ABSTRACT Losses in limb muscle mass and increased fatigability compromise the ability of older adults (≥65 yrs) to generate the power necessary to maintain mobility and perform daily activities. Recently, we showed that the age-related increase in fatigability during dynamic contractions is due to a greater accumulation of metabolites, hydrogen (H+), inorganic phosphate (Pi) and diprotonated phosphate (H2PO4-), eliciting greater disruptions in contractile function within the muscle. However, the mechanisms for the greater metabolite accumulation are unknown. Our central hypothesis is that the greater accumulation of metabolites and increased fatigability are due to age-related impairments in skeletal muscle bioenergetics and/or vascular function. To test this hypothesis, we will use cutting-edge techniques to assess whole-muscle and single fiber bioenergetics and macro- and micro-vascular function. Additionally, we will study the effectiveness of a novel exercise-training intervention in older men and women aimed at improving contractile economy, vascular function, muscle power and fatigability. Aim 1 will determine the bioenergetic basis for the age-related increase in fatigability in the whole quadriceps muscle and in single fibers isolated from muscle biopsies of the vastus lateralis. Quadriceps muscle contractile economy and the accumulation of intracellular metabolites (H+, Pi, H2PO4-) will be assessed with 31phosphorus nuclear magnetic resonance spectroscopy (31P-MRS) during dynamic knee extension exercise. Myofibrillar and sarcoplasmic reticulum-Ca2+ ATPase activity and fiber efficiency will also be measured during shortening contractions of single fibers using epifluorescence microscopy. We hypothesize that older adults will have a lower whole muscle and single fiber contractile economy compared with young adults. Aim 2 will assess whether dysfunction of the macro- and micro-vasculature is a mechanism for the increased fatigability with aging. During dynamic knee extension exercise, femoral artery blood flow will be quantified via Doppler ultrasonography and tissue oxygenation measured with near infrared spectroscopy (NIRS). Microvascular function will be assessed in arterioles isolated from vastus lateralis biopsies using video microscopy. We hypothesize that older adults will have reduced femoral artery blood flow and greater reductions in quadriceps muscle oxygenation compared with young adults, in part, due to a blunted vasoreactivity of arterioles. Aim 3 will determine the effectiveness of a high-velocity resistance exercise training coupled with blood flow restriction to improve fatigability in older men and women. Older adults will perform 8 weeks of dynamic unilateral resistance exercise, where one leg is exercised with freely perfused conditions and the other with blood flow restriction. We hypothesize that fatigability, bioenergetics and vascular function will improve in the exercise training leg with blood flow restriction and...