，包括只有两个FDA批准的药物，喷替福林和西洛他唑，这是适度的 有效用于治疗跛行PAD患者的有希望的药物是MitoQ，其是一种抗氧化剂， 在线粒体中浓缩了几百倍。线粒体氧化应激的重要贡献 对多种病理状况的损害刺激了临床研究，这些研究发现MitoQ 安全有效。我们的研究小组记录了跛行PAD患者的行走能力改善 接受单剂量MitoQ治疗我们建议首次研究长期MitoQ的影响 治疗跛行PAD患者的肌病和功能表现。我们的假设： 使用MitoQ治疗跛行PAD患者6个月可改善1）确定的患者性能 如行走能力、日常体力活动和生活质量，2）小腿肌肉组织病理学和 病理生理学，和3）全身生理参数肺O2摄取（VO 2）和代谢 profile.这些变化与小牛肌肉线粒体氧化损伤的减少， 线粒体自噬和改善线粒体功能。我们将通过实现以下内容来测试这个假设： 具体目标。具体目标“1”将检验MitoQ 6个月方案改善的假设 性能确定为步行性能、日常体力活动和跛行PAD的生活质量 患者，与改善的小腿肌肉组织病理学和病理生理学，以及改善的VO 2和 全身代谢特征。具体目标“2”将检验MitoQ 6个月方案可降低 线粒体氧化损伤，改善线粒体自噬，并改善大量， 肌纤维-线粒体区室，这些改善与改善的性能相关， PAD患者跛行，改善小腿肌肉组织病理学和病理生理学，改善VO 2和 全身代谢特征。具体目标“3”将检验MitoQ 6个月方案 改善内皮功能和下肢血流动力学，小腿肌肉血红素氧合， 从受影响的小腿肌肉中分离的微血管的内皮依赖性血管功能 导致肢体跛行的PAD患者，与微血管线粒体功能的改善有关。 如果我们的假设是正确的，那么这项工作将支持线粒体氧化和细胞凋亡之间的因果关系。 损伤和PAD肌病以及患者的表现;并确定MitoQ是一种有前途的PAD治疗方法。

Abstract Claudication, the most common clinical presentation of patients with Peripheral Artery Disease (PAD), is a severe functional limitation of the lower extremities identified as walking-induced leg muscle pain relieved by rest. Numerous studies have identified a lower-leg myopathy in these patients. There is general agreement that the proximate cause of this myopathy is dysfunctional mitochondria which produce oxidative damage in response to repeated episodes of walking-induced ischemia/hypoxia. These patients have few therapeutic options including only two FDA approved medications, Pentoxifylline and Cilostazol, which are modestly effective. A promising medication for treatment of claudicating PAD patients is MitoQ an antioxidant that concentrates several hundred-fold in mitochondria. The significant contribution of mitochondrial oxidative damage to a wide range of pathologic conditions has stimulated clinical studies which have found MitoQ to be safe and effective. Our group has documented improved walking performance of claudicating PAD patients receiving a single dose of MitoQ. We propose to study, for the first time, the effects of long-term MitoQ treatment on the myopathy and functional performance of claudicating PAD patients. Our Hypothesis: Treatment of claudicating PAD patients with MitoQ for six months improves 1) patient performance determined as walking performance, daily physical activity, and quality of life, 2) calf muscle histopathology and pathophysiology, and 3) the systemic physiological parameters pulmonary O2 uptake (VO2) and metabolic profile. These changes correlate directly with reduced oxidative damage to calf muscle mitochondria, improved mitophagy, and improved mitochondrial function. We will test this hypothesis by implementing the following Specific Aims. Specific Aim ‘1’ will test the hypothesis that a six-month regimen of MitoQ improves performance determined as walking performance, daily physical activity, and quality of life of claudicating PAD patients, in association with improved calf muscle histopathology & pathophysiology, and improved VO2 & systemic metabolic profile. Specific Aim ‘2’ will test the hypothesis that a six-month regimen of MitoQ reduces mitochondrial oxidative damage, improves mitophagy, and improves mitochondrial function of the voluminous, myofiber-mitochondrial compartment and that these improvements correlate with improved performance of claudicating PAD patients, improved calf muscle histopathology & pathophysiology, and improved VO2 & systemic metabolic profile. Specific Aim ‘3’ will test the hypothesis that a six-month regimen of MitoQ improves endothelial function and lower extremity hemodynamics, calf muscle heme oxygenation, and endothelium-dependent vasomotor function of micro-vessels isolated from the affected calf muscle of claudicating PAD patients, in association with improved mitochondrial function of the micro-vessels. If our hypothesis is correct, the work will support a causal connection between mitochondrial oxidative damage and PAD myopathy and patient performance; and identify MitoQ as a promising treatment for PAD.