Mitochondrial dysfunction, oxidative damage and inflammation in claudication

跛行时的线粒体功能障碍、氧化损伤和炎症

• 批准号: 7987752
• 负责人: Iraklis Ilias Pipinos
• 金额: $ 108.47万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-15 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7987752
• 关键词: Adopted; Affect; Age-Years; American; Arterial Occlusive Diseases; Arteries; Arts; Atherosclerosis; Biochemical; Bioenergetics; Biomechanics; Biopsy; Blood flow; Caring; Characteristics; Clinical; Clinical assessments; Complex; Data; Diagnosis; Disease; Disease Progression; Elderly; Evaluation; Event; Exercise; Fibrinogen; Functional disorder; Future; Gait; Gait abnormality; Gangrene; Gastrocnemius Muscle; Generations; Goals; Health; Impairment; Individual; Inflammation; Intermittent Claudication; Intervention; Ischemia; Laboratories; Laboratory Study; Leg; Life Style; Limb structure; Lower Extremity; Magnetic Resonance; Measurement; Measures; Metabolic; Mitochondria; Modality; Modeling; Muscle; Myalgia; Myopathy; Needle biopsy procedure; Older Population; Outcome; Oxidative Stress; Oxygen; Pain; Patients; Perfusion; Peripheral arterial disease; Phosphorus; Physical activity; Physical therapy exercises; Physiology; Positioning Attribute; Prevention; Procedures; Proteomics; Protocols documentation; Publications; Quality of life; Reactive Oxygen Species; Regimen; Rehabilitation therapy; Residual state; Rest; Risk; Series; Severities; Skeletal Muscle; Specimen; Staging; Staging System; Symptoms; System; Therapeutic; Therapeutic Intervention; Time; Trees; Vascular blood supply; Walking; Work; aggressive therapy; base; claudication; clinical care; cohort; conventional therapy; disability; experience; gait examination; hemodynamics; improved; mitochondrial dysfunction; novel diagnostics; operation; oxidative damage; programs; public health relevance; restoration; sedentary; skeletal; tool; treatment strategy

DESCRIPTION (provided by applicant): Claudication, defined as walking-induced leg discomfort and gait dysfunction relieved by rest, affects 5% of Americans over 55 years of age. Claudicating patients adopt sedentary lifestyles and cluster at the extreme low end of the physical activity spectrum, escalating risk for adverse health effects. The primary therapeutic goals for claudicating patients are restoration of leg function and prevention of disease progression. Current, rehabilitative interventions focus on inadequate blood flow as the only cause of claudication. Operative revascularization and/or exercise therapy are the principal conventional therapeutic modalities, providing only modest rehabilitative benefit. Applying biomechanical analysis to gait of claudicating patients, our team has developed preliminary data indicating that blood flow is not the only mechanism producing the limb dysfunction of claudication. Several laboratories including our own have demonstrated a myopathy, characterized by mitochondrial dysfunction, oxidative damage and inflammation, in leg skeletal muscle of claudicating patients. These conditions have not been quantified, comprehensively, in relation to claudication, and their association with severity of claudication is not known. Our hypothesis is that blood flow restriction is not a good predictor of limb dysfunction in claudication, whereas muscle mitochondrial dysfunction, oxidative damage and inflammation are strong predictors of limb dysfunction both at baseline and after conventional therapy with revascularization or supervised exercise. Under Aim #1, we will acquire precise measurements of gastrocnemius mitochondrial function, oxidative damage and inflammation in claudicating patients, at the time of their initial presentation, and evaluate these measurements as predictors of objective measures of limb function and subjective measures of quality of life. Under Aims #2 and #3, we will evaluate the effects of revascularization (Aim#2) and supervised exercise therapy (Aim#3) on mitochondrial dysfunction, oxidative damage and inflammation in claudicating gastrocnemius and on objective measures of limb function and subjective measures of quality of life. If our hypothesis is correct, the work in Aim #2 will for the first time definitively demonstrate that blood flow restriction due to blockages in the arterial tree is not the only cause of claudication. The work under Aims #2 and #3 will determine whether revascularization or exercise therapy has a beneficial effect on the myopathy of claudicating muscle with associated improvement in limb function and quality of life. Finally, the proposed studies under Aims #1, #2 and #3 will provide quantitative modeling of a panel of mechanistic (bioenergetics, oxidative stress and inflammation) parameters as predictors of objective measurements of claudicating limb function and subjective measures of quality of life commonly used for clinical assessment. Measurements of gastrocnemius mitochondrial function, oxidative damage and inflammation may be useful tools that permit staging of disease for optimum intervention and evaluation of therapeutic interventions that specifically target these conditions, improving rehabilitative outcomes. PUBLIC HEALTH RELEVANCE: Intermittent claudication afflicts 5% of the US population older than 55 years of age and develops along with hardening of the arteries of the legs. Claudicating patients limp and can only walk very short distances because their legs hurt. Our protocol evaluates the mechanisms that may produce the leg dysfunction of claudication and its successful completion can ultimately produce significant new diagnostic and treatment strategies for the care of claudicating patients.

描述(申请人提供)：跛行，定义为行走引起的腿部不适和通过休息缓解的步态障碍，影响5%的55岁以上的美国人。克洛德氏症患者采取久坐不动的生活方式，并聚集在体力活动谱的极低端，增加了对健康不利影响的风险。跛行患者的主要治疗目标是恢复腿部功能和防止疾病进展。目前，康复干预的重点是血流不足，这是跛行的唯一原因。手术血管重建术和/或运动疗法是主要的传统治疗方法，仅提供适度的康复益处。通过对跛行患者的步态进行生物力学分析，我们的团队获得了初步的数据，表明血流并不是导致跛行的肢体功能障碍的唯一机制。包括我们自己的实验室在内的几个实验室已经证明，跛行患者的腿部骨骼肌存在以线粒体功能障碍、氧化损伤和炎症为特征的肌病。这些情况还没有被全面地量化，与跛行有关，它们与跛行的严重程度的联系也不清楚。我们的假设是，血流受限不是跛行时肢体功能障碍的良好预测指标，而肌肉线粒体功能障碍、氧化损伤和炎症是肢体功能障碍的强大预测指标，无论是在基线还是在常规血运重建或监督运动治疗后都是如此。在目标1下，我们将获得在跛行患者最初出现时对腓肠肌线粒体功能、氧化损伤和炎症的准确测量，并评估这些测量作为肢体功能客观测量和生活质量主观测量的预测指标。在目标2和目标3下，我们将评估血运重建(目标2)和监督运动疗法(目标3)对跛行腓肠肌线粒体功能障碍、氧化损伤和炎症的影响，以及对肢体功能的客观测量和生活质量的主观测量的影响。如果我们的假设是正确的，AIM#2的工作将第一次明确地证明，动脉树堵塞导致的血流限制并不是跛行的唯一原因。AIMS#2和AIMS#3下的工作将确定血运重建或运动疗法是否对跛行肌肉的肌病具有有益的效果，并相关地改善肢体功能和生活质量。最后，根据AIMS#1、#2和#3建议的研究将提供一组机械学(生物能量学、氧化应激和炎症)参数的定量建模，作为临床评估常用的跛行肢体功能的客观测量和生活质量的主观测量的预测因子。对腓肠肌线粒体功能、氧化损伤和炎症的测量可能是有用的工具，可以为疾病分期提供最佳干预，并评估专门针对这些情况的治疗干预措施，以改善康复结果。 与公共卫生相关：间歇性跛行困扰着5%的55岁以上的美国人口，并伴随着腿部动脉的硬化而发展。克劳迪奇患者一瘸一拐的，因为腿疼，只能走很短的距离。我们的方案评估了可能导致跛行的腿功能障碍的机制，它的成功完成最终可以为跛行患者的护理产生重要的新的诊断和治疗策略。