Correction of salt-sensitive hypertension through changes in muscle mass

Despite decades of progress, hypertension remains one of the most prevalent risk factors for hypertension in Western cultures. Hypertension continues to increase in prevalence, despite the availability of several anti-hypertensive medications and 30% of hypertensives continue to have poor blood pressure control even on three combined medications. While progress has occurred, more work in this area continues to be of considerable clinical significance. A major lifestyle modification in the treatment of hypertension is exercise. Part of this improvement is weight loss but evidence indicates that even in populations that fail to lose weight, exercise offers powerful protection against hypertension. The mechanisms by which this occurs are unclear but may involve changes in aerobic capacity or the increased muscle mass present in the exercising population. Induction of the benefits of exercise without physical activity may be therapeutically beneficial in patients in which age or obesity limits the ability to exercise. In 1997, Se-Jin Lee discovered a TGF-BETA family growth factor, myostatin, which acts as a negative regulator of skeletal muscle mass. Mice deficient in myostatin are hypermuscular with a marked increase in muscle mass. Loss of myostatin has shown to be protective from metabolic effects of obesity or diabetes but whether the impact of increased muscle mass on cardiovascular disease such as hypertension is unknown. Using a novel rat model in which myostatin has been genetically silenced, we have identified profound improvement of salt-sensitive hypertension concomitant with significant increases in muscle mass. This improvement is associated with improved endothelial function and reduced plasma methylhistidine, a marker of renal dysfunction. The mechanisms and functional impact of these changes are unknown. The proposed experiments will test the hypothesis that Increasing muscle mass with myostatin deletion improves hypertension obesity in the following specific aims: Specific Aim 1: To determine the relationship between myostatin and the regulation of blood pressure: Specific Aim 2: To determine the mechanisms by which deletion of myostatin improves salt-sensitive hypertension Taken together, the results of these experiments will determine the extent to which increased muscle mass can result in the improvements in cardiovascular health and provide new information about the relationship been muscle mass and the regulation of blood pressure. (AHA Program: Grant-in-Aid)