Social Isolation and Loss of Physical Function: Defining a Novel Neuromuscular Phenotype

社会孤立和身体功能丧失：定义一种新的神经肌肉表型

• 批准号: 10263238
• 负责人: William David Arnold
• 金额: $ 7.8万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10263238
• 关键词: Acetylcholine; Affect; Age; Age-Months; Aging; Axon; Behavioral; Climacteric; Data; Economic Burden; Elderly; Electrophysiology (science); Equilibrium; Event; Exhibits; Failure; Female; Frequencies; Functional disorder; Gender; Hand Strength; Health Care Costs; Hospitalization; House mice; Housing; Individual; Life; Life Experience; Link; Loneliness; Longevity; Maintenance; Measures; Mental Health; Meta-Analysis; Modeling; Motor; Motor Neurons; Mus; Muscle; Muscle Contraction; Muscle Weakness; Muscle function; Muscular Atrophy; Neuraxis; Neuromuscular Junction; Outcome; Output; Pathologic; Phenotype; Physical Function; Physiological; Public Health; Quality of life; Research; Retirement; Social Network; Social isolation; Societies; Spouses; Stress; Synapses; Techniques; Testing; Training; Weight; Women' s Group; Work; age effect; age related; age-related muscle loss; aged; base; design; disability risk; driving force; experience; experimental study; in vivo; loved ones; male; middle age; mortality risk; mouse model; nerve supply; neuromuscular; neuromuscular function; neuromuscular system; novel; physical conditioning; postsynaptic; presynaptic; psychologic; quantum; resilience; sarcopenia; sex; synaptic function; transmission process; traumatic event

Summary of the proposed research Loss of physical function is a major public health problem that is associated with diminished quality of life, increased risk for disability, and increased healthcare costs. Sarcopenia, or pathological age-related muscle wasting and weakness, is a major contributor to loss of physical function in older individuals. Motor neurons represent the final common output for the central nervous system by converting descending inputs into forces by activating muscle contraction via neuromuscular junctions. Our prior work has demonstrated that aged mice have striking features of motor neuron dysfunction and loss of connectivity with muscle and that motor neuron connectivity is tightly associated with muscle size and function in aged mice. Our proposal is based on the following scientific premises supported by prior research and our recent preliminary data: 1. Loss of motor neuron connectivity with muscle is a driving force leading to age-related loss of muscle function, 2. Loss of muscle function is a major contributor to loss of physical function, and 3. Stress can exacerbate or accelerate the effects of aging on motor unit connectivity. Our recent data demonstrate that social isolation in aged mice results in accelerated losses of motor unit connectivity at the neuromuscular junction. Our prior work demonstrated that aged mice exhibit loss of NMJ transmission at 27 months. Following one month of single housing (one mouse per cage) 22-month-old mice show accelerated NMJ failure typical not seen until 27 months. The aims of the current proposal will investigate our novel findings of a link between social isolation and age-related loss of NMJ transmission. Aim 1 of the proposal will test the hypotheses that social isolation-accelerated loss of physical function is age- and sex-dependent. To achieve this aim, we will compare both group and single housed mice at three ages: 6, 15, and 22 months. Groups will be balanced for male and female mice to compare effects between genders. Based on preliminary data, it is predicted that: 1. Social isolation-accelerated loss of physical function will be evident in 15- and 22-month-old mice but not 6-month-old mice. Aim 2 will determine the pathophysiological mechanism of NMJ transmission failure following social isolation. Recent work has highlighted the importance of sympathetic innervation of the NMJ for maintenance of synaptic integrity and presynaptic acetylcholine release. Based on these findings and the fact that stress impacts sympathetic tone, we predict that social isolation may impact sympathetic function at the NMJ and thus result in presynaptic NMJ transmission failure. The results of these studies will help us understand the relationship between physical function and social-isolation induced stress as well as define social isolation-induced neuromuscular decline as a potential model to study age-related resiliency in older adults. Our results will have implications in older adults experiencing life-changing or traumatic events such as losing a spouse or loved one, retirement, or hospitalization which may all be associated with negative mental and physical health implications.

拟议研究摘要 身体机能丧失是一个重大的公共卫生问题，与身体质量下降有关 生命、残疾风险增加以及医疗费用增加。肌肉减少症，或与年龄相关的病理性肌肉 消瘦和虚弱是老年人身体机能丧失的主要原因。运动神经元 通过将下降的输入转换为力来表示中枢神经系统的最终共同输出 通过神经肌肉接头激活肌肉收缩。我们之前的工作表明，老年小鼠 具有运动神经元功能障碍以及与肌肉和运动神经元的连接丧失的显着特征 连接性与老年小鼠的肌肉大小和功能密切相关。我们的建议是基于 以下科学前提得到先前研究和我们最近的初步数据的支持： 1. 运动神经元损失 与肌肉的连接是导致与年龄相关的肌肉功能丧失的驱动力，2. 肌肉丧失 功能是导致身体功能丧失的主要原因，并且 3. 压力会加剧或加速这种影响 运动单元连接的老化。我们最近的数据表明，老年小鼠的社会隔离会导致 神经肌肉接头处运动单位连接性的加速丧失。我们之前的工作表明 老年小鼠在 27 个月时表现出 NMJ 传输丧失。单独饲养一个月后（一只老鼠 每笼）22 个月大的小鼠表现出加速的 NMJ 衰竭，典型情况直到 27 个月才出现。该组织的目标 当前的提案将调查我们关于社会孤立与年龄相关的 NMJ 丧失之间联系的新发现 传播。该提案的目标 1 将检验以下假设：社会隔离加速身体丧失 功能与年龄和性别有关。为了实现这一目标，我们将比较组小鼠和单养小鼠 三个年龄：6个月、15个月和22个月。将平衡雄性和雌性小鼠的组，以比较不同组间的效果 性别。根据初步数据预测： 1. 社会隔离——加速身体机能丧失 这种现象在 15 个月和 22 个月大的小鼠中很明显，但在 6 个月大的小鼠中则不明显。目标 2 将确定 社会隔离后 NMJ 传播失败的病理生理机制。最近的工作有 强调了 NMJ 交感神经支配对于维持突触完整性的重要性 突触前乙酰胆碱释放。基于这些发现以及压力影响交感神经张力的事实， 我们预测社会隔离可能会影响 NMJ 的交感功能，从而导致突触前 NMJ 传输失败。这些研究的结果将帮助我们理解物理之间的关系 功能和社会隔离引起的压力，以及将社会隔离引起的神经肌肉衰退定义为 研究老年人与年龄相关的弹性的潜在模型。我们的结果将对老年人产生影响 经历改变生活或创伤性事件，例如失去配偶或亲人、退休或 住院治疗可能会带来负面的心理和身体健康影响。