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.

总结： SNS失败在老年和神经退行性疾病中很常见，这些疾病损害了对常见疾病的适应。 生理应激源我们和其他人发现交感神经轴突支配骨骼肌纤维， 维持骨骼肌组成的完整性和突触前和突触后的功能 神经肌肉接头（NMJ）在健康和疾病。我们还证明，（a）SNS损伤导致 （B）SNS和拟交感神经药都调节运动神经元突触， 囊泡释放和突触后分子组成;以及（c）衰老减弱SNS对NMJ的影响 传输这些数据支持SNS对运动神经元和肌纤维分子的强烈影响 组成和功能。 进一步研究发现，SNS和拟交感神经药调节运动神经元突触囊泡的释放 通过细胞外Ca 2+和诸如TRPV 1和P/Q-和N-型电压激活的Ca 2+等分子靶点 渠道最近，我们证明了？1-肾上腺素受体在运动神经元中表达并下降 显着老化。这些研究揭示了影响的分子基质 外周交感神经元对幼年小鼠NMJ传递的影响及其随增龄的下降。但我们 我不知道是否以及如何中央自主中继（汽车）-特别是脑桥A5核， 投射到脊髓中间外侧（IML）柱-调节骨骼肌质量，强度， 神经支配和NMJ传输以及这种影响是否随时间而下降。光遗传学结合 神经元逆行标记提供了一个独特的机会，以确定A5核在生活中的确切作用， 小鼠 基于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去神经支配和质量损失 和力量 以下具体目标被设计来测试该假设：目标1定义A5交感神经的作用 肌运动神经元失神经支配时，NMJ受损 传输，和肌肉减少症与老化，和目标2将决定是否持续表达的主人 A5 SNPHLM中交感神经转录因子Phox-2b减弱骨骼肌交感神经和运动 随着年龄的增长， 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神经中的作用的项目。 神经支配它将阐明上层控制的电机单元，以实现集成，全面 了解衰老性肌肉减少症。成功的结果将使肌肉减少症的治疗目标从 骨骼肌到中枢交感神经元。