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: 10180828
• 负责人: Osvaldo Delbono
• 金额: $ 34.67万
• 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/10180828
• 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 reinnervation; muscle strength; muscular structure; nerve supply; neuron development; novel; postsynaptic; preservation; 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.

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