Mitochondrial energetics, exercise intolerance and fatigability in older people with HIV

老年艾滋病毒感染者的线粒体能量、运动不耐受和疲劳

• 批准号: 10601219
• 负责人: ROBERT G WEISS
• 金额: $ 17.29万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-15 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10601219
• 关键词: Address; Adult; Age; Aging; Attenuated; Bioenergetics; Biological Markers; Biopsy; Body Composition; Body mass index; Clinical Data; Clinical Research; Dual-Energy X-Ray Absorptiometry; Elderly; Energy Metabolism; Exercise; Exercise Test; Exercise Tolerance; Fatigue; Fatty acid glycerol esters; Frail Elderly; Functional disorder; Future; Gait; Gait speed; Gender; General Population; HIV; HIV Infections; Human; Impairment; Individual; Inflammation; Intervention; Life; Lipids; Lower Extremity; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Measures; Metabolic; Metabolism; Mitochondria; Mitochondrial DNA; Morbidity - disease rate; Muscle; Muscle Fatigue; Muscle Mitochondria; Muscular Dystrophies; Myopathy; Nutrient; Older Population; Performance; Persons; Phenotype; Population; Preparation; Quality of life; Race; Rest; Role; Skeletal Muscle; Stress; Syndrome; Testing; Time; United States National Institutes of Health; Walking; cohort; design; disability; effective therapy; exercise intolerance; experience; frailty; functional decline; immune activation; in vivo; inorganic phosphate; insight; metabolic myopathies; middle age; mortality; novel; older men; older women; patient population; pre-clinical; premature; sex; skeletal

People living with HIV infection (PLWH) are living longer but with advancing age experience accelerated functional decline (decreased strength, slowed gait, reduced exercise tolerance) and increased frailty, as compared to non-infected individuals. The syndromes of functional decline and frailty are associated with impaired quality of life, increased vulnerability to superimposed stresses, and the likelihood of premature morbidity and mortality. The mechanisms underlying this accelerated dysfunction and disability, however, are poorly understood. The proposed project examines the contribution of altered skeletal muscle (SM) mitochondrial function and high energy phosphate metabolism to the related, but distinct syndromes of fatigue, exercise intolerance, and frailty often present in older PLWH. Considerable pre-clinical data and our pilot clinical studies using a 31P magnetic resonance spectroscopy (MRS) fatigability test during and following lower- extremity exercise suggest an “energetic myopathy” as a possible basis for the fatigue and decreased performance in older PLWH individuals. However the extent, underlying responsible factors, and functional significance of altered SM mitochondrial bioenergetics in this population have not been characterized. In addition, two potential mechanisms responsible for altered SM high energy phosphate metabolism in other populations, increased inflammation and SM lipid accumulation, have not been examined and related to muscle energetics in PLWH and so these too will be examined. The central hypothesis is that impaired SM mitochondrial energy metabolism, initiated by aging and accelerated in the setting of contemporary HIV, is a central contributor to the geriatric syndromes of fatigue, exercise intolerance, and frailty in older PLWH. We propose to use state-of-the art 31P MRS exercise testing, detailed muscle and whole body composition measures, functional assessments during observed and free-living conditions, and biomarkers of inflammation and immune activation in 200 older (age>=60) women and men derived from four local NIH-sponsored cohorts to address these questions. The specific aims are 1) to define the scope of SM metabolic changes in older women and men living with HIV, 2) to probe whether inflammation, skeletal fat and other underlying factors are related to the energetic abnormalities in older PLWH and 3) to determine the functional significance of SM energetic changes in older PLWH by examining the relationships between the energetic changes and exercise tolerance and other functional assessments as well as the frailty phenotype. Fatigue, exercise intolerance, and frailty are common in older PLWH and the underlying mechanisms remain poorly understood These novel, timely studies will provide new insights and guide future intervention strategies designed to attenuate or reverse mitochondrial and bioenergetic decline and thereby reduce the personal and societal toll of these geriatric conditions in older women and men living with HIV.

患有艾滋病毒感染（PLWH）的人的寿命更长，但具有增长年龄的经验 加速功能下降（强度降低，收集减慢，运动耐受性降低）并增加 脆弱，与未感染的个体相比。功能下降和脆弱的综合征是相关的 生活质量受损，增加叠加压力的脆弱性以及过早的可能性 发病率和死亡率。然而，这种加速功能障碍和残疾的机制是 理解不佳。拟议的项目考试改变了骨骼肌（SM）的贡献 线粒体功能和高能磷酸代谢对疲劳的相关但不同的综合症， 运动摄入率和脆弱的旧PLWH。大量的临床前数据和我们的飞行员 使用31p磁共振光谱（MRS）疲劳性测试的临床研究 肢体运动暗示了“充满活力的肌病”，以使疲劳和改善 在较老的PLWH个体中的表现。但是，负责因素的基本程度和功能 SM线粒体生物能在该人群中的重要性尚未表征。在 此外，其他两个潜在的机制，导致SM磷酸盐代谢改变了其他 人群，感染增加和SM脂质积累，尚未检查并与 PLWH中的肌肉能量技术也将被检查。中心假设是SM受损 通过衰老和在当代艾滋病毒的环境中发起的线粒体能量代谢是一种 在较老的PLWH中，疲劳，运动和脆弱的老年综合症的中心贡献者。我们 提议使用最先进的31p MRS运动测试，详细的肌肉和全身成分 措施，观察到的自由生活条件期间的功能评估以及炎症的生物标志物 来自200年龄（年龄> = 60岁）的女性和男性的免疫激活来自四个本地NIH赞助的队列 解决这些问题。具体目的是1）定义较老的SM代谢变化范围 患有艾滋病毒的男性和男性，2）探测炎症，骨骼脂肪和其他潜在因素是否是 与较老的PLWH和3）的能量异常有关，以确定SM的功能意义 通过检查能量变化与锻炼之间的关系，旧PLWH的能量变化 耐受性和其他功能评估以及脆弱的表型。疲劳，锻炼和 脆弱在较旧的PLWH中很常见，而潜在的机制仍然很了解这些小说， 及时的研究将提供新的见解，并指导旨在减弱或 反向线粒体和生物能下降，从而减少了这些人的个人和社会损失 老年男女艾滋病毒的老年病情。