Angiotensin II, IGF-1 and Skeletal Muscle Atrophy

描述（由申请人提供）：骨骼肌萎缩发生在各种疾病中，包括充血性心力衰竭（CHF），这是心血管疾病死亡和发病的主要原因。骨骼肌萎缩是慢性心力衰竭预后不良的重要预测指标，但其机制尚不清楚。全身神经体液兴奋是CHF的一个标志，包括肾素-血管紧张素-醛固酮系统（RAS）的激活。我们有证据表明血管紧张素II （ang II）通过激活泛素-蛋白水解途径和增加细胞凋亡而导致啮齿动物骨骼肌萎缩。同时，ang II通过PI 3-激酶/Akt通路降低骨骼肌胰岛素样生长因子-1 （IGF-1）和IGF-1信号通路，并增加肌肉caspase-3活性，导致肌动蛋白裂解。IGF-1在肌肉中的转基因表达可防止这些变化和angii诱导的肌肉损失。我们在压力超负荷心力衰竭模型中也有类似的初步发现。为了阐明angii和压力过载心力衰竭导致骨骼肌萎缩的分子机制，我们提出：1。表征改变的IGF-1信号机制介导angii或压力过载心力衰竭引起的骨骼肌萎缩。2. 表征angii或压力过载心力衰竭触发肌肉蛋白水解的分子机制，特别是导致肌动蛋白裂解和泛素化增加的机制。3. 通过表达一种肌肉特异性IGF-1转基因，可以预防angii或压力过载心力衰竭引起的骨骼肌萎缩。4. 表征干细胞在自分泌IGF-1预防II型诱导骨骼肌萎缩能力中的作用。这些发现将为研究慢性心力衰竭骨骼肌萎缩的分子机制提供新的见解，并为开发新的治疗策略奠定基础。

DESCRIPTION (provided by applicant): Skeletal muscle atrophy occurs in a variety of diseases including congestive heart failure (CHF), a leading cause of cardiovascular mortality and morbidity. Skeletal muscle atrophy is an important predictor of poor outcome in CHF, but mechanisms are poorly understood. The generalized neurohumoral excitation that is a hallmark of CHF includes activation of the renin-angiotensin-aldosterone system (RAS). We have evidence that angiotensin II (ang II) produces skeletal muscle atrophy in rodents via activation of the ubiquitin-protea- some proteolytic pathway and increased apoptosis. Concomitantly ang II reduces skeletal muscle insulin-like growth factor-1 (IGF-1) and IGF-1 signaling via the PI 3-kinase/Akt pathway and increases muscle caspase-3 activity leading to actin cleavage. Transgenic expression of IGF-1 in muscle prevents these changes and ang II induced muscle loss. We have preliminary similar findings in a pressure-overload heart failure model. To elucidate molecular mechanisms whereby ang II and pressure-overload heart failure produce skeletal muscle atrophy we propose: 1. To characterize altered IGF-1 signaling mechanisms mediating ang II or pressure-overload heart failure induced skeletal muscle atrophy. 2. To characterize molecular mechanisms whereby ang II or pressure-overload heart failure triggers muscle proteolysis, specifically mechanisms leading to actin cleavage and increased ubiquitinization. 3. To demonstrate that ang II or pressure-overload heart failure induced skeletal muscle atrophy can be prevented by expression of a muscle-specific IGF-1 transgene. 4. To characterize the role of stem cells in the ability of autocrine IGF-1 to prevent ang II induced skeletal muscle atrophy. These findings should provide novel insights into molecular mechanisms of skeletal muscle atrophy in CHF, and lay the basis for development of new therapeutic strategies.