PROJECT SUMMARY Heart failure with preserved ejection fraction (HFpEF) accounts for approximately half of the heart failure population in the United States, and the primary chronic symptom experienced by these patients is severe exercise intolerance. Exercise intolerance is quantified as reduced peak oxygen uptake during exercise, and to date, therapies targeting central cardiac limitations have invariably failed to improve peak VO2, quality of life, or survival in HFpEF. Emerging evidence from our lab suggests reduced skeletal muscle oxidative capacity may contribute to exercise intolerance in HFpEF patients. However, the mechanisms responsible for peripheral metabolic inefficiency remain unclear. Reduced blood flow (oxygen delivery), and slowed oxygen uptake kinetics (O2 utilization), may be primary contributors to reduced skeletal muscle oxidative capacity and result in the production of metabolites known to activate muscle afferent nerves and stimulate reflex increases in muscle sympathetic (vasoconstrictor) nervous system activity (MSNA). Elevated MSNA can in turn, result in further impairments in hemodynamic control during exercise. However, to date there have been no studies specifically investigating the contribution of peripheral vascular, metabolic, and neural impairments to reduced exercise capacity in HFpEF. The first goal of this proposal will be to identify impairments in peripheral vascular, metabolic, and sympathetic neural function in HFpEF. To accomplish this, we will measure the dynamic blood flow response (oxygen delivery) and oxygen uptake kinetics (oxygen utilization) during knee extensor (KE) exercise, as well as MSNA during exercise to characterize the contribution of peripheral abnormalities to exercise intolerance in HFpEF. The second goal will be to utilize small muscle mass KE training, specifically targeting these peripheral skeletal muscle deficiencies, to improve aerobic capacity and exercise tolerance in HFpEF. We will assess vascular, metabolic, and neural function before and after completing 8 weeks of single KE exercise training, in conjunction with measures of maximal aerobic capacity and functional capacity. The isolated KE training approach will minimize the central hemodynamic stress of whole body exercise, while simultaneously targeting skeletal muscle function to improve exercise tolerance in HFpEF. Importantly, this proposal will advance our understanding of the basic pathophysiology of exercise intolerance in HFpEF. Considering that vascular function, oxidative capacity, and a MSNA are independent predictors of mortality in heart failure patients, strategies aimed at improving these functional markers may have important implications for the treatment of HFpEF, a condition for which there are currently no known therapies to reduce morbidity and mortality.