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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：
7339832
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/7339832
关键词：
1-Phosphatidylinositol 3-Kinase 70-kDa Ribosomal Protein S6 Kinases Abbreviations Actins Age Agglutinins Aldosterone Angiotensin II Angiotensins Anterior Descending Coronary Artery Apoptosis Apoptotic Area Atrophic Body Weight Boxing Cardiovascular system Caspase Cells Chronic Condition Congestive Congestive Heart Failure Constriction procedure 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 Protein Overexpression 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 alginic acid compound autocrine base caspase-3 human FRAP1 protein insight mortality multicatalytic endopeptidase complex muscle RING finger 1 novel novel therapeutics 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），这是心血管死亡率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（angII）通过激活泛素-蛋白酶体蛋白水解途径和增加细胞凋亡，导致啮齿动物骨骼肌萎缩。同时，ang II通过PI 3-激酶/Akt途径降低骨骼肌胰岛素样生长因子-1（IGF-1）和IGF-1信号传导，并增加肌肉半胱天冬酶-3活性，导致肌动蛋白裂解。IGF-1在肌肉中的转基因表达防止了这些变化和血管紧张素II诱导的肌肉损失。我们在压力超负荷心力衰竭模型中有初步的类似发现。为了阐明血管紧张素II和压力负荷性心力衰竭导致骨骼肌萎缩的分子机制，我们提出：1。研究IGF-1介导血管紧张素II或压力超负荷心力衰竭引起骨骼肌萎缩的信号机制改变。2.描述血管紧张素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.证明血管紧张素II或压力超负荷心力衰竭诱导的骨骼肌萎缩可以通过表达肌肉特异性IGF-1转基因来预防。4.研究干细胞在自分泌IGF-1预防血管紧张素II诱导的骨骼肌萎缩中的作用。这些研究结果将为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。