Motoneuronal mechanisms underlying age-related muscle weakness

年龄相关性肌肉无力的运动神经机制

基本信息

批准号：
10612078
负责人：
William David Arnold
金额：
$ 59.4万
依托单位：
OHIO UNIVERSITY ATHENS
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10612078
关键词：
Action Potentials Age Age Months Aging Animal Experiments Animals Calcium-Activated Potassium Channel Cell membrane Clinical Communities Cross-Sectional Studies Data Development Disease Elderly Exhibits Extensor Functional disorder Goals Human Immunohistochemistry Impairment In Situ In Vitro Incidence Intervention Ion Channel Knowledge Leg Measures Membrane Mission Molecular Motor Motor Neurons Mus Muscle Muscle Fibers Muscle function Muscular Atrophy National Institute on Aging Neurologic Physiological Play Preparation Public Health Research Research Design Risk Factors Role Sensory Series Spinal Cord Testing Time United States National Institutes of Health Up-Regulation Western Blotting Work age related age-related muscle weakness aged base biomarker development calcium-activated potassium channel small-conductance cohort early detection biomarkers experience experimental study frailty human data human old age (65+)in vivo muscle form muscle strength neuromechanism neuronal excitability physically handicapped prevent protein expression sarcopenia sex timeline

项目摘要

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.

抽象的 42% 的老年人在执行重要的日常任务时存在一种或多种身体限制与年龄相关的虚弱是身体健康的一个重要因素。几十年来，虚弱使老年人的身体限制增加了四倍。与年龄相关的虚弱很大程度上归因于肌肉质量的损失，但最近的数据表明，肌肉质量的损失发挥的作用比最初想象的要小，强调与其他神经和/或肌肉质量相关的尽管保持体力很重要，但因素对虚弱的发展至关重要。随着年龄的增长，大多数研究都集中在维持肌肉质量上，但人们知之甚少。关于可能导致与年龄相关的弱点的神经机制。阻碍了开发新的干预措施以增强老年人的力量和功能。在本申请中，我们将测试中心假设，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），导致类型- 先前的研究表明，衰老会导致内在神经元兴奋性和放电率的降低。 MU（α-MN 及其支配的肌纤维）数量和较低的放电率然而，之前的工作。尚未确定 MU 数量与年龄相关的减少是否与临床相关有意义的弱点，并确定衰老过程中 MN 放电率降低的离子机制。在这个应用中，我们提出了一系列平行、横截面和纵向的动物（目标 1 和 2）测试我们中心假设的人体实验（目标 3）将确定 MN 兴奋性功能障碍是否存在。与年龄相关的虚弱有关，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将决定 MN 的作用。老年人具有临床意义的、与年龄相关的无力的兴奋性和数量与这项工作一致。国家老龄化研究所 (NIA) 提出的目标从这项工作中获得的知识有：有潜力从根本上将肌肉减少症和虚弱研究领域转向 MN 兴奋性作为早期研究弱点发展的生物标志物，并确定可作为关键 MN 离子通道用于治疗或预防与年龄相关的无力的神经治疗靶标。