Sarcopenia and the motor neuron

项目摘要： 骨质疏松症是一种与年龄相关的肌肉质量和力量的丧失，是一种重要的与年龄相关的疾病 神经肌肉系统与活动能力受损、丧失独立性和增加 死亡率。尽管锻炼似乎有一些有益的效果，但目前还没有经过验证的治疗方法。 而且对推动退化过程的因素的了解还不完整。神经肌肉系统是 由由单个阿尔法运动神经元、运动轴突和突触支配的一组肌肉纤维组成， 称为马达单元。运动单位的正常发育和功能依赖于营养相互作用 肌肉和运动神经元之间。肌肉纤维的失神经会导致高达80%的肌肉纤维大小损失， 同样，来自肌肉的逆行信号对运动神经元的健康也很重要。肌肉纤维的损失， 突触和运动神经元功能都被认为是老年性骨质疏松症的重要因素 和软弱。大多数对骨肉减少机制的研究都集中在肌肉上。 然而，老化过程中运动单位内退化的主要来源以及 这种丧失尚不清楚，神经对随年龄增长的肌肉功能丧失的影响也较少。 请注意。我们已经开发出体内电生理技术，可以纵向量化 能够量化来自肌肉群的功能输出的小鼠模型中的运动单位功能， 功能性运动神经元的数量和突触的完整性。我们的初步结果显示显著的 老年小鼠后肢肌肉运动神经单位池功能丧失提示 运动单位的丧失是与衰老相关的肌肉无力和骨质疏松症的主要因素。我们 假设运动神经单位功能丧失是年龄相关性痴呆的主要机制 神经肌肉功能，然而我们预测，直接调节目标组织(肌肉)可以保持 电机单元的编号和功能。对这一建议的研究将确定 运动单位在衰老相关的肌肉损失，并确定神经肌肉系统的组成部分，是 在老化过程中最易受影响(目标1)。此外，我们将通过以下方式调节肌肉(纤维的大小和数量) 过量表达卵泡抑素，以测试这是否会维持或改善神经肌肉功能，特别是 运动神经元和突触(目标2)。我们假设运动神经单位功能的丧失是早期的 衰老的功能后果，这与随后的突触衰竭和肌肉纤维有关 萎缩和功能障碍。我们预测，肌肉营养因子逆行信号的丧失是一种 对于骨质疏松症的发展具有重要的刺激作用，因此我们假设改善肌肉纤维的大小 会改善运动神经元的功能。我们的方法是创新的，因为我们将利用的技术允许 神经肌肉系统的纵向功能评估，这些措施可以提供重要的 洞察肌肉、神经元和突触因素在骨质疏松症发展过程中的相互作用。

Project Abstract: Sarcopenia, the age-related loss of muscle mass and strength, is an important age-related disorder of the neuromuscular system associated with impaired mobility, loss of independence, and increased risk of mortality. Although exercise appears to have some beneficial effect, there are no proven therapies available, and understanding of the factors driving the degenerative process is incomplete. The neuromuscular system is comprised of groups of muscle fibers innervated by a single alpha motor neuron, motor axon, and synapses, termed a motor unit. The normal development and function of the motor unit is dependent on trophic interaction between muscle and motor neurons. Denervation of muscle fibers results in up to 80% muscle fiber size loss, and similarly retrograde signaling from muscle is important to motor neuron health. Losses of muscle fiber, synaptic, and motor neuron function have all been identified as important factors in aging-related sarcopenia and weakness. The majority of investigations into the mechanisms of sarcopenia have focused on muscle. However, the primary source of degeneration within the motor unit during aging and the temporal aspects of this loss remain unknown, and the neural influence on loss of muscle function with aging has received less attention. We have developed in vivo electrophysiological techniques that allow longitudinal quantification of motor unit function in mouse models that enable quantification of the functional output from a muscle group, the number of functional motor neurons, and synaptic integrity. Our preliminary results demonstrate prominent functional loss from the motor nerve unit pool innervating the hind limb muscles in aging mice suggesting that loss of motor units is a major contributing factor to aging-related muscle weakness and sarcopenia. We hypothesize that loss of motor nerve unit function is the primary mechanism underlying age-related loss of neuromuscular function, however we predict that directly modulating the target tissue (muscle) can preserve motor unit numbers and function. The studies of this proposal will determine the degenerative changes of the motor unit during aging-related muscle loss and identify the components of the neuromuscular system that are most susceptible during aging (Aim 1). Furthermore we will modulate muscle (fiber size and number) via follistatin overexpression to test whether this will maintain or improve neuromuscular function, specifically of the motor neuron and synapse (Aim 2). We hypothesize that loss of motor nerve unit function is an early functional consequence of aging, and that this is associated with subsequent synaptic failure and muscle fiber atrophy and dysfunction. We predict that loss of retrograde signaling of trophic factors from muscle is an important stimulus for sarcopenia development, and therefore we hypothesize that improving muscle fiber size will improve motor neuron function. Our approach is innovative because the techniques that we will utilize allow longitudinal functional assessment of neuromuscular system, and these measures can provide important insight into the interaction of muscle, neuron, and synaptic factors in the development of sarcopenia.