DIAPHRAGM ADAPTATIONS TO CHRONIC RESISTIVE LOADING

描述（申请人摘要）：长期目标： 慢性阻塞性肺疾病（COPD），呼吸肌疲劳 必须增加阻力，以保持通风，在面对慢性 呼吸阻力负荷（CRRL）。 不幸的是，呼吸肌 强度通常不足以满足抵抗性工作负载的急剧增加 在临床恶化期间发生。 我们的努力是为了了解 隔膜适应CRRL的机制，并提供一个基础 科学的方法来预防和逆转呼吸肌 需要呼吸支持或 自发性排便能力不足以进行日常活动。 假设1：如果有足够的血流量，2个因素对疲劳很重要 耐药是：a）ATP周转的经济性，主要由肌球蛋白决定 重链（MHC）同种型组成，和B）线粒体氧化 磷酸化能力。 该补助金的重点是如何这两个因素是 随着隔膜适应CRRL而改变。 使用长期（6个月）模型 CRRL，我们发现了隔膜，一种混合纤维型肌肉和主要的 吸气肌，通过增加数量和横截面积来适应 I型耐疲劳纤维 我认为MHC亚型的变化和 因此，纤维类型负责创建性能 悖论--增加了抗疲劳性，但降低了比力。 具体目标1：确定CRRL对膈肌结构和MHC的影响 基因表达。 假设2：增加抗疲劳性也需要 隔膜线粒体氧化磷酸化的一种机制， 与胞质能量需求相关，从而维持稳定状态。 在 同样的长期CRRL模型，我们发现横膈膜的增加， 线粒体氧化磷酸化（状态3）容量 我提议 隔膜适应CRRL与工作相关的线粒体变化， 氧化磷酸化能力和主要控制点是 ATP合成酶 具体目标2：确定CRRL对 隔膜线粒体氧化磷酸化的控制。 假设三： 在COPD患者中，导致抗疲劳性增加的适应性仍然存在， 只要力量超过需求，就很有利。 然而，当电阻 在临床加重期间负荷急剧增加，强度不再 可能会发生适当的和解释性的失败。 我建议呼吸道 COPD患者的肌肉功能障碍主要是由于 （maladaptation）适应。 具体目标3：确定艾滋病毒/艾滋病急剧增加的影响 呼吸阻力负荷对膈肌结构和功能的影响 已经适应了CRRL。 先前的适应性调整是否使隔膜更大或 更不容易受到运动引起的肌肉损伤

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?