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

基本信息

  • 批准号:
    10363160
  • 负责人:
  • 金额:
    $ 59.41万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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.
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项目成果

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Osvaldo Delbono其他文献

Osvaldo Delbono的其他文献

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{{ truncateString('Osvaldo Delbono', 18)}}的其他基金

Accelerated Sarcopenia in Early Alzheimer's Disease
早期阿尔茨海默病加速肌肉减少症
  • 批准号:
    10589353
  • 财政年份:
    2022
  • 资助金额:
    $ 59.41万
  • 项目类别:
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
  • 财政年份:
    2022
  • 资助金额:
    $ 59.41万
  • 项目类别:
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:
    9921285
  • 财政年份:
    2017
  • 资助金额:
    $ 59.41万
  • 项目类别:
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:
    9386285
  • 财政年份:
    2017
  • 资助金额:
    $ 59.41万
  • 项目类别:
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
  • 财政年份:
    2017
  • 资助金额:
    $ 59.41万
  • 项目类别:
Administrative Research Supplement to Promote Diversity in Health-Related Research
促进健康相关研究多样性的行政研究补充
  • 批准号:
    10227360
  • 财政年份:
    2017
  • 资助金额:
    $ 59.41万
  • 项目类别:
FBT-PET Study of Aging Skeletal Muscle
衰老骨骼肌的 FBT-PET 研究
  • 批准号:
    7758242
  • 财政年份:
    2009
  • 资助金额:
    $ 59.41万
  • 项目类别:
Role of Calcium Channels in Aging Skeletal Muscle
钙通道在骨骼肌衰老中的作用
  • 批准号:
    8207958
  • 财政年份:
    2009
  • 资助金额:
    $ 59.41万
  • 项目类别:
Role of Calcium Channels in Aging Skeletal Muscle
钙通道在骨骼肌衰老中的作用
  • 批准号:
    8010208
  • 财政年份:
    2009
  • 资助金额:
    $ 59.41万
  • 项目类别:
Role of Calcium Channels in Aging Skeletal Muscle
钙通道在骨骼肌衰老中的作用
  • 批准号:
    7764524
  • 财政年份:
    2009
  • 资助金额:
    $ 59.41万
  • 项目类别:

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