Motoneuronal mechanisms underlying age-related muscle weakness

摘要 42%的老年人有一个或多个身体限制执行日常任务是必不可少的 在社区中保持独立。与肥胖相关的虚弱是身体 这是一个很大的障碍，因为虚弱使老年人的身体限制增加了4倍。几十年来， 与年龄相关的虚弱主要归因于肌肉质量的损失，但最近的数据表明， 起的作用比最初想象的要小，突出表明其他神经和/或肌肉质量相关 这些因素对弱点的发展至关重要。尽管保持体力的重要性， 随着年龄的增长，大多数研究都集中在保持肌肉质量上。所知甚少 关于可能导致年龄相关性虚弱的神经机制。这一知识空白 是开发新干预措施以增强老年人力量和功能的障碍。 在本申请中，我们将检验中心假设，即与年龄相关的虚弱部分是由于， 运动神经元（MN）SK通道（小电导钙激活钾通道），导致 固有MN兴奋性和放电率的依赖性降低。先前的研究表明，老化导致 MU（α-MN及其神经支配的肌纤维）数量减少，放电频率降低。然而，先前的工作 已经停止了确定是否年龄相关的减少MU数量与临床有关- 有意义的弱点，并确定离子机制的基础上减少MN的发射率老化。在 在本申请中，我们提出了一系列平行、横截面和纵向的动物（目的1和2）， 人类实验（目标3）来检验我们的中心假设。目标1将确定MN兴奋性功能障碍是否是 参与与年龄相关的虚弱，并确定其与小鼠MU损失的时间关系。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将确定MN的作用 兴奋性和数量在临床上有意义的，年龄相关的弱点在老年人。这项工作符合 国家老龄化研究所（NIA）的目标。从这项工作中获得的知识有 有可能从根本上将肌肉减少症和虚弱研究领域转向MN兴奋性， 生物标志物的发展弱点，并确定关键的MN离子通道，可以作为一个 用于治疗或预防与年龄相关的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.