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: 8110078
• 负责人: David W Stepp
• 金额: $ 22.35万
• 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 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8110078
• 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（由申请人提供）：肥胖是西方医学中主要的健康威胁，主要是由于它对心血管功能的影响。随着这种流行病的发展，我们需要新的治疗方法和干预措施，我们可以从运动是包括肥胖在内的所有疾病的心血管结果的主要积极因素这一事实中找到线索。由于肥胖个体通常很难在有效水平上进行锻炼以获得心血管方面的益处，因此使用替代方法在这一人群中重新创造锻炼的效果将是有用的。锻炼的主要好处是肌肉质量的大小和质量，这可能会改善代谢或血液动力学功能，从而有助于心血管的益处。在这个应用中，我们提出了一种新的肥胖模型，在这种模型中，我们通过基因缺失肌肉生长抑制素来增加肌肉质量，肌肉生长抑制素是一种在正常情况下抑制肌肉质量的生长因子。结果是，肥胖的老鼠肌肉增加，代谢状况改善，心血管功能也有了初步改善。我们将用这只动物来测试应用的广泛假设，即肌肉质量的增加可以改善肥胖的心血管缺陷，有两个特定的目的。目的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能防止肥胖引起的氧化剂的增加，这被认为是肥胖个体心血管缺陷的原因。目的3将检查心脏功能，通过确定其肌肉量减少收缩功能障碍的进展，并降低肥胖的缺血风险。综上所述，这些数据将为肥胖患者的肌肉质量和心脏代谢状态之间的关系提供新的信息，并可能为这一新兴流行病找到新的治疗途径。