MitoQ treatment of claudication: myofiber and micro-vessel pathology

MitoQ 治疗跛行：肌纤维和微血管病理学

• 批准号: 10608773
• 负责人: George Pasco Casale
• 金额: $ 63.11万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-30 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10608773
• 关键词: Affect; Age; Age-Years; Agreement; Aldehydes; Antioxidants; Arteries; Brain Hypoxia-Ischemia; Cilostazol; Clinic; Clinical; Clinical Research; Cross-Over Studies; DNA; Development; Disease; Dose; Drug Targeting; Elderly; Electron Transport; Electrons; Endothelium; Exercise; FDA approved; Fibrosis; Functional disorder; Gait; Heme; Histopathology; Hydrogen Peroxide; Hydroquinones; Hydroxyl Radical; Hypoxia; Impairment; Individual; Inflammation; Inner mitochondrial membrane; Ischemia; Leg; Lipid Peroxidation; Lipids; Long-Term Effects; Lower Extremity; Lung; Measurement; Mitochondria; Molecular; Muscle; Muscle Mitochondria; Myalgia; Myopathy; NADH dehydrogenase (ubiquinone); Older Population; Oral; Oxidative Phosphorylation; Oxides; Oxygen; Pain in lower limb; Participant; Pathologic; Pathology; Patient Care; Patients; Pentoxifylline; Performance; Peripheral arterial disease; Pharmaceutical Preparations; Physical activity; Physiological; Physiology; Placebo Control; Placebos; Plasma; Production; Property; Proteins; Protocols documentation; Quality of life; Quinones; RNA; Randomized; Reactive Oxygen Species; Regimen; Rest; Succinate dehydrogenase (ubiquinone); Superoxide Dismutase; Superoxides; System; Testing; Therapeutic; Time; Unsaturated Fats; Vasomotor; Visit; Walking; Woman; Work; adduct; base; claudication; hemodynamics; improved; metabolic profile; mitochondrial membrane; oxidation; oxidative damage; pain relief; response; uptake

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.

抽象的 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，被认为是行走引起的腿部肌肉疼痛，可通过以下方法缓解 休息。大量研究已发现这些患者患有小腿肌病。有普遍共识 这种肌病的直接原因是功能失调的线粒体，它会产生氧化损伤 对步行引起的缺血/缺氧反复发作的反应。这些患者的治疗方法很少 选项仅包括两种 FDA 批准的药物，己酮可可碱和西洛他唑，这两种药物的价格适中 有效的。 MitoQ 是一种治疗跛行 PAD 患者的有前途的药物，它是一种抗氧化剂， 线粒体中浓度数百倍。线粒体氧化的重要贡献 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。我们的团队记录了跛行 PAD 患者步行能力的改善 接受单剂量 MitoQ。我们建议首次研究长期 MitoQ 的影响 对跛行 PAD 患者肌病和功能表现的治疗。我们的假设： 使用 MitoQ 治疗跛行 PAD 患者六个月可改善 1) 确定患者的表现 如步行表现、日常身体活动和生活质量，2) 小腿肌肉组织病理学和 病理生理学，3) 全身生理参数肺吸氧量 (VO2) 和代谢 轮廓。这些变化与小腿肌肉线粒体氧化损伤的减少、改善 线粒体自噬，改善线粒体功能。我们将通过实施以下内容来检验这个假设 具体目标。具体目标“1”将检验为期六个月的 MitoQ 方案改善的假设 表现确定为步行表现、日常体力活动和跛行 PAD 的生活质量 患者，与改善小腿肌肉组织病理学和病理生理学以及改善 VO2 和 全身代谢概况。具体目标“2”将检验以下假设：为期六个月的 MitoQ 方案可减少 线粒体氧化损伤，改善线粒体自噬，改善线粒体功能， 肌纤维线粒体室，这些改进与改善的性能相关 跛行 PAD 患者，改善小腿肌肉组织病理学和病理生理学，并改善 VO2 和 全身代谢概况。具体目标“3”将检验为期六个月的 MitoQ 方案的假设 改善内皮功能和下肢血流动力学、小腿肌肉血红素氧合，以及 从受影响的小腿肌肉中分离出的微血管的内皮依赖性血管舒缩功能 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，这项工作将支持线粒体氧化之间的因果关系 损伤和 PAD 肌病以及患者表现；并确定 MitoQ 是一种有前景的 PAD 治疗方法。