Neural mechanisms of age-related weakness

年龄相关性无力的神经机制

• 批准号: 10733022
• 负责人: William David Arnold
• 金额: $ 65.05万
• 依托单位: OHIO UNIVERSITY ATHENS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-15 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10733022
• 关键词: Accounting; Acute; Aging; Agonist; Animals; Chronic; Clinical; Clinical Research; Cre lox recombination system; Data; Dose; Elderly; Exhibits; Extensor; Future; Generations; Genetic; Hand Strength; Health; Human; Impairment; Injury; Intervention; Isotonic Exercise; Leg; Level of Evidence; Link; Longevity; Longitudinal Studies; Mission; Modeling; Motor; Motor Neurons; Mus; Muscle; Phenotype; Public Health; Rattus; Reporting; Research; Rodent; Role; Sepsis; Serotonin; Serotonin Receptor 5-HT2C; Shapes; Tamoxifen; Testing; Thigh structure; Thinness; Translating; United States National Institutes of Health; Work; age related; age-related muscle loss; aged; design; experimental study; human data; human old age (65+); indexing; insight; longitudinal design; motor disorder; muscle form; muscle strength; neural; neuromechanism; neuronal excitability; pharmacologic; physically handicapped; pre-clinical; response; septic; treatment strategy

ABSTRACT More than 40% of older adults (OAs) report limitations to performing tasks that are essential to maintain independence. Weakness is an important contributor to physical impairments; indeed, weakness predisposes OAs to a four-fold increase in physical limitations. Because strength is a vital factor for health and longevity, more comprehensive understanding of the causes of weakness is needed to develop targeted interventions to enhance strength and function in OAs. While age-related loss of muscle mass and quality are partly responsible for weakness, there is increasing evidence that deficits in neural activation are critically linked to age-related weakness. In particular, we and others have demonstrated that weakness associated with aging and other conditions (e.g., disuse, injury, sepsis) is due, in part, to neural hypoexcitability. In this application, we seek to fundamentally advance our understanding of the mechanisms of and treatment strategies for age-related weakness and mobility limitations through translational human (Aim 1) and pre-clinical rodent (Aim 2) experiments that, collectively, will provide strong data indicating a causal association between neural hypoexcitability and age-related weakness. The first aim will test the hypothesis that indices of neural hypoexcitability are associated with greater future (longitudinal) losses of strength in OAs. Here, we will leverage data from a prior R01 to conduct a longitudinal study in humans where we quantify indices of neural excitability, lean mass, strength, and mobility after ~ 8-years in older adults. These data will be used to determine the relative contribution of indices of neural excitability and thigh lean mass on future decline in muscle strength in older adults, with a robust design accounting for alternative mechanisms. By using a longitudinal design in humans, this aim will provide the strongest level of evidence for neural excitability being a key predictor of age-related strength loss, which is a paradigm shift away from the current consideration of primarily muscular factors (e.g., muscle mass). The second aim will consist of four experiments. Experiments 1-3 will use a 5-HT2c agonist (lorcaserin) with a well-known mechanism of action that increases persistent inward currents and motoneuron excitability. SA2.1 will test the hypothesis that there is an inverted U-shape relationship between 5-HT2c agonist dose and motor function response in old mice. SA2.2 will test the hypothesis that a 5-HT2c agonist will enhance motor function in aged mice by increasing neural excitation to demonstrate that the reduction in MN excitability is a significant contributor to motor dysfunction in old mice. SA2.3 will test chronic effects of lorcaserin treatment on motor unit number and function in aged mice. SA2.4 will test the impact of tamoxifen-inducible genetic deletion of 5-HT2c receptors in MNs using Cre-Lox system. In the long-term, this proof-of-concept, proof-of-mechanism work could serve as evidence for a neurotherapeutic agent to enhance motor function in older adults.

抽象的 超过40％的老年人（OAS）报告对维护至关重要的任务的限制 独立。弱点是造成身体障碍的重要原因。确实，弱点易于体现 OAS的身体局限性增加了四倍。因为力量是健康和寿命的重要因素，所以 需要对弱点的原因进行更全面的了解，以开发针对性的干预措施 增强OA中的强度和功能。而与年龄有关的肌肉质量和质量的损失部分负责 对于弱点，有越来越多的证据表明神经激活的缺陷与年龄有关 弱点。特别是，我们和其他人已经证明，与衰老和其他人有关的弱点 条件（例如，废除，损伤，败血症）部分归因于神经性脱位性。在此应用程序中，我们试图 从根本上促进我们对与年龄有关的机制和治疗策略的理解 通过翻译人（AIM 1）和临床前啮齿动物（AIM 2）的弱点和流动性限制（AIM 2） 共同提供了强大的数据，表明神经之间存在因果关系 低兴奋性和与年龄相关的弱点。第一个目的将检验神经索引的假设 低兴奋性与OAS中强度的更大未来（纵向）损失有关。在这里，我们将利用 来自先前R01的数据在人类中进行纵向研究，在该研究中，我们量化了神经兴奋性指标， 老年人约8年后，瘦小的质量，力量和流动性。这些数据将用于确定亲戚 神经兴奋性和大腿瘦质量指标的贡献对较老的肌肉力量的未来下降 成人，具有强大的设计会计，以替代替代机制。通过在人类中使用纵向设计， 这个目标将为神经兴奋性成为与年龄相关的关键预测指标提供最强的证据 强度损失，这是一个范式转移到目前主要是肌肉因素的考虑（例如， 肌肉质量）。第二个目标将由四个实验组成。实验1-3将使用5-HT2C激动剂 （Lorcaserin）具有众所周知的作用机理，可增加持续的内向电流和运动神经元 兴奋性。 SA2.1将检验以下假设：5-HT2C激动剂之间存在倒的U形关系 老鼠的剂量和运动功能反应。 SA2.2将测试5-HT2C激动剂的假设将增强 通过增加神经激发，证明MN兴奋性的降低，在老年小鼠中的运动功能 是老鼠运动功能障碍的重要贡献者。 SA2.3将测试Lorcaserin治疗的慢性影响 关于老年小鼠的运动单位编号和功能。 SA2.4将测试他莫昔芬诱导的遗传缺失的影响 使用Cre-Lox系统在MNS中的5-HT2C受体的摄入。从长远来看，这种概念验证，机构证明 工作可以作为神经治疗剂的证据，以增强老年人的运动功能。