Motoneuronal mechanisms underlying age-related muscle weakness

摘要 42%的老年人在执行重要的日常任务时有一个或多个身体缺陷 维护社区的独立性。与年龄相关的虚弱是导致身体虚弱的一个重要因素 身体缺陷，因为虚弱使老年人的身体限制增加了4倍。几十年来， 与年龄相关的虚弱很大程度上归因于肌肉质量的丧失，但最近的数据表明， 起的作用比最初认为的要小，突出了与其他神经和/或肌肉质量相关的 在弱势的发展中，因素是至关重要的。尽管在中国保持体力的重要性 随着年龄的增长，大多数研究都集中在保持肌肉质量上。我们所知的要少得多 关于可能导致年龄相关性虚弱的神经机制。这种知识鸿沟 对开发新的干预措施以增强老年人的力量和功能是一种障碍。 在本应用程序中，我们将检验中心假设，即年龄相关的虚弱在一定程度上是由于 运动神经元(MN)SK通道(小电导钙激活钾通道)，导致类型- 内源性MN兴奋性和放电率的依赖性降低。先前的研究表明，老化会导致 MU的数量(α-MN及其支配的肌肉纤维)和较低的放电率。但是，以前的工作 尚未确定与年龄相关的MU数量减少是否与临床相关- 有意义的弱点，并确定了老化过程中MN发放率降低的离子机制。在……里面 在这个应用中，我们提出了一系列平行的、横截面的和纵向的动物(目标1和2)和 人体实验(目标3)来验证我们的中心假设。目标1将确定MN兴奋性功能障碍是否 参与衰老相关的虚弱，并确定其与MU丢失的时间关系。目标2将确定 老年小鼠MN兴奋性功能障碍的细胞机制。目标3将决定MN的角色 老年人中具有临床意义的年龄相关性虚弱的兴奋性和数量。这项工作符合 国家老龄研究所(NIA)提出的目标。从这项工作中获得的知识有 有可能从根本上将骨质疏松症和脆弱研究领域转移到MN兴奋性的早期 虚弱发展的生物标志物，并确定关键的MN离子通道可以作为 治疗或预防年龄相关性虚弱的神经治疗靶点。

ABSTRACT Forty-two percent of older adults have one or more physical limitations performing daily tasks that are essential for maintaining independence in the community. Age-related weakness is an important contributor to physical impairments, as weakness predisposes older adults to a 4-fold increase in physical limitations. For decades, age-related weakness was largely attributed to the loss of muscle mass, but recent data indicates that mass plays a lesser role than originally thought, highlighting that other neurological and/or muscle quality related factors are critical in the development of weakness. Despite the significance of maintaining physical strength in aging, the majority of the research has focused on maintaining muscle mass. Considerably less is known regarding the neural mechanisms potentially contributing to age-related weakness. This knowledge gap represents a barrier to the development of new interventions to enhance strength and function in older adults. In this application we will test the central hypothesis that age-related weakness is due, in part, to upregulation in motor neuron (MN) SK channels (small conductance calcium-activated potassium channels) that results in type- dependent reductions in intrinsic MN excitability and firing rates. Prior work indicates that aging results in reduced number of MUs (the α-MN and the muscle fibers that it innervates) and lower firing rates. However, prior work has stopped short of determining whether age-related reductions in MU numbers are related to clinically- meaningful weakness, and determining the ionic mechanisms underlying reduced MN firing rates in aging. In this application we propose a series of parallel, cross-sectional and longitudinal animal (Aims 1 and 2) and human experiments (Aim 3) to test our central hypothesis. Aim 1 will determine if MN excitability dysfunction is involved in age-related weakness and determine its temporal relationship to MU loss in mice. Aim 2 will identify the cellular mechanisms underlying MN excitability dysfunction in aged mice. Aim 3 will determine the role of MN excitability and number in clinically-meaningful, age-related weakness in older adults. This work aligns with stated goals from the National Institute on Aging (NIA). The knowledge to be gained from this work has the potential to fundamentally shift the fields of sarcopenia and frailty research towards MN excitability as an early biomarker for the development of weakness, and identifying key MN ion channels that could serve as a neurotherapeutic targets for treating or preventing age-related weakness.