Bioenergetics and fatigability in older individuals

描述（由申请人提供）：疲劳是老年人常见且重要的症状，与残疾和死亡率成倍增加有关。由于 ATP 是正常肌肉收缩功能所必需的，并且疲劳已被概念化为一种能量缺乏状态，因此一种表征老年疲劳受试者生物能学的方法既合乎逻辑，又令人信服。我们在此提出一种肌肉生物能学疲劳测试，采用标准化、分级运动进行表现疲劳，并结合 31P 磁共振波谱，以便将活动的水平、持续时间和强度与疲劳症状以及锻炼骨骼肌生物能学联系起来，包括重复测量高能磷酸盐水平、无机磷酸盐积累和细胞内 pH 值。此外，我们将通过测量最大氧化能力、细胞内脂质含量以及我们实验室开发的磁化转移技术来研究导致代谢物水平变化的潜在机制， 确定通过肌酸激酶产生 ATP 的速率，肌酸激酶是主要的肌肉能量储备反应。这些参数还将与疲劳和心血管健康的整体指数、全身炎症生物标志物以及包括肌肉质量和血流量在内的局部因素相关。与 NIA BLSA 人群合作，我们建议测试以下假设：1）在相似的工作负荷下，与易疲劳性低的老年受试者相比，高能磷酸盐水平降低，Pi 增加；2）高疲劳性受试者在相同的能量阈值下，但工作负荷/活动较低时出现表现性疲劳；3）可以确定高能磷酸盐水平中与表现性疲劳相关的变化的一些机制。这种新颖且具有潜在变革性的方法将首次提供一种客观识别肌肉疲劳增加的方法，定义肌肉能量代谢减少在衰老相关疲劳中的作用，探索负责任的机制，并提供标准化方法来评估未来干预措施对患有性能疲劳的老年人生物能量谱的影响。

DESCRIPTION (provided by applicant): Fatigue is a common and important symptom among the elderly that is associated with a several-fold increase in disability and mortality. Because ATP is absolutely required to fuel normal muscle contractile function and fatigue has been conceptualized as a state of energy deficiency, an approach to characterizing bioenergetics in older subjects with fatigue is both logical and compelling. We propose here a muscle bioenergetics fatigability test that employs standardized, graded exercise conducted to performance fatigue coupled with 31P magnetic resonance spectroscopy so as to relate the level, duration and intensity of activity with fatigue symptoms and with exercising skeletal muscle bioenergetics, including repeated measures of high-energy phosphate levels, inorganic phosphate accumulation, and intracellular pH. In addition, potential mechanisms responsible for changes in metabolite levels will be studied by measuring maximal oxidative capacity, intracellular lipid content, and by magnetization transfer techniques, developed in our laboratory, to determine the rate of ATP production via creatine kinase, the primary muscle energy reserve reaction. These parameters will also be related to global indices of fatigue and cardiovascular fitness, to systemic inflammatory biomarkers, and to local factors including muscle mass and blood flow. In collaboration with the NIA BLSA populations we propose to test the hypotheses that 1) at similar workloads, muscle high-energy phosphates are reduced and Pi increased in older subjects with high, as compared to those with low, fatigability, that 2) performance fatigue occurs at the same energetic threshold but at lower workload/activity in those with high fatigability, and that 3) some responsible mechanisms for performance fatigue-related changes in high energy phosphate levels can be identified. This novel and potentially transformative approach will offer for the first time a means to objectively identify increased muscle fatigabilit, to define the role of reduced muscle energy metabolism in aging-associated fatigability, to explore responsible mechanisms, and to provide a standardized method to assess the impact of future interventions on the bioenergetic profile in older individuals with performance fatigue.