Molecular Mechanisms of Fit but Fat: Coronary Function and Muscle Mass

健康但肥胖的分子机制：冠状动脉功能和肌肉质量

• 批准号: 7991000
• 负责人: David W Stepp
• 金额: $ 18.63万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-15 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7991000
• 关键词: Accounting; Adipocytes; Aerobic; Agonist; Animals; Blood Vessels; Body Weight decreased; Cardiac; Cardiovascular Diseases; Cardiovascular Physiology; Cardiovascular system; Coronary; Data; Disease; Endothelium; Epidemic; Exercise; Family; Fatty acid glycerol esters; Functional disorder; Gene Expression; Generations; Genes; Genetic; Goals; Growth Factor; Health; Human; Impairment; Individual; Intervention; Ischemia; Knock-out; Knockout Mice; Leptin; Medicine; Metabolic; Metabolic syndrome; Modeling; Molecular; Morbidity - disease rate; Mus; NG-Nitroarginine Methyl Ester; Obese Mice; Obesity; Outcome; Oxidants; Oxides; Pathology; Performance; Phenotype; Physical activity; Population; Production; Reactive Oxygen Species; Resistance; Risk; Skeletal Muscle; Superoxides; Testing; Therapeutic Intervention; Weight; cardiovascular disorder therapy; db/db mouse; effective therapy; functional restoration; hemodynamics; improved; mortality; muscle form; myostatin; novel; novel therapeutics; obesity treatment; oxidant stress; prevent; public health relevance; research study; response

DESCRIPTION (provided by applicant): Obesity is a major health threat in Western medicine primarily due to its effects on cardiovascular function. As this epidemic unfolds, new therapies and interventions are needed and clues can be found in the fact that exercise is a major positive factor in cardiovascular outcome in all disease states, including obesity. Since obese individuals often have difficult exercising at an effective level to achieve cardiovascular benefit, it would be useful to re-create in this population the effects of exercise using alternative approaches. A major benefit of exercise in the size and quality of muscle mass, which may improve metabolic or hemodynamic function in ways that contribute to cardiovascular benefit. In this application, we present a novel model of obesity in which we have increased muscle mass by genetic deletion of myostatin, a growth factor which restrains muscle mass under normal conditions. The result is an obese mouse that has increase muscularity, improvements in metabolic status and initial evidence of improved cardiovascular performance. We will use this animal to test the broad hypothesis of the application, that increases in muscle mass ameliorate the cardiovascular deficits of obesity in two specific aims. Aim 1 will examine vascular function, specifically in the form of endothelial dilation to determine if improvement in muscle mass restores endothelium-dependent dilation. Aim 2 will determine is increases in muscle mass prevent the increase in oxidants induced by obesity which are thought to account for many of the cardiovascular deficits in obese individuals. Aim 3 will examine cardiac function by determining is muscle mass reduces the progression of contractile dysfunction and reduces risk of ischemia in obesity. Taken together these data will provide new information about the relationship between muscle mass and cardiometabolic status in obesity and may identify a novel therapeutic venue in this emerging epidemic. PUBLIC HEALTH RELEVANCE: Obesity is one of the leading cause of cardiovascular diseases, but the therapies are few. Exercise provides good protection from cardiovascular disease but mechanisms are unclear and obese individual cannot exercise enough to get benefit. This application will focus on a new intervention, increasing muscle mass with deletion of myostatin in obesity and determine the extent to which this manipulation improves cardiovascular function and confers the benefits of exercise on obese individuals.

描述(申请人提供)：肥胖是西医的一个主要健康威胁，主要是由于它对心血管功能的影响。随着这种流行病的蔓延，需要新的治疗方法和干预措施，而且可以从以下事实中找到线索：运动是包括肥胖在内的所有疾病状态下心血管结果的主要积极因素。由于肥胖者通常很难在有效的水平上进行锻炼以获得心血管益处，因此在这一人群中使用替代方法重新创造锻炼的效果将是有用的。锻炼对肌肉的大小和质量有很大的好处，可以改善代谢或血流动力学功能，从而对心血管有益。在这个应用中，我们提出了一种新的肥胖模型，在该模型中，我们通过基因缺失Myostatin来增加肌肉质量，Myostatin是一种在正常情况下抑制肌肉质量的生长因子。结果是肥胖的小鼠肌肉发达，代谢状态得到改善，心血管功能得到改善的初步证据。我们将使用这只动物来测试这一应用的广泛假设，即增加肌肉质量在两个特定目标上改善肥胖的心血管缺陷。目标1将检查血管功能，特别是内皮扩张的形式，以确定肌肉质量的改善是否恢复内皮依赖性扩张。目标2将确定肌肉质量的增加是否可以防止肥胖引起的氧化剂的增加，后者被认为是肥胖者许多心血管缺陷的原因。目标3将通过确定肌肉质量是否可以减少肥胖症患者收缩功能障碍的进展并降低缺血风险来检查心脏功能。综上所述，这些数据将提供有关肥胖症患者肌肉质量和心脏代谢状态之间关系的新信息，并可能确定这一新流行病的治疗地点。 公共卫生相关性：肥胖是心血管疾病的主要原因之一，但治疗方法很少。运动可以很好地预防心血管疾病，但机制尚不清楚，肥胖者无法进行足够的运动来获得好处。这项应用将专注于一种新的干预措施，通过删除肥胖患者的肌肉抑制素来增加肌肉质量，并确定这种操作在多大程度上改善心血管功能，并赋予肥胖者运动的好处。