Bioenergetics and fatigability in older individuals

描述(由申请人提供)：疲劳是老年人的一种常见和重要的症状，与残疾和死亡率增加几倍有关。由于正常的肌肉收缩功能绝对需要三磷酸腺苷，而疲劳已被概念化为一种能量缺乏的状态，因此，一种在患有疲劳的老年受试者中表征生物能量学的方法既合乎逻辑又令人信服。我们在这里提出了一种肌肉生物能量疲劳性测试，它使用标准化的分级运动来进行运动性疲劳，并结合31P磁共振波谱，以将活动的水平、持续时间和强度与疲劳症状和锻炼骨骼肌生物能量相联系，包括重复测量高能磷酸盐水平、无机磷积累和细胞内pH。此外，将通过测量最大氧化能力、细胞内脂质含量和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。 测定肌酸激酶产生ATP的速率，肌酸激酶是肌肉的主要能量储备反应。这些参数还将与疲劳和心血管健康的全球指数、全身炎症生物标记物以及包括肌肉质量和血流在内的局部因素相关。在与NIA BLSA人群的合作中，我们建议检验以下假设：1)在类似的工作负荷下，与低疲劳性受试者相比，高疲劳性老年人的肌肉高能磷酸盐减少而PI增加，2)高疲劳性受试者在相同的能量阈值下发生性能疲劳，但在高疲劳性受试者的工作负荷/活动量较低，以及3)可以确定与高能量磷酸盐水平的运动疲劳相关变化的一些负责任的机制。这一新的和潜在的变革性方法将首次提供一种手段来客观地识别肌肉疲劳性的增加，确定肌肉能量代谢降低在衰老相关疲劳性中的作用，探索相关的机制，并提供一种标准化的方法来评估未来干预对患有运动疲劳的老年人的生物能量谱的影响。

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.