ABSTRACT
As classically dened, glycolysis of glucose produces lactate [59]. However, in working muscle, the major precursor for glycolysis is glycogen [8,25,69]. In resting muscle, and venous efuent of most tissues, the [lactate]/[pyruvate] concentration ration (L/P) approximates 10, but the L/P rises more than an order of magnitude into the hundreds during submaximal, fully aerobic exercise [49,53,82], meaning that lactate, not pyruvate, is the main product of aerobic glycolysis. To an extent, the pulmonary mesenchymal intervenes and raises the L/P by converting pyruvate to lactate [54], thus raising the arterial L/P further. Depending on the species, the dietary carbohydrate converted to lactate varies, but hepatic glycogen synthesis relies on the conversion of dietary glucose to lactate in muscles and other peripheral tissues with lactate circulating in the liver. This pathway by which dietary carbohydrate escapes hepatic uptake from the portal vein, but recirculates to the liver as lactate in the arterial circulation, is described as the “indirect pathway of hepatic glycogen synthesis” or alternatively “the glycogen paradox” as lactate, not glucose, is the main precursor for hepatic glycogen synthesis following carbohydrate nutrition [38]. In
7.1 Introduction .................................................................................................. 131 7.2 The Lactate Shuttle ....................................................................................... 132 7.3 Cell Membrane Lactate Transporters ........................................................... 138 7.4 Mitochondrial MCTs .................................................................................... 138 7.5 The Mitochondrial Lactate Oxidation Complex .......................................... 142 7.6 Lactate and ROS Signaling ........................................................................... 144 7.7 Lactate Shuttles and mLOCs Beyond Muscle .............................................. 147
7.7.1 Brain ................................................................................................. 147 7.7.2 Cancer ............................................................................................... 147
7.8 Summary ...................................................................................................... 148 References .............................................................................................................. 150
rodents, most hepatic glycogen synthesis from dietary carbohydrate originates from the indirect pathway, but this percentage appears to be less in humans [68,98]. That lactate is formed under fully aerobic conditions [15,82] and that most of the glycolytic ux passes through the various body lactate pools is typically of little consequence because lactate is rapidly disposed off [7,18,64,90] via oxidation and gluconeogenes (GNG) [6,39,40]. To reiterate, the capacity for mitochondrial sequestration of lactate minimizes its accumulation and, until recently, has obscured the role of lactate shuttling in the regulation of intermediary metabolism.
