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: 10380614
• 负责人: ROBERT G WEISS
• 金额: $ 60万
• 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/10380614
• 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.

HIV 感染者 (PLWH) 的寿命更长，但年龄增长 加速功能衰退（力量下降、步态减慢、运动耐量降低）并增加 与未感染者相比，身体虚弱。功能衰退和虚弱的综合症是相关的 生活质量受损、对叠加压力的脆弱性增加以及早产的可能性 发病率和死亡率。然而，这种加速功能障碍和残疾的机制是 不太了解。拟议的项目研究了骨骼肌（SM）改变的贡献 线粒体功能和高能磷酸盐代谢与相关但独特的疲劳综合征， 运动不耐受和虚弱经常出现在老年感染者身上。大量的临床前数据和我们的试点 使用 31P 磁共振波谱 (MRS) 疲劳测试进行的临床研究 四肢运动表明“精力充沛的肌病”可能是疲劳和能力下降的基础 老年 PLWH 个体的表现。然而，程度、潜在的责任因素和功能 SM 线粒体生物能学改变在该人群中的重要性尚未得到表征。在 此外，有两种潜在机制导致其他细胞中 SM 高能磷酸盐代谢的改变 人群中，炎症增加和 SM 脂质积累，尚未经过检查并与 感染者的肌肉能量学等也将受到检查。中心假设是 SM 受损 线粒体能量代谢是由衰老引发的，并在当代艾滋病毒的背景下加速，是一种 是导致老年 PLWH 出现疲劳、运动不耐受和虚弱等老年综合征的主要原因。我们 建议使用最先进的31P MRS运动测试，详细的肌肉和全身成分 观察和自由生活条件下的测量、功能评估以及炎症生物标志物 来自 NIH 资助的四个当地队列的 200 名老年（年龄 >=60 岁）女性和男性的免疫激活和免疫激活 来解答这些问题。具体目标是 1) 确定老年人 SM 代谢变化的范围 感染艾滋病毒的女性和男性，2) 探讨炎症、骨骼脂肪和其他潜在因素是否 与老年 PLWH 的能量异常相关，3) 确定 SM 的功能意义 通过检查老年感染者的能量变化与运动之间的关系 耐受性和其他功能评估以及虚弱表型。疲劳、运动不耐受等 虚弱在老年感染者中很常见，而其潜在机制仍知之甚少。 及时的研究将提供新的见解并指导未来的干预策略，旨在减轻或 逆转线粒体和生物能量下降，从而减少个人和社会损失 感染艾滋病毒的老年妇女和男子的老年病。