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

艾滋病毒感染者（PLWH）的寿命更长，但年龄增长 加速功能下降（力量下降，步态减慢，运动耐量降低）和增加 与未感染的个体相比，功能衰退和虚弱的综合征是相关的 生活质量受损，对叠加压力的脆弱性增加，以及过早死亡的可能性 发病率和死亡率。然而，这种加速的功能障碍和残疾的机制是 不太了解。拟议的项目审查的贡献改变骨骼肌（SM） 线粒体功能和高能磷酸盐代谢相关，但不同的疲劳综合征， 运动不耐受和虚弱常出现在老年PLWH中。大量的临床前数据和我们的试点 使用31 P磁共振波谱（MRS）疲劳性试验的临床研究， 肢体运动提示“能量性肌病”可能是疲劳的基础， 老年PLWH患者的表现。然而，程度，潜在的责任因素， 在这个群体中改变SM线粒体生物能量学的意义还没有被表征。在 此外，两个潜在的机制，负责改变SM高能磷酸盐代谢在其他 人群中，炎症增加和SM脂质蓄积，尚未检查和相关 PLWH的肌肉能量学，因此这些也将被检查。核心假设是受损的SM 线粒体能量代谢，由衰老启动，在当代HIV的背景下加速，是一种 是老年PLWH患者疲劳、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31 P MRS运动测试，详细的肌肉和全身成分 在观察和自由生活条件下的功能评估，以及炎症生物标志物 来自四个当地NIH赞助的队列的200名老年（年龄≥ 60岁）女性和男性的免疫激活 来解决这些问题。具体目的是：1）确定老年人SM代谢变化的范围， 女性和男性艾滋病毒感染者，2）检测炎症，骨骼脂肪和其他潜在因素是否 与老年PLWH的能量异常有关; 3）确定SM的功能意义 通过检查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， 虚弱在老年PLWH中是常见的， 及时的研究将提供新的见解，并指导未来的干预战略，旨在减轻或 逆转线粒体和生物能量的下降，从而减少个人和社会的损失， 艾滋病毒感染者中老年妇女和男子的老年状况。

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.