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

艾滋病毒携带者(PLWH)寿命更长，但年龄更大 加速功能衰退(力量下降、步态减慢、运动耐量降低)并增加 与未受感染的人相比，虚弱。功能衰退和虚弱的症状是相关的 生活质量受损，更容易受到叠加压力的影响，以及早产的可能性 发病率和死亡率。然而，这种加速的功能障碍和残疾背后的机制是 人们对此知之甚少。拟议的项目考察了改变的骨骼肌(SM)的贡献。 线粒体功能和高能磷酸盐代谢与相关但不同的疲劳症状有关， 运动不耐受和虚弱经常出现在老年PLWH中。大量的临床前数据和我们的试点 使用31P磁共振波谱(MRS)疲劳性试验在低血压期间和之后的临床研究 肢体运动提示一种“精力型肌病”可能是疲劳和减少的基础 在老年PLWH患者中的表现。然而，程度、潜在的责任因素和功能 改变的SM线粒体生物能量学在该人群中的意义尚未确定。在……里面 此外，导致SM高能磷酸盐代谢改变的两种潜在机制 人群，炎症增加和SM脂质堆积，尚未被检查并与之相关 PLWH中的肌肉能量学，因此这些也将被检查。中心假设是受损的SM 线粒体能量代谢由衰老启动，并在当代艾滋病毒的背景下加速，是一种 是老年PLWH中疲劳、运动不耐受和虚弱等老年综合征的主要因素。我们 建议使用最先进的31P MRS运动测试，详细的肌肉和全身组成 测量，观察和自由生活条件下的功能评估，以及炎症的生物标记物 来自四个当地NIH赞助队列的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。具体目标是1)确定老年人SM代谢变化的范围 女性和男性艾滋病毒携带者，2)调查炎症、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 老年PLWH的能量变化与运动之间的关系 耐受性和其他功能评估，以及脆弱的表型。疲劳，运动不耐受，和 脆弱在老年PLWH中很常见，其潜在机制仍然知之甚少。 及时的研究将提供新的见解并指导未来的干预策略，旨在减少或 逆转线粒体和生物能量的下降，从而减少个人和社会对这些疾病的损失 老年妇女和艾滋病毒携带者男子的老年状况。

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.