Novel gastrocnemius muscle characteristics in peripheral artery disease patients associated with impaired functional performance

外周动脉疾病患者腓肠肌的新特征与功能表现受损相关

• 批准号: 10544314
• 负责人: Kate Kosmac
• 金额: $ 31.09万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10544314
• 关键词: Affect; Aging; Ankle; Area; Atrophic; Autophagocytosis; Biogenesis; Biological Markers; Biological Process; Biological Specimen Banks; Biopsy; Blood flow; Characteristics; Classification; Clinical; Clinical Trials; Data; Defect; Denervation; Development; Diagnosis; Diagnostic; Disease; Disease Progression; Effectiveness; Fiber; Foundations; Future; Gastrocnemius Muscle; Goals; Grouping; Impairment; Individual; Injury; Intervention; Ischemia; Lower Extremity; Measures; Medical; Mitochondria; Modeling; Morphology; Motor Neurons; Muscle; Muscle Fibers; Myopathy; Myosin Heavy Chains; Myosin Type I; NCAM1 gene; Outcome; Oxidative Stress; Participant; Pathology; Patients; Performance; Perfusion; Peripheral arterial disease; Persons; Phase; Population; Property; Proteins; Reperfusion Injury; Reperfusion Therapy; Reporting; Sampling; Severity of illness; Skeletal Muscle; Testing; Theoretical model; Training; Walking; biobank; cohort; coping; disability; efficacious intervention; exercise intervention; follow-up; functional decline; functional disability; functional improvement; functional outcomes; improved; indexing; mitochondrial autophagy; mitochondrial dysfunction; novel; oxidative damage; pharmacologic; predictive modeling; preservation; prevent; reinnervation; response; tool

Lower extremity peripheral artery disease (PAD) significantly affects aging populations and results in functional impairment. Although the clinical importance of finding efficacious interventions for PAD is well-recognized, few medical therapies are currently available. PAD is diagnosed using the ankle brachial index (ABI), a measure of blood flow to the lower extremities. Lower ABI is associated with worse function; however, low ABI alone cannot fully explain functional impairments in PAD. Small studies have reported oxidative stress, mitochondrial dysfunction and/or fiber damage in gastrocnemius muscle biopsies from PAD patients, suggesting skeletal muscle perturbations may contribute to functional decline. We reported highly variable fiber type composition and fiber type grouping in a small cohort of PAD patients, and observed lack of intermyofibrillar mitochondria (IMFM-) in oxidative, myosin heavy chain (MyHC) type I fibers. We have provocative new preliminary data suggesting variability in response to ongoing denervation, and in fiber type and mitochondrial adaptations, with PAD. The purpose of this study is to define specific characteristics of muscle in PAD associated with impaired walking performance through detailed immunohistochemical analyses of 400 baseline gastrocnemius muscle biopsies stored in the Northwestern biorepository, collected from 9 different clinical trials. This biorepository of muscle from PAD patients is one-of-a-kind and is associated with detailed clinical and functional characteristics of the donors. We hypothesize that variability in fiber size, fiber type and mitochondrial adaptations in response to ischemia-reperfusion damage and denervation in individuals with PAD will have value in predicting walking impairment. In Aim 1, we will quantify the proportion of IMFM- areas in type I fibers with normal type I MyHC abundance, or accumulation of type IIX MyHC and/or LC3, a marker of autophagy, and determine associations with fiber type composition and fiber size, as well as relationships of muscle features to walking performance in PAD. We hypothesize that LC3 will co-localize with IIX MyHC in IMFM- areas, suggesting both incomplete autophagic clearance of IIX MyHC and mitochondrial biogenesis during fiber transition from type IIX to type I as a result of denervation and reinnervation. In Aim 2 we will quantify denervated, NCAM+ fibers and fibers with elevated oxidative damage markers by fiber type. We hypothesize that denervation in PAD will preferentially affect fibers expressing IIX MyHC and that only IMFM- areas that accumulate IIX MyHC will be NCAM+. In Aim 3 we will perform predictive modeling of PAD disease severity and functional impairment using morphological characteristics of muscle quantified in Aims 1 and 2 as biomarkers in conjunction with supervised classification approaches. In Aim 4 we will test the hypothesis that baseline muscle characteristics will predict longitudinal functional outcomes at 6-month follow up. This model will provide a powerful tool to aide in identifying biologic processes for targeted interventions and to assess the mechanism of action and effectiveness of current pharmacological and exercise interventions in ongoing PAD clinical trials.

下肢外周动脉疾病(PAD)显著影响老龄化人群并导致功能性 减损。尽管找到有效干预措施的临床重要性已被广泛认识，但很少有 目前已有治疗方法可用。PAD的诊断使用踝臂指数(ABI)，这是一种衡量 血液流向四肢。较低的ABI与较差的功能相关；然而，仅有较低的ABI 不能完全解释PAD的功能障碍。小型研究已经报道了氧化应激，线粒体 PAD患者腓肠肌活检中的功能障碍和/或纤维损伤，提示骨骼 肌肉的紊乱可能会导致功能衰退。我们报告了高度可变的纤维类型组成 在一小部分PAD患者中进行纤维类型分组，观察到缺乏肌原纤维线粒体 (IMFM-)在氧化的肌球蛋白重链(MyHC)I型纤维中。我们有了最新的初步数据 提示对持续失神经的反应以及纤维类型和线粒体适应的可变性， 垫子。本研究的目的是明确PAD中与受损相关的肌肉的特定特征 400例基线腓肠肌详细免疫组织化学分析的步行能力 存储在西北生物信息库的活组织检查，从9个不同的临床试验中收集。这个生物储存库 PAD患者的肌肉是独一无二的，与详细的临床和功能特征有关 捐赠者的名字。我们假设纤维大小、纤维类型和线粒体适应性的变化作为响应 对PAD患者的缺血再灌注损伤和失神经支配有预测步行的价值 减损。在目标1中，我们将量化具有正常I型MyHC的I型纤维中IMFM区域的比例 IIX型MyHC和/或LC3的丰度或积累，这是自噬的标志，并确定关联 与纤维类型组成和纤维大小以及肌肉特征与步行能力的关系 垫子。我们假设LC3将与IIX MyHC共同定位于IMFM-区域，这表明两者都不完整 IIX型向I型转变过程中IIX-MyHC的自噬清除和线粒体生物发生 作为去神经和再神经支配的结果。在目标2中，我们将量化失神经、NCAM+纤维和纤维 纤维类型的氧化损伤标记物升高。我们假设PAD的去神经作用将 优先影响表达IIX MyHC的纤维，并且只有积聚IIX MyHC的IMFM区域将 NCAM+。在目标3中，我们将使用以下工具对PAD疾病严重程度和功能损害进行预测建模 AIMS 1和AIMS 2中量化为生物标志物的肌肉形态特征与 监督分类方法。在目标4中，我们将测试基线肌肉特征的假设 将在6个月的随访中预测纵向功能结果。该模型将提供一个强大的工具来 协助确定有针对性的干预的生物过程，并评估作用机制和 正在进行的PAD临床试验中当前药理学和运动干预的有效性。