Muscle Fatigue and its Impact on Mobility Function in Aging

项目总结 与年轻人相比，65岁以上的人在高潮时肌肉疲劳更严重。 收缩速度，如行走过程中出现的收缩速度。尽管疲劳，或者是身体的急剧下降 最大的力量或力量，是骨骼肌的一个基本特征，从受损的途径 细胞能量学、收缩功能和疲劳对增龄相关运动功能的改变仍然存在 未知。老年人行动不便会增加罹患疾病和生活质量差的风险， 这反过来又造成了巨大的个人和社会负担。老年人的活动障碍是 与膝关节伸肌(KE)功能下降有关。值得注意的是，老年人的KE表现出 体内氧化能量产生不足，与年轻人相比有更大的疲劳感。一本小说 解决KE疲劳的临床问题及其对衰老时活动能力的影响的方法是确定 导致老年人更疲劳的基本分子和细胞缺陷，以及这些缺陷是如何 疲劳机制导致行动能力障碍。我们研究的总体目标是提供这一新的 知识和缓解我们老龄化人口流动性下降的问题。我们的中心假设是 老年人，特别是那些有活动功能障碍的人，体内线粒体能量将会不足 在精力充沛的运动过程中，会加剧受损的收缩功能并导致更大的疲劳 要求很高的工作，包括走路。为了验证这一假设，我们将收集疲劳前后的数据 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)的高速收缩 行动不便的成年人。所有小组都将相对久坐不动，这将得到定量验证 使用加速度计。我们将使用集成和转换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)光谱学的细胞内能量； 磁共振成像的肌肉形态；单肌纤维钙敏感性和肌球蛋白-肌动蛋白跨桥 疲劳条件下的动力学；单个纤维和完整肌肉的力-速度关系；较低 四肢关节力学、行走的能量成本、感觉到的精力消耗和活动任务(椅子站起来， 平衡)疲劳前后。我们将确定赤字在能源生产中的作用(目标1)和 老年人肌肉疲劳程度更大时的收缩功能(目标2)以及疲劳对步态的影响 机械、运输的能源成本和机动性(目标3)。潜在的基于性别的差异将是 在每个目标中进行评估。需要解决的问题--疲劳加剧的原因及其对行动能力的影响 在老年人中--解决NIH和NIA的既定目标。我们的成功将产生重大的积极影响， 弥合现有的知识鸿沟，这一鸿沟目前限制了我们保持人口老龄化的能力 积极健康。有希望缓解的目标(例如，收缩功能或线粒体的方面 能量学？)将在未来的研究中确定和研究。

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.