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.

摘要： SNS失败在老年和神经退行性疾病中很常见，这些疾病损害了对共同 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 在突触前和突触后维持骨骼肌组成和功能的完整性 神经肌肉接头(NMJ)与健康和疾病我们还证明：(A)SNS功能受损会导致 骨骼肌运动失神经；(B)三叉神经节和拟交感神经对运动神经元突触的调节 囊泡释放和突触后分子组成；以及(C)衰老减弱了SNS对NMJ的影响 变速箱。这些数据支持了SNS对运动神经元和肌纤维分子的强烈影响 组成和功能。 进一步研究，我们发现SNS和拟交感神经调节运动神经元突触小泡的释放 通过细胞外钙离子和TRPV1、P/Q和N型电压激活的钙离子等分子靶点 频道。最近，我们发现？1-肾上腺素能受体在运动神经元中表达，并呈递减趋势。 随着年龄的增长显著增加。这些研究揭示了分子底物，它解释了 幼年小鼠外周交感神经元对NMJ传递的影响及其随年龄的下降。然而，我们 不知道中枢自主神经是否和如何传递(CARS)--特别是桥脑A5核，它 投射到脊髓中间外侧(IML)柱-调节骨骼肌质量，力量， 神经支配和NMJ传递，以及这种影响是否会随着时间的推移而减弱。光遗传学与 神经元逆行标记为确定A5核在生活中的确切作用提供了一个独特的机会 老鼠。 根据我们已发表的和初步的数据，我们认为衰老损害了A5核对 外周SNS，增加骨骼肌交感神经和运动神经的失神经和质量损失 和力量。 以下具体目标旨在检验这一假设：目标1定义A5交感神经的作用 NMJ受损肌肉运动神经元失神经投射到后肢肌肉的神经元(SNPHLM) 随着年龄的增长，骨质疏松症的持续表达和目标2将决定是否持续表达的主人 A5SNPHLM中交感转录因子Phox-2b减弱骨骼肌交感神经和运动 随着年龄的增长而丧失神经。 这个项目将第一次定义汽车在NMJ传递以及肌肉交感和运动中的作用 神经支配。它将阐述对电机单元的上层控制，实现一体化、全面化 对老年性石棺减少症的认识。成功的结果将使石棺减少症的治疗目标从 从骨骼肌到中枢交感神经元。