This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Our objective is to examine the effects of the drug dichloroacetate (DCA) on aerobic function and maximal work capacity in patients with congenital lactic acidosis (CLA). We will recruit approximately 10 individuals with documented disease to comprise our patient cohort. In addition, we will enroll an age and gender matched cohort of healthy volunteers to serve as a normal comparison group. This investigation will employ two experimental conditions to test the specific hypotheses listed below. In experiment 1, we will examine the effect of DCA on lactate kinetics, maximal oxygen uptake (VO2max) and maximal work capacity during graded exercise on a cycle ergometer in patients with CLA. Using a randomized, double blind, placebo controlled crossover design; patients will perform a graded exercise test to voluntary maximal exertion on a cycle ergometer while treated with either DCA or placebo. We hypothesize that DCA treatment will significantly increase the VO2 at the individual lactate threshold (LT), VO2max, and maximal work capacity in patients with CLA. In experiment 2, we will examine the effect of DCA treatment on lactate production, substrate utilization, and hemodynamic responses to submaximal exercise in patients with CLA. Using the data from the graded exercise test in experiment 1, patients will perform a 15-minute exercise bout at an intensity designed to elicit 80% of the VO2 at LT. We hypothesize that patients with CLA who are treated with DCA, compared with placebo, will demonstrate reduced levels of lactic acid, increased rates of carbohydrate oxidation, increased cardiac and ventilatory efficiency, and decreased ratings of perceived exertion (RPE) during a submaximal exercise bout prescribed at a level related to their individual LT. Finally, we will compare the exercise responses under these two experimental conditions to a cohort of healthy volunteers, adjusting for age and sex, not treated with either DCA or placebo. We hypothesize that patients with CLA will have reduced levels of aerobic function, compared to the control group. However, DCA treatment in patients with CLA will attenuate these differences. By accomplishing these objectives, we hope to demonstrate that DCA can improve aerobic function in patients with CLA, and that this enhanced aerobic function can be translated into improvements in quality of life. In particular, the use of the individual LT could potentially result in a novel approach to prescribing exercise in patients with CLA. This would enable them to perform activities of daily living without undue fatigue and would allow them to enjoy the well-established therapeutic and recreational benefits of physical a
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