Acute Lung Injury Induces Skeletal Muscle Atrophy

描述（由申请人提供）：肌肉无力在急性肺损伤（ALI）患者中很常见。这种虚弱迅速发作，住院后至少持续两年。虚弱，而不是肺功能受损，似乎是造成ALI幸存者相关发病率的原因。这一弱点的机制尚不清楚。我们使用气管内脂多糖的小鼠ALI模型产生严重的肺损伤和肌肉重量减轻。我们的初步数据表明，通过组织学变化和骨骼肌特异性蛋白质降解途径的激活，ALI小鼠发生骨骼肌萎缩。为了确定ALI小鼠肌肉萎缩的分子机制，我们提出以下计划：Specific Aim 1将确定ALI小鼠骨骼肌萎缩的结构和生化表型以及功能后果。我们计划描述ALI小鼠的功能和组织学表型，探索蛋白质合成与降解，并阐明这些动物肌肉萎缩的潜在机制。我们将确定纤维的大小和类型，并测量完整和外植骨骼肌的力量。我们将使用离体肌肉制剂、RT-qPCR和Western blot分析来探索这些小鼠肌肉萎缩的分子途径。由于ALI小鼠也减少了自愿食物摄入量，因此特异性目标2的目标将是确定减少食物摄入量对ALI小鼠骨骼肌萎缩的影响。我们计划通过配对喂养对照组和通过胃造口管强制喂养ALI小鼠来严格控制ALI小鼠食物摄入量的减少。我们还将研究这些动物明显的食欲抑制是否表明恶病质状态，以及这种状态如何改变肌肉萎缩和损害恢复过程。本建议的重点是ALI中肌肉萎缩的机制以及减少食物摄入如何影响这一过程。肌肉萎缩在ALI中解决了一个重要的健康问题和一个相对未开发的科学研究领域。我们的最终目标是开发干预措施或治疗方法，以减轻与ALI相关的肌肉无力的发病率。摘要：急性肺损伤（ALI）的幸存者会经历严重的肌肉无力，这种肌肉无力快速发作，并在住院后持续至少两年。这一缺陷的病因尚不清楚。在我们的ALI模型中，小鼠经历了严重的体重减轻和肌肉损伤。我们建议描述肌肉损伤的类型和程度，并确定这个过程是如何发生的。我们的最终目标是发展对这一过程的理解，这将导致合理和特定的治疗，以预防和逆转all诱导的肌肉损伤。

DESCRIPTION (provided by applicant): Muscle weakness is common among patients who develop acute lung injury (ALI). The weakness is rapid in onset and persists for at least two years following hospitalization. Weakness, not impaired lung function, appears to account for the morbidity associated with survivors of ALI. The mechanisms for this weakness are poorly understood. Our murine model of ALI using intratracheal lipopolysaccharide produces profound lung injury and muscle weight loss. Our preliminary data show that ALI mice develop skeletal muscle atrophy, measured by histological changes and by activation of skeletal muscle specific protein degradation pathways. To define the molecular mechanisms of muscle wasting in ALI mice, we propose the following plan: Specific Aim 1 will define the structural and biochemical phenotypes and functional consequences of skeletal muscle wasting in ALI mice. We plan to describe the functional and histologic phenotype of ALI mice, explore protein synthesis versus degradation, and elucidate potential mechanisms of muscle atrophy in these animals. We will determine fiber size and type, and measure force of both intact and explanted skeletal muscles. We will use ex vivo muscle preparations, RT-qPCR, and Western blot analysis to explore molecular pathways of muscle atrophy in these mice. Because ALI mice also have reduced voluntary food intake, the goal of Specific Aim 2 will be to define the effects that reduced food intake plays on the skeletal muscle wasting seen in ALI mice. We plan to rigorously control for the reduction in food intake in ALI mice both by pair-feeding the controls and by enforced feeding of ALI mice through gastrostomy tubes. We will also investigate whether the apparent suppression of appetite in these animals is indicative of a state of cachexia and how this state may alter muscle wasting and impair the recovery process. The emphasis of this proposal is on the mechanisms of muscle wasting in ALI and how decreased intake of food may affect this process. Muscle wasting in ALI addresses a significant health issue and a relatively unexplored area of investigational science. Our ultimate goal is to develop interventions or therapies which would alleviate the morbidity of muscle weakness associated with ALI. LAY ABSTRACT: Survivors of acute lung injury (ALI) experience severe muscle weakness that is rapid in onset and persists for at least two years following hospitalization. The etiology of this weakness is not understood. In our model of ALI, mice undergo profound weight loss and have injured muscles. We propose to describe the type and extent of muscle injury and determine how this process occurs. Our ultimate goal is to develop an understanding of the process that will lead to rational and specific treatments to prevent and reverse ALl-induced muscle injury.