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

拟议研究的摘要 身体机能丧失是一个主要的公共卫生问题，与身体素质下降有关 生命，残疾风险的增加，以及医疗费用的增加。骨质疏松症，或病理性年龄相关肌肉 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 通过将下行输入转换为力来表示中枢神经系统的最终公共输出 通过神经肌肉连接激活肌肉收缩。我们之前的工作已经证明，衰老的老鼠 具有运动神经元功能障碍和与肌肉失去连接的显著特征，以及运动神经元 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 根据先前的研究和我们最近的初步数据支持的科学假设：1.运动神经元的丧失 与肌肉的连通性是导致与年龄相关的肌肉功能丧失的驱动力，2.肌肉丧失 功能是身体功能丧失的主要原因，3.压力会加剧或加速这种影响 老化对发动机单元连接性的影响。我们最近的数据表明，老年小鼠的社交孤立会导致 神经肌肉连接处运动单位连接性的加速丧失。我们之前的工作证明了 老龄小鼠在27个月时表现出NMJ传播的丧失。在一个月的单人住房(一只鼠标 22个月大的小鼠表现出加速的NMJ衰竭，典型的是直到27个月才见过。该计划的目标是 目前的提案将调查我们的新发现，即社会隔离与NMJ年龄相关性丧失之间的联系 变速箱。该提案的目标1将检验以下假设：社会隔离--加速身体损失 功能与年龄和性别有关。为了达到这一目标，我们将比较群体和单独饲养的小鼠在 三岁：6个月、15个月和22个月。将对雄性和雌性小鼠进行分组平衡，以比较它们之间的效果 性别。根据初步数据预测：1.社会隔离--身体机能加速丧失 在15个月和22个月大的小鼠身上会很明显，但在6个月大的小鼠身上不会。目标2将决定 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的交感神经支配对维持突触完整性和 突触前乙酰胆碱释放。根据这些发现和压力影响交感神经的事实， 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 变速箱故障。这些研究的结果将有助于我们理解生理和心理之间的关系。 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复原力的潜在模型。我们的结果将对老年人产生影响 经历改变生活的事件或创伤性事件，如失去配偶或所爱的人，退休或 住院治疗可能都会对心理和身体健康产生负面影响。

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.