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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
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Adhikari, Bishow B
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Tulane University
Internal Medicine/Medicine
Schools of Medicine
New Orleans
United States
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