MitoQ treatment of claudication: myofiber and micro-vessel pathology

摘要 跛行是周围动脉疾病(PAD)患者最常见的临床表现，是一种 严重的功能受限，被认为是步行引起的腿部肌肉疼痛，通过 好好休息。许多研究都证实了这些患者的小腿肌病。大家普遍同意 这种肌病的直接原因是线粒体功能失调，它会在体内产生氧化损伤 对反复出现步行引起的缺血/缺氧的反应。这些病人几乎没有治疗方法。 选择只包括FDA批准的两种药物，己酮可可碱和西洛他唑，这两种药物都是适度的 有效。治疗跛脚垫患者的一种有前途的药物是MitoQ，一种抗氧化剂，它可以 在线粒体中浓缩几百倍。线粒体氧化的重大贡献 对一系列病理条件的损害刺激了临床研究，发现MitoQ是 安全有效。我们小组记录了跛脚垫患者行走能力的改善 接受单剂量的MitoQ治疗。我们建议第一次研究长期MitoQ的影响 跛行垫患者肌病及功能表现的治疗。我们的假设是： MitoQ治疗跛脚垫患者6个月可改善1)患者功能 作为步行能力、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；3)全身生理参数肺摄氧量(VO2)和代谢 侧写。这些变化与减少对小腿肌肉线粒体的氧化损伤直接相关，改善了 有丝分裂，并改善了线粒体功能。我们将通过实现以下内容来验证这一假设 明确的目标。《特殊目标1》将检验这一假设，即6个月的MitoQ疗法可以改善 以步行能力、日常体力活动和跛行垫的生活质量为指标的表现 患者的小腿肌肉组织病理学和病理生理学得到改善，VO2和VO2有所改善。 全身性代谢特征。《特殊目标2》将检验这样一种假设，即6个月的MitoQ疗法可以减少 线粒体氧化损伤，改善线粒体吞噬作用，改善线粒体功能， 肌纤维-线粒体间隔，这些改善与改善的性能有关 跛行垫患者，改善小腿肌肉组织病理学和病理生理学，改善VO2和 全身性代谢特征。具体目标3将检验这样一个假设，即为期6个月的MitoQ方案 改善血管内皮功能和下肢血流动力学，改善小腿肌肉血红素氧合，以及 小牛患侧肌肉微血管内皮依赖性运动功能的研究 跛行垫患者，伴有微血管线粒体功能的改善。 如果我们的假设是正确的，这项工作将支持线粒体氧化之间的因果联系 损害和PAD肌病和患者的表现；并确定MitoQ是PAD的一种有前途的治疗方法。

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.