DIAPHRAGM ADAPTATIONS TO CHRONIC RESISTIVE LOADING

描述(申请人摘要)：长期目标：在患有 慢性阻塞性肺疾病(COPD)，呼吸肌疲劳 面对慢性肺炎，必须增加阻力以保持通风 呼吸阻力负荷(CRRL)。不幸的是，呼吸肌 体力往往不足以应付抵抗力工作量的急剧增加 这发生在临床病情恶化的时候。我们的努力是为了理解 横隔膜适应CRRL并提供基础的机制 以科学的方法预防和逆转呼吸肌 需要机械支持的慢性阻塞性肺疾病患者的功能障碍 自主通气量不足以应付日常活动。 假设1：如果有足够的血流量，有两个因素对疲劳很重要 阻力是：a)ATP周转的经济性，主要由肌球蛋白决定 重链(MHC)亚型组成，以及b)线粒体氧化 磷酸化能力。这项资助的重点是这两个因素是如何 随着隔膜适应CRRL而改变。使用长期(6个月)模型 CRRL，我们发现了横隔肌，一种混合纤维型的肌肉和主要的 吸气肌，通过增加数量和横截面积来适应 第一类，耐疲劳纤维。我认为MHC亚型的转变和 因此，纤维类型负责创造性能 悖论--提高了抗疲劳性，但降低了比力。 具体目标1：确定CRRL对横隔膜结构和MHC的影响 基因表达。假设2：提高抗疲劳性还需要 横隔膜线粒体氧化磷酸化的机制 与胞质能量需求相关联，从而维持稳定状态。在……里面 同样的长期CRRL模型，我们发现横隔膜增加 线粒体氧化磷酸化(状态3)容量。我建议 横隔膜适应与工作相关的线粒体变化的CRRL 氧化磷酸化能力和主要控制点是 三磷酸腺苷合成酶。具体目标2：确定CRRL对 膜线粒体氧化磷酸化的调控。假设3： 在COPD患者中，导致疲劳性增加的适应仍然存在 只要力量大于需求，就是有利的。然而，当阻性 在临床恶化期间负荷急剧增加，力量不再 随之而来的可能是充分性和呼吸性衰竭。我建议用呼吸系统 慢性阻塞性肺疾病患者肌肉功能障碍的主要原因是 (男)适应。具体目标3：确定人口急剧增加的影响 呼吸阻力负荷对横隔肌结构和功能的影响 已经适应了CRRL。先前的适应是使横隔膜更多还是 不那么容易受到运动性肌肉损伤的影响？

DESCRIPTION (Applicant's abstract): Long-term goal: In patients with chronic obstructive pulmonary diseases (COPD), respiratory muscle fatigue resistance must be increased to maintain ventilation in the face of chronic respiratory resistive loading (CRRL). Unfortunately, respiratory muscle strength is often not adequate to meet acute increases in resistive workload that occurs during clinical exacerbations. Our efforts are to understand the mechanisms by which the diaphragm adapts to CRRL and to provide a basis for a scientific approach to prevention and reversal of respiratory muscle dysfunction in COPD patients who require ventilatory support or whose spontaneous ventilatory capacity is insufficient for daily activities. Hypothesis 1: Given adequate blood flow, 2 factors important for fatigue resistance are: a) economy of ATP turnover, determined largely by myosin heavy chain (MHC) isoform composition, and b) mitochondrial oxidative phosphorylation capacity. This grant focuses on how these 2 factors are altered as the diaphragm adapts to CRRL. Using a model of long-term (6 mo) CRRL, we found the diaphragm, a mixed fiber type muscle and the principal inspiratory muscle, adapts by increasing number and cross-sectional area of type I, fatigue resistant fibers. I propose that shifts in MHC isoforms and thus fiber types are responsible for creating a performance paradox--increased fatigue resistance but decreased specific force. Specific aim 1: Determine effect of CRRL on diaphragm structure and MHC gene expression. Hypothesis 2: Increased fatigue resistance also requires a mechanism by which diaphragm mitochondrial oxidative phosphorylation is linked to cytosolic energy demands so that a steady state is maintained. In this same long-term CRRL model, we found an increase in diaphragm mitochondrial oxidative phosphorylation (state 3 resp.) capacity. I propose that the diaphragm adapts to CRRL with work related changes in mitochondrial oxidative phosphorylation capacity and that the primary control point is the enzyme ATP synthase. Specific aim 2: Determine the effect of CRRL on the control of diaphragm mitochondrial oxidative phosphorylation. Hypothesis 3: In COPD patients, adaptations leading to increased fatigue resistance remain favorable as long as strength exceeds demand. However, when the resistive load acutely increases during clinical exacerbations, strength is no longer adequate and ventilatory failure may ensue. I propose that respiratory muscle dysfunction in COPD patients results primarily from this (mal)adaptation. Specific aim 3: Determine effects of an acute increase in respiratory resistive load on the structure and function of diaphragm muscle already adapted to CRRL. Do prior adaptations make the diaphragm more or less susceptible to exercise-induced muscle injury?