Mitochondrial dysfunction, oxidative damage and inflammation in claudication

描述（由申请人提供）：跛行，定义为步行引起的腿部不适和休息后缓解的步态功能障碍，影响5%的55岁以上的美国人。跛行患者采用久坐不动的生活方式，聚集在身体活动谱的极低端，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预防疾病进展。目前，康复干预侧重于血流不足作为跛行的唯一原因。手术血运重建术和/或运动治疗是主要的常规治疗方式，仅提供适度的康复效果。通过对跛行患者步态的生物力学分析，我们的团队已经获得了初步的数据，表明血流不是产生跛行肢体功能障碍的唯一机制。包括我们自己的几个实验室已经证明了一种肌病，其特征是线粒体功能障碍，氧化损伤和炎症，在跛行患者的腿部骨骼肌。这些条件还没有被量化，全面，与跛行有关，它们与跛行严重程度的关系尚不清楚。我们的假设是，血流受限并不能很好地预测跛行患者的肢体功能障碍，而肌肉线粒体功能障碍、氧化损伤和炎症是基线和常规治疗（血运重建术或监督运动）后肢体功能障碍的有力预测因素。在Aim #1下，我们将在跛行患者最初出现时获得腓肠肌线粒体功能、氧化损伤和炎症的精确测量，并将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进行评估。根据目标#2和#3，我们将评估血运重建术（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，目标2中的工作将首次明确地证明，由于动脉树阻塞导致的血流限制并不是跛行的唯一原因。目标#2和#3下的工作将确定血运重建术或运动疗法是否对跛行肌的肌病有有益的影响，并伴有肢体功能和生活质量的改善。最后，在目标#1、#2和#3下提出的研究将提供一组机制（生物能量学、氧化应激和炎症）参数的定量建模，作为跛行肢体功能客观测量和生活质量主观测量的预测因子，通常用于临床评估。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，可以进行疾病分期，以便进行最佳干预，并评估专门针对这些疾病的治疗干预措施，改善康复结果。

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.