Bioenergetics and fatigability in older individuals

描述（由申请人提供）：疲劳是老年人中常见的重要症状，与残疾和死亡率增加数倍相关。由于ATP是绝对需要燃料正常的肌肉收缩功能和疲劳已被概念化为一种状态的能量缺乏，一种方法来表征生物能量学在老年受试者与疲劳是合乎逻辑的和令人信服的。我们在这里提出了一种肌肉生物能量学疲劳性测试，该测试采用标准化的分级运动，进行运动疲劳，再加上31 P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和运动骨骼肌生物能量学联系起来，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。将通过测量最大氧化能力、细胞内脂质含量，以及通过磁化转移技术，研究导致代谢物水平变化的潜在机制，所述磁化转移技术是在我们的实验室中开发的， 以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。在与NIA BLSA人群的合作中，我们建议测试以下假设：1）在相似的工作负荷下，与低疲劳性的受试者相比，高疲劳性的老年受试者肌肉高能磷酸盐减少，Pi增加，2）高疲劳性的受试者在相同的能量阈值下但在较低的工作负荷/活动下发生疲劳，以及3）可以确定与运动疲劳相关的高能磷酸盐水平变化的一些负责机制。这种新的和潜在的变革性的方法将首次提供一种手段，以客观地识别增加的肌肉疲劳性，以确定减少的肌肉能量代谢在衰老相关的疲劳性中的作用，探索负责任的机制，并提供一种标准化的方法来评估未来干预措施对老年人的生物能量特征的影响。

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.