Aging, Exercise and Mechanisms of Altered Tongue Function

描述（由申请人提供）：有大量证据表明，肌肉减少症，肌肉大小、力量和功能的年龄相关变化，与运动神经元、神经-肌肉连接和肌肉本身的解剖和生理变化有关。除了四肢的骨骼肌外，与年龄相关的变化无疑也发生在颅肌和支配它们的脑干神经元上。舌肌和舌下运动神经元结构和功能的改变可能导致与年龄相关的吞咽和语言能力下降。然而，对于颅神经肌肉系统中与年龄相关的变化的病理生理学知之甚少。在我们的实验室中，我们在啮齿动物模型中发现了舌肌、神经肌肉连接处（NMJ）和舌下运动神经元及其血清素能神经调节输入的年龄相关变化。在我们提出的研究中，我们计划使用我们在清醒的大鼠中开发的渐进式阻力舌运动计划来研究运动在预防或逆转舌头和舌下核内与年龄相关的变化中的作用。我们的假设是，与年龄相关的舌下核变化以及去神经支配-再神经支配过程是舌肌减少症的主要原因，而这些过程可以通过运动来预防或逆转。我们将通过比较年轻、中年和老年大鼠的舌头肌肉和舌下运动神经元的生理、形态、生化和分子参数来验证这一假设，这些大鼠进行了舌头行为训练，而对照组则进行了模拟训练。拟议的研究有5个具体目标。在年轻、中年和老年大鼠中，我们将确定：(1)行为性舌力和肌肉收缩特性随年龄和运动变化的程度，以及预测舌肌肉收缩特性变化的形态学、生化和分子变量；(2)年龄和运动对舌肌形态和生化特性的影响；(3)年龄和运动对神经-肌肉连接形态的影响；(4)年龄和运动对舌下核神经元可塑性的影响；(5)神经营养因子在运动诱导的中老年大鼠神经元可塑性中的作用。这项工作具有创新性和重要性，因为运动可能影响舌运动系统神经保护作用的机制在很大程度上尚未被探索。我们的神经肌肉模型是第一个评估行为锻炼计划对颅运动神经元和舌头生理的影响的模型。此外，这项工作在理解运动作为治疗性干预颅肌年龄相关变化的潜在益处的机制方面具有重要意义。

DESCRIPTION (provided by applicant): There is an overwhelming body of evidence that links sarcopenia, the age-related changes in muscle size, strength, and function, to anatomical and physiological changes within motoneurons, nerve-muscle connections, and the muscles themselves. In addition to skeletal muscle in the limbs, age-related changes undoubtedly occur in cranial muscles and the brainstem neurons that innervate them. Alterations in tongue muscle and hypoglossal motoneuron structure and function may contribute to the age-related decline in swallowing and speech. However, little is known about the pathophysiology underlying age-related changes in the cranial neuromuscular system. In our laboratories, we have found age-related changes in tongue muscles, the neuromuscular junction (NMJ), and in hypoglossal motoneurons and their serotonergic neuromodulatory inputs in a rodent model. In the proposed research, we plan to use a progressive resistance tongue exercise program we have developed in awake rats to investigate the role of exercise in preventing or reversing age-related changes within the tongue and hypoglossal nucleus. Our hypothesis is that age-associated changes in the hypoglossal nucleus, together with denervation-reinnervation processes, are major contributors to lingual sarcopenia, and that these processes can be prevented or reversed by exercise. We will test this hypothesis by comparing physiological, morphological, biochemical, and molecular parameters of tongue muscles and hypoglossal motoneurons in young, middle-aged, and old rats that have undergone behavioral tongue exercise versus those in a sham-exercise control group. The proposed research has 5 specific aims. In young, middle-aged and old rats, we will determine: (1) the degree to which behavioral tongue forces and muscle contractile properties change as a function of age and exercise, and morphological, biochemical, and molecular variables that are predictive of changes in tongue muscle contractile properties; (2) the effect of age and exercise on morphological and biochemical properties of tongue muscles; (3) the effect of age and exercise on morphology of nerve-muscle connections, (4) the effect of age and exercise on neuronal plasticity in the hypoglossal nucleus; and, (5) the role of neurotrophins in exercise-induced neuronal plasticity in young, middle-aged, and old rats. This work is innovative and important because the mechanisms by which exercise may impact neuroprotective effects in the lingual motor system are largely unexplored. Our neuromuscular model is the first to evaluate the effects of a behavioral exercise program on cranial motoneurons and tongue physiology. Further, this work is highly significant in providing a basis for understanding mechanisms underlying the putative benefits of exercise as a therapeutic intervention for age-related changes in cranial muscles.