Mechanisms of age-related susceptibility of NMJ function

摘要 本应用的目标是确定营养相互作用在易感性(或恢复力)中的作用 衰老对神经肌肉系统的影响。与年龄相关的神经肌肉功能障碍是一个重要的 总体健康的决定因素，限制了独立性，增加了虚弱，使个人更容易衰老- 相关的合并症和死亡率。运动神经元与其支配的肌纤维之间的相互作用 确定肌肉纤维特性，并在整个生命周期内对肌肉功能产生重大影响。 运动神经元-肌肉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)在成人NMJ的维持中具有已知的作用。然而，BDNF/TrkB的作用 目前还不了解老年时的信号传递。令人振奋的最新研究表明，TrkB激酶的抑制 活动对不同年龄段的神经肌肉传递产生有害影响，复制 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来 从机制上探讨营养因子信号中断在老年NMJ的作用。我们的工作 假设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信号在NMJ(目标1)和运动神经元(目标2)施加的纤维营养影响。 此外，营养因子可以决定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物的积累和老年时的退化。两个具体目标是 建议：具体目标1)确定潜在的细胞(营养因子依赖)机制 老年人对神经肌肉功能障碍的易感性。具体目标2)确定分子(营养 因素依赖)运动神经元的年龄相关效应的潜在机制。这些结果构成了 开发靶向治疗以减轻神经肌肉衰老效应的必要基础 通过在晚年开始的治疗来对抗老龄化人口的表现和延长健康寿命 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.