Why Lactate is a Friend to Exercise

1. Why Lactate is a Friend to Exercise

2. 1st: Lactate & H+ • temporal relationship b/w in force & H+ accumulation • at same time, metabolic products : ADP, Pi, PCr; and ATP  • H+ ions: not just from Lactate, formed in glycolytic rxns w/ ATP hydrolysis • H+ concentration can impair PFK when enzyme isolated but not in whole body exercise

3. Glycolysis  2 pyruvate, 2 H+ ions, 2 NADH, & 2 ATP

4. Lactate/H+ and Fatigue • 1st studies of fatigue, amphibian muscle more readily generates La/H+ • Fatigue – caused by disturbance in any step of EC Coupling: • Build-up of K+  depolarizes fiber and  action potentials • “Metabolic fatigue”- accumulation of metabolites ADP, Pi, Mg2+, ROS, and  in ATP, PCr, glycogen in fibers • Force production  w/  in Ca2+ release from SR • Lactate ions – don’t impair EC coupling • Lactate may even counter force-depressing effects of high extracellular K+

5. 2nd: Acidosis • pH can drop by .3 - .4 pH units to ~6.7 and only moderate loss of force. More severe acidosis: marked  in force = safety margin

6. Acidosis, cont’d • Benefits of acidosis: • release of O2 from hemoglobin for working muscles = Bohr Effect • stimulation of ventilation • enhanced muscle blood flow • feedback to CNS to  cardiovascular drive • protects against K+ induced force depression • Improves depolarization-induced impairment of Ca2+ release and force in mechanically skinned fast-twitch fiber

7. Additional Benefits of Lactate • Lactate – a scavenger for free radicals • Glucose-sparing as a substrate for gluconeogenesis • significant  in lactate oxidation &  glucose oxidation • Maintains red-ox state of cell – as pyruvate  lactate, accepts H+ from NADH  NAD. NAD allows β-oxidation & glycolysis to continue

8. Now, the Lactate Shuttle Hyp… • CCLS: • Lactate produced from glycolysis in fast twitch fibers • Distributed out of glycolytic fibers via MCT4 and transported throughout body • Lactate then taken up by neighboring cells for oxidation through MCT 1 • Successfully competes w/ glucose as a CHO fuel source • one of most important substrates for gluconeogenesis • example: heart – highly oxidative. As VO2 lactate becomes preferred fuel for heart • Co-localization of MCT, CD-147, & COX – positioned specifically to facilitate lactate shuttle

9. Lactate Shuttle, cont’d • ILS • Lactate major product of glycolysis • Direct uptake and oxidation of lactate by isolated mitochondria w/o extra-mitochondrial conversion of lactate  pyruvate • Presence of intramitochondrial LDH • MCT-1 in inner mitochondrial membrane • Once lactate inside mitoc. matrix, w/ LDH  pyruvate  oxidized via PDH to acetyl CoA  TCA cycle • Consistent w/ idea of compartmentation • Possible LDH in inne-rmembrane space

10. Visual…

11. Lactate Shuttle  Signal Role • As Lactate released signals progressive switch in fuel source from fat  CHO • down-regulates CPT1-facilitated FFA transport through acting w/ H+ to  pH, decreasing FFA available for CPT complex • = regulates fuel supply, allowing continuation of glycolysis and oxidative phosphorylation • Lactate provides a mechanism for CNS to detect localized exercise stress and causes exercise to end

12. Benefits of Lactate Shuttle • Coordinates energy systems of different cells and tissues • As endurance training  = MCT  and  lactate clearance, and  oxid. Thus, lactate signals a rapidly adaptable process maintaining cellular homeostasis

13. Review: Lactate = Friend •  force and fatigue: probably due to metabolite accumulation and disturbances in EC coupling • Would take severe  in pH to have negative effects • Yet normal acidosis – some beneficial effects • Maintains cell red-ox state • Spares blood glucose • Lactate Shuttle – intricate coordination of energy systems to  lactate clearance and increase lactate availability as a substrate for oxidation