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MitoQ treatment of claudication: myofiber and micro-vessel pathology

MitoQ 治疗跛行：肌纤维和微血管病理学

基本信息

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
项目类别：
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

项目摘要

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.

摘要