Role of Central Autonomic Relays in Aging Sarcopenia

中枢自主神经继电器在老年性肌肉减少症中的作用

• 批准号: 10363160
• 负责人: Osvaldo Delbono
• 金额: $ 59.41万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-15 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10363160
• 关键词: 4-ethoxymethylene-2-phenyl-2-oxazoline-5-one; Adrenergic Receptor; Affect; Age; Aging; Attenuated; Axon; Cell Nucleus; Chronic; Collection; Data; Denervation; Development; Disease; Elderly; Failure; G-Protein-Coupled Receptors; Gene Expression; Gene Expression Profiling; Gene Silencing; Genes; Halorhodopsins; Health; Hindlimb; Homeobox; Imaging Techniques; Impairment; Intervention; Label; Measures; Mediating; Methylation; Molecular; Molecular Target; Monitor; Motor; Motor Neurons; Mus; Muscle; Muscle Fibers; Muscle function; Muscular Atrophy; Neurodegenerative Disorders; Neuromuscular Junction; Neurons; Neurotransmitters; Norepinephrine; Patch-Clamp Techniques; Peripheral; Physiological; Pontine structure; Proteins; Publishing; Quality of life; Reaction; Regulation; Role; Signal Transduction; Skeletal Muscle; Spinal Cord; Sympathetic Nervous System; Sympathomimetics; Synaptic Vesicles; TRPV1 gene; Testing; Time; Tissues; Transcript; Wasting Syndrome; age related; base; delivery vehicle; demethylation; design; disability; extracellular; human old age (65+); improved; innovation; light gated; motor control; muscle form; muscular structure; nerve supply; novel strategies; optogenetics; physiologic stressor; postsynaptic; presynaptic; protein expression; retrograde transport; sarcopenia; side effect; tool; transcription factor; transcriptome sequencing; transmission process; vector; vesicular release; voltage

Summary: SNS failure is common in old age and neurodegenerative diseases that impair adaptation to common physiological stressors. We and others found that sympathetic axons innervate skeletal muscle fibers and maintain the integrity of skeletal muscle composition and function at the presynaptic and postsynaptic neuromuscular junction (NMJ) in health and disease. We also demonstrated that (a) SNS impairment leads to skeletal muscle motor denervation; (b) both the SNS and sympathomimetics regulate motoneuron synaptic vesicle release and postsynaptic molecular composition; and (c) aging blunts the influence of the SNS on NMJ transmission. These data support the strong influence of the SNS on motoneuron and myofiber molecular composition and function. Probing deeper, we found that the SNS and sympathomimetics regulate motoneuron synaptic vesicle release via extracellular Ca2+ and such molecular targets, as TRPV1 and P/Q- and N-type voltage-activated Ca2+ channels. Recently, we demonstrated that ?1-adrenoceptor is expressed in motoneurons and declines significantly with aging. These studies unveil the molecular substrate that accounts for the influence of peripheral sympathetic neurons on NMJ transmission in young mice and its decline with aging. However, we do not know whether and how the central autonomic relays (CARs)—particularly the pontine A5 nucleus, which projects to the spinal cord intermediolateral (IML) column—regulate skeletal muscle mass, strength, innervation, and NMJ transmission and whether this influence declines over time. Optogenetics combined with neuron retrograde labeling provides a unique opportunity to determine the precise role of A5 nucleus in living mice. Based on our published and preliminary data, we propose that aging impairs A5 nucleus regulation of the peripheral SNS, increasing skeletal muscle sympathetic and motor denervation and loss of mass and strength. The following specific aims are designed to test this hypothesis: Aim 1 define the role of A5 sympathetic neurons projecting to hindlimb muscles (SNPHLM) in muscle motoneuron denervation, impaired NMJ transmission, and sarcopenia with aging, and Aim 2 will determine whether sustained expression of the master sympathetic transcription factor Phox-2b in A5 SNPHLM attenuates skeletal muscle sympathetic and motor denervation with aging. This project will be the first to define CARs’ role in NMJ transmission and muscle sympathetic and motor innervation. It will elucidate upper level control of the motor unit to achieve an integrated, comprehensive understanding of aging sarcopenia. Successful results will shift the treatment target for sarcopenia from the skeletal muscle to the central sympathetic neuron.

概括： SNS失败在老年和神经退行性疾病中很常见，这些疾病会损害对常见的适应 生理压力源。我们和其他人发现交感神经轴突支配骨骼肌纤维和 在突触前和突触后保持骨骼肌组成和功能的完整性 健康和疾病中的神经肌肉结（NMJ）。我们还证明了（a）SNS损害导致 骨骼肌运动神经； （b）SNS和交感神经学调节运动神经元突触 囊泡释放和突触后分子组成； （c）衰老钝化SNS对NMJ的影响 传播。这些数据支持SNS对运动神经元和肌纤维分子的强大影响 组成和功能。 更深入地探讨，我们发现SNS和交感神经调节运动神经元突触囊泡释放 通过细胞外Ca2+和此类分子靶标，例如TRPV1，P/Q-和N型电压激活的Ca2+ 频道。最近，我们证明了1-肾上腺素受体在运动神经元中表达并下降 大量衰老。这些研究揭示了解释的分子底物 年轻小鼠NMJ传播的外周交感神经元及其随着衰老而下降。但是，我们 不知道中央自主神经（CARS）是否以及如何尤其是pontine a5核的中心自主。 脊髓中间侧面（IML）柱的项目 - 调节骨骼肌肉质量，力量， 神经和NMJ的传播以及这种影响是否随着时间的推移而下降。光遗传学结合 神经元逆行标签提供了一个独特的机会来确定A5核在生命中的精确作用 老鼠。 基于我们发布的和初步数据，我们建议衰老会损害A5核调节 外围社交媒体，增加了骨骼肌肉交感神经和运动神经，质量的损失 和力量。 以下特定目的旨在检验以下假设：目标1定义A5同情的作用 在肌肉运动神经元改造中投射到后肢肌肉（SNPHLM）的神经元受损NMJ 传播和随老化的肌肉减少症，AIM 2将决定主的持续表达 A5 snphlm中的交感神经转录因子PHOX-2B减弱骨骼肌肉交感神经和运动 衰老的神经。 该项目将是第一个定义汽车在NMJ传输和肌肉交感神经和运动中的作用的项目 神经。它将阐明电动机的上层控制，以实现集成，全面的 了解衰老的肌肉减少症。成功的结果将使肌肉减少症的治疗目标从 骨骼肌到中央交感神经元。