Mechanisms of age-related susceptibility of NMJ function

摘要 本申请的目的是确定营养相互作用在对环境的敏感性（或恢复力）中的作用。 衰老对神经肌肉系统的影响神经肌肉功能障碍是一个重要的 整体健康的决定因素，限制独立性，增加脆弱性和使个体易衰老- 相关的合并症和死亡率。运动神经元及其支配的肌纤维之间的相互作用 决定肌肉纤维的特性，并在整个寿命期间对肌肉功能产生重大影响。 运动神经元-肌纤维的相互作用可能是通过不同肌群的营养因子来实现的。 脑源性神经营养因子（BDNF）通过其高亲和力受体原肌球蛋白相关激酶发挥作用 受体（TrkB）在维持成人NMJ中具有已知的作用。然而，BDNF/TrkB的作用 老年的信号传导目前还不清楚。最近令人兴奋的研究表明，抑制TrkB激酶 活动对不同年龄组的神经肌肉传递产生有害影响， 老年对年轻NMJ的影响。目前的提案将使用高度创新的方法组合， 机械地探索在老年NMJ中破坏的营养因子信号传导的作用。我们的工作 一种假说认为，与年龄相关的神经肌肉功能障碍的易感性取决于运动神经元-肌肉 BDNF/TrkB信号传导在NMJ（aim 1）和运动神经元（aim 2）处施加的纤维营养影响。 此外，营养因子可以决定对自噬引起的神经肌肉损伤的易感性 不平衡导致蛋白质聚集和老年退化。两个具体目标是 提出的：具体目的1）确定细胞（营养因子依赖性）机制， 易患老年神经肌肉功能障碍。具体目的2）确定分子（营养 因素依赖性）的机制在运动神经元的年龄相关的影响。这些结果构成了 开发靶向治疗以减轻神经肌肉老化影响的必要基础 性能和增加健康寿命的老龄化人口与治疗开始后，在生活中，以打击 脆弱和残疾。

ABSTRACT The goal of this application is to determine the role of trophic interactions in the susceptibility (or resilience) to the effects of aging on the neuromuscular system. Age-related neuromuscular dysfunction is an important determinant of overall health, limiting independence, increasing frailty and predisposing individuals to age- related co-morbidities and mortality. Interactions between motoneurons and the muscle fibers they innervate determine muscle fiber properties and have a significant impact on muscle function throughout the lifespan. Motoneuron-muscle fiber interactions are likely exerted via trophic factors that vary across muscle groups. Brain-derived neurotrophic factor (BDNF) acting via its high-affinity receptor tropomyosin related kinase receptor (TrkB) has a known role in the maintenance of the adult NMJ. However, the role of BDNF/TrkB signaling in old age is not presently understood. Exciting recent studies show that inhibition of TrkB kinase activity exerts deleterious effects on neuromuscular transmission that vary across age groups, replicating the effects of old age at young NMJs. The current proposal will use a combination of highly-innovative methods to explore mechanistically the role of disrupted trophic factor signaling at the NMJ in old age. Our working hypothesis is that susceptibility to age-related neuromuscular dysfunction depends on motoneuron-muscle fiber trophic influences exerted by BDNF/TrkB signaling at the NMJ (aim 1) and motoneuron (aim 2). Furthermore, trophic factors can determine susceptibility to neuromuscular damage resulting from autophagy imbalance causing accumulation of protein aggregates and degeneration in old age. Two specific aims are proposed: Specific Aim 1) To determine the cellular (trophic factor dependent) mechanisms underlying susceptibility to neuromuscular dysfunction in old age. Specific Aim 2) To determine the molecular (trophic factor dependent) mechanisms underlying age-related effects at motoneurons. These results constitute the necessary foundation for the development of targeted therapies to mitigate aging effects on neuromuscular performance and increase the health span in the aging population with therapies initiated later in life to combat frailty and disability.