Muscle Fatigue and its Impact on Mobility Function in Aging

项目摘要 与年轻人相比，65岁以上的人在高血压时会经历更大的肌肉疲劳。 收缩速度，例如在行走过程中发生的收缩速度。虽然疲劳，或急性减少， 最大力或功率，是骨骼肌的基本特征，从受损的途径， 细胞能量学、收缩功能和疲劳与年龄相关的运动功能变化仍然存在 未知老年人活动能力的降低会增加发病率和生活质量的风险， 这反过来又造成了巨大的个人和社会负担。老年人的运动功能障碍是 与膝伸肌（KE）功能减退有关。值得注意的是，老年人的KE表现出 体内氧化能量产生的不足，以及与年轻人相比更大的疲劳。一种新型 解决KE疲劳的临床问题及其对老年人活动能力的影响的方法是确定 基本的分子和细胞缺陷，导致老年人更大的疲劳，以及这些缺陷是如何产生的。 疲劳机制导致运动功能障碍。我们研究的总体目标是提供这种新的 知识和减轻我们老龄化人口的流动性下降。我们的中心假设是， 老年人，特别是那些有运动功能障碍的老年人，体内线粒体能量将缺乏， 生产，加剧受损的收缩功能，并导致更大的疲劳期间，精力充沛， 高要求的工作，包括走路。为了验证这一假设，将在疲劳前后收集数据 30名健康青年（30-40岁）、30名健康老年人（70-80岁）和30名老年人（70-80岁）高速收缩 行动不便的成年人。所有群体都会相对久坐，这将被量化验证 使用加速度计。我们将使用整合和翻译的方法来构建从分子到 行为，通过测量：使用非侵入性磁共振（MR）光谱的细胞内能量学; MR成像的肌肉形态学;单个肌纤维钙敏感性和肌球蛋白-肌动蛋白交叉桥 疲劳条件下的动力学;单纤维和完整肌肉的力-速度关系;较低的 四肢关节力学、行走的能量消耗、感知的用力和移动性任务（椅子上升， 在疲劳之前和之后。我们将确定赤字在能源生产（目标1）和 收缩功能（目标2）在更大的肌肉疲劳的老年人，以及对步态疲劳的影响 力学、运输的能源成本和机动性（目标3）。潜在的性别差异将是 在每个目标中进行评估。要解决的问题-更大的疲劳的原因，以及它如何影响流动性 在老年人中-解决了NIH和NIA的既定目标。我们的成功将产生重大的积极影响， 弥合现有的知识差距，目前限制我们的能力，以保持我们的人口老龄化的身体 积极和健康。有希望的减缓目标（例如，收缩功能或线粒体 能量学？）将在今后的研究中加以确定和探讨。

PROJECT SUMMARY Compared with young adults, people over the age of 65 years experience greater muscle fatigue at high contraction velocities, such as those that occur during walking. Although fatigue, or the acute decrease in maximal force or power, is a fundamental characteristic of skeletal muscle, the pathway from impaired cellular energetics, contractile function and fatigue to age-related changes in mobility function remains unknown. Mobility reduction in older adults carries an increased risk for morbidities and a poor quality of life, which in turn creates tremendous personal and societal burdens. Mobility dysfunction in older adults is associated with decrements in knee extensor muscle (KE) function. Notably, the KE of older adults exhibit a deficit in oxidative energy production in vivo, as well as greater fatigue compared with young adults. A novel means to address the clinical problem of KE fatigue and its impact on mobility in aging is to determine the fundamental molecular and cellular deficits that contribute to greater fatigue in older adults, and how these fatigue mechanisms lead to mobility dysfunction. The overall goal of our research is to provide this new knowledge and mitigate decreased mobility in our aging population. Our central hypothesis is that the KE of older adults, particularly those with mobility dysfunction, will have deficits of in vivo mitochondrial energy production that exacerbate impaired contractile function and result in greater fatigue during energetically- demanding work, including walking. To test this hypothesis, data will be gathered before and after fatiguing high-velocity contractions in 30 healthy young (30-40 yr), 30 healthy older (70-80) and 30 older (70-80) adults with mobility impairment. All groups will be relatively sedentary, which will be verified quantitatively using accelerometry. We will use an integrated and translational approach to build from the molecular to the behavioral, by measuring: intracellular energetics using non-invasive magnetic resonance (MR) spectrosopy; muscle morphology by MR imaging; single muscle fiber calcium sensitivity and myosin-actin cross-bridge kinetics during fatigue conditions; force-velocity relationships of single fibers and intact muscle; lower extremity joint mechanics, the energy cost of walking, perceived exertion and mobility tasks (chair rises, balance) before and after fatigue. We will determine the role of deficits in both energy production (Aim 1) and contractile function (Aim 2) in the greater muscle fatigue of older adults, as well as the impact of fatigue on gait mechanics, the energy cost of transport, and mobility (Aim 3). Potential sex-based differences will be evaluated in each Aim. The problem to be addressed- the causes of greater fatigue and how it impacts mobility in older adults- tackles stated goals of the NIH and NIA. Our success will have a significant, positive impact by bridging an existing knowledge gap that currently limits our ability to keep our aging population physically active and healthy. Promising targets for mitigation (e.g., aspects of contractile function or mitochondrial energetics?) will be identified and pursued in future studies.