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.
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