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。这种虚弱起病迅速，并在住院后至少持续两年。虚弱，而不是肺功能受损，似乎是与ALI幸存者相关的发病率的原因。人们对这种疲软的机制知之甚少。我们的小鼠ALI模型使用气管内脂多糖，可造成严重的肺损伤和肌肉重量减轻。我们的初步数据显示，ALI小鼠出现骨骼肌萎缩，通过组织学变化和骨骼肌特定蛋白降解途径的激活来衡量。为了明确ALI小鼠肌肉萎缩的分子机制，我们提出了以下计划：特定目标1将定义ALI小鼠骨骼肌萎缩的结构和生化表型及其功能后果。我们计划描述ALI小鼠的功能和组织表型，探索蛋白质合成与降解的关系，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，并测量完整和伸展的骨骼肌的力量。我们将使用体外肌肉准备、RT-qPCR和Western印迹分析来探索这些小鼠肌肉萎缩的分子途径。因为ALI小鼠的自愿食物摄入量也减少了，所以具体目标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和通过胃造口管强制喂养ALI小鼠来严格控制ALI小鼠的食物摄入量的减少。我们还将调查这些动物明显的食欲抑制是否预示着恶病质的状态，以及这种状态如何改变肌肉萎缩和损害恢复过程。这项建议的重点是ALI肌肉萎缩的机制以及食物摄入量的减少如何影响这一过程。ALI的肌肉萎缩解决了一个重要的健康问题，也是一个相对未被探索的调查科学领域。我们的最终目标是开发干预或治疗方法，以减轻与ALI相关的肌肉无力的发病率。急性肺损伤(ALI)的存活者会出现严重的肌肉无力，发病迅速，住院后至少持续两年。这种疲软的原因尚不清楚。在我们的ALI模型中，小鼠体重大幅下降，肌肉受损。我们建议描述肌肉损伤的类型和程度，并确定这一过程是如何发生的。我们的最终目标是发展对这一过程的理解，这将导致合理和具体的治疗方法，以预防和逆转所有诱发的肌肉损伤。

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.