Motoneuronal mechanisms underlying age-related muscle weakness

年龄相关性肌肉无力的运动神经机制

• 批准号: 10641197
• 负责人: William David Arnold
• 金额: $ 23.49万
• 依托单位: OHIO UNIVERSITY ATHENS
• 依托单位国家: 美国
• 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/10641197
• 关键词: Action Potentials; Age; Age-Months; Aging; 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; Lead; 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; TimeLine; United States National Institutes of Health; Up-Regulation; Western Blotting; Work; age related; age-related muscle weakness; aged; base; biomarker development; cohort; early detection biomarkers; experience; experimental study; frailty; human data; human old age (65+); in vivo; muscle form; muscle strength; neuromechanism; physically handicapped; prevent; protein expression; sarcopenia; sex

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％的老年人有一个或多个身体限制，执行日常任务，这是必不可少的 保持社区独立。与年龄有关的弱点是身体的重要贡献 障碍，因为弱点使老年人的身体局限性增加了4倍。几十年来， 与年龄有关的弱点主要归因于肌肉质量的损失，但最近的数据表明质量 扮演的角色比最初想象的要少，强调了其他神经和/或肌肉质量相关的角色 因素对于弱点的发展至关重要。尽管保持体力 衰老，大多数研究都集中于维持肌肉质量。少得多 关于神经机制可能导致与年龄有关的弱点。这个知识差距 代表了开发新干预措施以增强老年人力量和功能的障碍。 在此应用中，我们将测试中心假设，即与年龄相关的弱点部分是由于上调 运动神经元（MN）SK通道（小电导钙激活的钾通道），导致类型 固有的MN兴奋性和发射速率的依赖性降低。先前的工作表明衰老导致减少 MUS的数量（α-MN和其支配的肌肉纤维）和降低速率。但是，先前的工作 缺乏确定与年龄相关的MU数量的减少是否与临床上的相关 有意义的弱点，并确定衰老中Mn发射率降低的离子机制。在 我们提出了一系列平行，横截面和纵向动物（目标1和2），以及 人类实验（目标3）以检验我们的中心假设。 AIM 1将确定MN兴奋性功能障碍是否为 涉及与年龄相关的弱点，并确定其与小鼠中MU损失的暂时关系。 AIM 2将确定 老年小鼠中MN兴奋性功能障碍的细胞机制。 AIM 3将决定MN的作用 老年人的兴奋性和临床上与年龄相关的弱点的兴奋性和数量。这项工作与 陈述了美国国家老化研究所（NIA）的目标。从这项工作中获得的知识具有 从根本上将肌肉减少症和脆弱研究的领域转变为MN令人兴奋的潜力 生物标志物用于发展弱点，并确定可以用作的关键MN离子渠道 用于治疗或预防与年龄相关的弱点的神经治疗靶标。