The Role of the Sympathetic Nervous System in the Onset and Development of Sarcopenia

交感神经系统在肌少症发生和发展中的作用

• 批准号: 9386285
• 负责人: Osvaldo Delbono
• 金额: $ 31.5万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9386285
• 关键词: Adult; Affect; Age; Aging; Atrophic; Autophagocytosis; Axon; Cholinergic Receptors; Chronic; Data; Denervation; Development; Elderly; Elements; Failure; Fiber; Human; Impairment; Intervention; Lead; Link; Maintenance; Modeling; Motor; Motor Neurons; Mus; Muscle; Muscle Fibers; Muscle Weakness; Muscle denervation procedure; Muscle function; Muscular Atrophy; Nervous system structure; Neuromuscular Junction; Neurons; Peripheral Nervous System; Play; Process; Quality of life; Regimen; Regulation; Reporting; Rodent; Role; Schwann Cells; Secondary to; Skeletal Muscle; Sympathectomy; Sympathetic Nervous System; Synapses; System; Testing; Therapeutic; Time; Ubiquitin; Viral; Walking; age related; axonal sprouting; base; design; disability; innovation; multicatalytic endopeptidase complex; muscle form; muscle strength; muscular structure; nerve supply; neuron development; novel; postsynaptic; presynaptic; prevent; receptor expression; reduced muscle mass; reinnervation; relating to nervous system; sarcopenia; strength training; transcription factor; transmission process

PROJECT SUMMARY: Over time, declining muscle force and power impair mobility and quality of life. In aging rodents and humans, skeletal muscle undergoes a process of denervation and reinnervation; denervation is strongly implicated in the onset and progressive decline of skeletal muscle mass, composition, and function, termed sarcopenia. Whether muscle denervation starts at the myofiber or the central or peripheral nervous system is controversial. Answering this question is crucial for developing targeted interventions to prevent or reverse age-related decline in skeletal muscle innervation and consequent loss of mass and force. Increasing evidence supports a decline in neural influence on skeletal muscle at older ages. The neuromuscular junction (NMJ) is a tripartite synapse composed of the presynaptic motor neuron axon, postsynaptic myofiber specialization, and nonmyelinating perisynaptic or terminal Schwann cells (tSCs). With age, the NMJ becomes unstable in a process characterized by fragmentation, shrinkage, and simplification of the postterminal. Detailed studies indicate that the tripartite model includes elements that are crucial for normal skeletal muscle structure and function, so why, does the normally stable NMJ eventually destabilize? In humans, autonomic innervation and function become impaired with age. Our preliminary data support direct sympathetic innervation of the myofiber at the NMJ, sympathetic regulation of motor/somatic fiber innervation, and regulation of muscle autophagy with aging. Based on our novel preliminary data, we hypothesize that: (1) Hand2, a key transcription factor for sympathetic neuron development and maintenance, steeply declines with aging, inducing motor pre- and postsynaptic NMJ instability and disorganization, muscle denervation, and sarcopenia; and (2) Expressing Hand2 exclusively in sympathetic neurons will significantly prevent: (a) motor denervation, (b) increased ubiquitin-proteasome system (UPS) activity, (c) impaired autophagy and NMJ transmission, and (d) sarcopenia, in old (22-month) and geriatric (28-month) mice. The following specific aims are designed to test these hypotheses: Aim 1. To determine whether age-dependent sympathetic denervation causes motor denervation, NMJ disorganization and transmission failure, and sarcopenia. Aim 2. To establish whether preserving muscle sympathetic innervation prevents increased UPS, decreased autophagy flux, decreased acetylcholine receptor (AChR), and muscle motor denervation with aging. This project will be the first to define the link between two hallmarks of aging skeletal muscle—denervation and sarcopenia—and the cross-talk between the sympathetic and motor nervous systems at the skeletal muscle with aging.

项目总结： 随着时间的推移，肌肉力量和力量的下降会损害活动能力和生活质量。在老化的啮齿动物和人类身上， 骨骼肌经历去神经和再神经的过程；去神经与 骨骼肌质量、组成和功能的开始和进行性下降，称为骨质疏松症。 肌肉去神经是从肌纤维开始，还是从中枢或外周神经系统开始，目前还存在争议。 回答这个问题对于制定有针对性的干预措施以预防或扭转与年龄有关的疾病至关重要 骨骼肌神经支配功能下降，从而导致质量和力量的丧失。 越来越多的证据支持老年人神经对骨骼肌的影响有所下降。这个 神经肌肉接头(NMJ)是由突触前运动神经元轴突组成的三部分突触， 突触后肌纤维特化和非髓鞘突触周围或终末雪旺细胞(TSCS)。使用 随着年龄的增长，NMJ变得不稳定，其特征是碎裂、收缩和简化 邮局。详细的研究表明，三方模型包括对正常至关重要的元素 骨骼肌的结构和功能，那么为什么正常稳定的NMJ最终会变得不稳定？在……里面 人类的自主神经和功能会随着年龄的增长而受损。我们的初步数据直接支持 NMJ肌纤维的交感神经支配，运动/躯体纤维支配的交感神经调节， 以及随年龄增长对肌肉自噬的调节。根据我们新的初步数据，我们假设： (1)Hand2，交感神经元发育和维持的关键转录因子，急剧 随着年龄的增长而下降，导致运动突触前和突触后NMJ的不稳定和紊乱， 肌肉失神经和骨质疏松症 (2)仅在交感神经元中表达Hand2将显著阻止：(A)运动 去神经，(B)泛素-蛋白酶体系统(UPS)活性增加，(C)自噬受损和 老年鼠(22月龄)和老年鼠(28月龄)的NMJ传播和(D)骨质疏松症。 为了检验这些假设，我们设计了以下具体目标： 目的1.确定年龄依赖性交感神经去神经是否导致运动神经去神经 组织解体和传输失败，以及石棺减少。 目的2.确定保留肌肉交感神经支配是否可以防止UPS增加， 自噬流量减少，乙酰胆碱受体(AChR)减少，肌肉运动失神经 随着年龄的增长。 该项目将首次确定骨骼肌衰老的两个特征之间的联系-去神经支配和 骨质疏松症--以及骨骼肌交感神经系统和运动神经系统之间的相互作用 随着年龄的增长。