Angiotensin II, IGF-1 and Skeletal Muscle Atrophy

血管紧张素 II、IGF-1 和骨骼肌萎缩

基本信息

批准号：
7762718
负责人：
PATRICE DELAFONTAINE
金额：
$ 37.13万
依托单位：
TULANE UNIVERSITY OF LOUISIANA
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-01-15 至 2011-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7762718
关键词：
1-Phosphatidylinositol 3-Kinase 70-kDa Ribosomal Protein S6 Kinases Abbreviations Actins Age Agglutinins Aldosterone Angiotensin II Anterior Descending Coronary Artery Apoptosis Apoptotic Area Atrophic Body Weight Boxing Cardiovascular system Caspase Cells Chronic Congestive Heart Failure Coronary artery Development Disease Dominant-Negative Mutation Down-Regulation Electroporation Enzyme-Linked Immunosorbent Assay F Box Domain Fiber Gene Transfer Grant Heart failure Infusion procedures Insulin Insulin-Like Growth Factor Binding Protein 3 Insulin-Like Growth Factor Binding Protein 5 Insulin-Like Growth Factor I Insulin-Like Growth-Factor Binding Protein 1 Insulin-Like-Growth Factor I Receptor Left Ligation Mediating Modeling Molecular Mononuclear Morbidity - disease rate Mus Muscle Muscle Cells Muscular Atrophy Outcome Pathway interactions Phosphorylation Plasmids Prevention Production Proteasome Inhibition Protein Isoforms Proteins Proteolysis Rattus Renin Renin-Angiotensin-Aldosterone System Research Personnel Rodent Role Serine Signal Transduction Skeletal Muscle Stem cells Superoxides System Transgenes Transgenic Organisms Ubiquitin Ubiquitin-Conjugating Enzymes Vent autocrine base caspase-3 constriction extensor digitorum human FRAP1 protein insight mortality multicatalytic endopeptidase complex muscle RING finger 1 novel novel therapeutics overexpression pressure prevent programs protein degradation satellite cell stem transcription factor ubiquitin ligase wasting

项目摘要

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.

描述（由申请人提供）：骨骼肌萎缩发生在多种疾病中，包括充血性心力衰竭（CHF），这是心血管死亡和发病的主要原因。骨骼肌萎缩是 CHF 预后不良的重要预测因素，但其机制尚不清楚。作为 CHF 标志的全身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-蛋白酶体蛋白水解途径并增加细胞凋亡，导致啮齿类动物骨骼肌萎缩。同时，Ang II 通过 PI 3-激酶/Akt 途径减少骨骼肌胰岛素样生长因子-1 (IGF-1) 和 IGF-1 信号传导，并增加肌肉 caspase-3 活性，导致肌动蛋白裂解。肌肉中 IGF-1 的转基因表达可以防止这些变化以及 ang II 引起的肌肉损失。我们在压力超负荷心力衰竭模型中得到了初步的类似发现。为了阐明血管紧张素II和压力超负荷心力衰竭导致骨骼肌萎缩的分子机制，我们建议： 1. 表征介导血管紧张素II或压力超负荷心力衰竭引起的骨骼肌萎缩的IGF-1信号传导机制的改变。 2. 表征血管紧张素II或压力超负荷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.证明Ang II或压力超负荷心力衰竭引起的骨骼肌萎缩可以通过肌肉特异性IGF-1转基因的表达来预防。 4. 表征干细胞在自分泌IGF-1预防Ang II诱导的骨骼肌萎缩的能力中的作用。这些发现将为CHF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。