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: 10569556
• 负责人: Osvaldo Delbono
• 金额: $ 58.18万
• 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/10569556
• 关键词: Acceleration; 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; Recombinant adeno-associated virus (rAAV); Regulation; Role; Signal Transduction; Skeletal Muscle; Spinal Cord; Sympathetic Nervous System; Sympathomimetics; Synaptic Vesicles; TRPV1 gene; Testing; Time; Tissues; Transcript; Wasting Syndrome; age related; 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; remediation; 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 故障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问题的适应。 我们和其他人发现交感神经轴突支配骨骼肌纤维和 维持突触前和突触后骨骼肌组成和功能的完整性 我们还证明，(a) SNS 损伤会导致神经肌肉接头 (NMJ) 的健康和疾病。 (b) SNS 和拟交感神经药均调节运动神经元突触 囊泡释放和突触后分子组成；(c) 衰老减弱了 SNS 对 NMJ 的影响 这些数据支持 SNS 对运动神经元和肌纤维分子的强烈影响。 组成和功能。 更深入的探索，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 Ca2+ 和 TRPV1 以及 P/Q- 和 N 型电压激活 Ca2+ 等分子靶标 最近，我们证明α1-肾上腺素受体在运动神经元中表达并下降。 这些研究揭示了影响衰老的分子底物。 外周交感神经元对年轻小鼠 NMJ 传递的影响及其随年龄的增长而下降。 不知道中枢自主神经中继 (CAR) 是否以及如何进行——特别是脑桥 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随着时间的推移而减弱。 神经元逆行标记提供了一个独特的机会来确定 A5 核在活体中的精确作用 老鼠。 根据我们已发表的初步数据，我们认为衰老会损害 A5 核的调节 外周 SNS，增加骨骼肌交感神经和运动去神经支配以及质量损失 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 肌肉运动神经元去神经支配、NMJ 受损时投射到后肢肌肉的神经元 (SNPHLM) 传播，肌肉减少症与衰老有关，目标2将决定主控是否持续表达 A5 SNPHLM 中的交感神经转录因子 Phox-2b 减弱骨骼肌交感神经和运动神经 随衰老而去神经支配。 该项目将是第一个定义 CAR 在 NMJ 传输以及肌肉交感神经和运动中的作用的项目 它将阐明运动单元的上层控制以实现集成的、全面的。 对衰老性肌少症的认识。成功的结果将改变肌少症的治疗目标。 骨骼肌到中枢交感神经元。