Current understanding of the metabolic role of lactate is embodied in the """"""""lactate shuttle hypothesis"""""""". This hypothesis holds that lactic acid formation and its distribution throughout the body is a major mechanism whereby the coordination of intermediary metabolism in different tissues, and cells within those tissues, is accomplished. Some major, broad based questions are raised by the """"""""lactate shuttle hypothesis"""""""". How does lactic acid cross the sarcolemmal membrane, the red blood cell membrane, and the membranes of other tissues which release and take up lactic acid? What physiological/biochemical factors regulate the uptake and metabolism of lactic acid, particularly in skeletal muscle? Does skeletal muscle (and other tissues) from animals with divergent metabolic capacities reflect quantitative differences in these lactate shuttle components? These questions represent the broad, long-term objectives of this project. Specifically, this grant seeks to determine: A) the kinetics of lactate transport in giant sarcolemmal vesicles of animals differing in aerobic/glycolytic power; B) the effects of metabolic rate, perfusate flow rate, acid-base balance; and energy substrates, TCA cycle intermediates, and hormones on unidirectional lactate influx into resting and contracting skeletal muscle; C) the metabolic fate of lactate during unidirectional influx measurements with multiple tracer methods and models; D) the signals which """"""""turn on"""""""" net lactate uptake during periods of elevated lactate concentration and increased metabolic rate due to contractions; E) the role of aerobic/glycolytic potential of muscle in unidirectional lactate influx, and net muscle lactate uptake and metabolism; and F) the role of epinephrine in net lactate uptake and metabolism by resting and contracting skeletal muscle. Answers to these questions can be integrated to suggest the prominent sites for regulation and control of lactate transport, uptake, and metabolism within the lactate shuttle. These answers will be sought through experimental investigations at several different levels of organization within the same general experimental preparation: 1) lactate transport kinetics in giant sarcolemmal vesicles from canine skeletal muscle, 2) unidirectional lactate influx and rapid lactate metabolism via multiple tracers (125/I-albumin, 3/H - L - glucose, and 14/C-lactate) in artificially perfused in situ canine skeletal muscle, and 3) net lactate uptake and 14/C-lactate tracer metabolism in blood perfused in situ canine skeletal muscle. Additional insight will be gained through comparison of muscles from animals differing in aerobic/glycolytic power. Results of these studies have important implications for physiological or pathophysiological conditions in which tissue and blood lactate concentrations are elevated, including clinical lactic acidosis which is most often due to circulatory insufficiency.
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