Angiotensin II, IGF-1 and Skeletal Muscle Atrophy

描述(申请人提供)：骨骼肌萎缩发生在包括充血性心力衰竭(CHF)在内的各种疾病中，充血性心力衰竭是心血管死亡和发病率的主要原因。骨骼肌萎缩是CHF预后不良的重要预测因子，但其机制尚不清楚。作为CHF标志的全身性神经体液兴奋包括肾素-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-蛋白质-某些蛋白分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PI3-K/Akt通路减少骨骼肌胰岛素样生长因子-1(IGF-1)和IGF-1信号，增加肌肉caspase-3活性，导致肌动蛋白切割。在肌肉中转基因表达IGF-1可以防止这些变化和Ang II导致的肌肉损失。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Ang II和压力超负荷心力衰竭导致骨骼肌萎缩的分子机制，我们提出：1.研究介导Ang II或压力超负荷心力衰竭所致骨骼肌萎缩的IGF-1信号转导机制。2.研究血管紧张素转换酶II或压力超负荷性心力衰竭触发肌肉蛋白分解的分子机制，特别是导致肌动蛋白断裂和泛素化增加的机制。3.证明血管紧张素转换酶II或压力超负荷心力衰竭所致的骨骼肌萎缩可以通过表达肌肉特异性的IGF-1基因来预防。4.探讨干细胞在自分泌IGF-1预防Ang II诱导的骨骼肌萎缩中的作用。这些发现将为了解充血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.