Stable isotopic and metabolomic studies in a model of lactic acidosis tolerance

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DESCRIPTION (provided by applicant): The goal of the proposed research is to use the profoundly anoxia and acidosis-resistant painted turtle to better understand the basic processes underlying vertebrate anaerobic metabolism, which is closely associated with a large number of human metabolic diseases, particularly those involving impaired oxygen transport. Insights from conventional studies utilizing mammalian models of vertebrate anaerobic metabolism and subsequent aerobic recovery are limited by mammals' low tolerance to anoxia and lactic acidosis and the rapid metabolite turnover rates resulting from high metabolic rates, particularly in rodents. The painted turtle is the most anoxia-tolerant air-breathing vertebrate species known, has metabolic rates an order of magnitude lower than a similar sized mammal, and can accumulate lactic acid to concentrations 4-5x greater than the lethal limit for mammals. With the long-term goal of better understanding the mechanisms underlying anaerobic metabolism and metabolite fluxes during recovery, our aims are to: 1) Characterize the plasma and tissue metabolomic profiles during and following anoxia, 2) Investigate the metabolic fates of lactate within the metabolome during and after anoxia, and 3) Determine what substrates fuel normal and recovery metabolism. The interaction of temperature-induced changes in metabolic rate on all of these processes will also be investigated. This work represents an innovative approach to studies of anaerobic metabolism by combining, for the first time, an ideal model organism for studies of metabolic stress with stable isotopic and metabolomics approaches. We expect to gain a deeper understanding of the relationship between metabolic rate and lactate kinetics in vertebrates and to gain new and general insights into these clinically important metabolic processes. PUBLIC HEALTH RELEVANCE: This study will provide new insights into the mechanisms underlying anaerobic metabolism and lactic acid clearance in vertebrates. Ultimately, this will contribute to our broader understanding of the causes and consequences of many metabolic diseases in humans, particularly those involving metabolic acidosis and those related to limitations in oxygen transport.