1. Why Lactate is a Friend to Exercise

2. 1 st : 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 1 st studies of fatigue, amphibian muscle more readily generates La/H+ Lactate may even counter force-depressing effects of high extracellular K+

5. Lactate & Fatigue, cont’d 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, Mg 2+, ROS, and  in ATP, PCr, glycogen in fibers Force production  w/  in Ca 2+ release from SR Lactate ions – don’t impair EC coupling

6. 2 nd : 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

7. Acidosis, cont’d Benefits of acidosis:  release of O 2 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 Ca 2+ release and force in mechanically skinned fast-twitch fiber

8. 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

9. Redox Reaction

10. Now, the Lactate Shuttle Hyp… CCLS: Lactate produced from glycolysis in fast twitch fibers Leaves glycolytic fibers via MCT4 to rest of body Taken up by neighboring cells for oxidation via MCT 1 Successfully competes w/ glucose as a CHO fuel source one of most important substrates for gluconeogenesis ex: heart – highly oxidative. As VO 2  lactate = preferred fuel Co-localization of MCT, CD-147, & COX

11. Lactate Shuttle, cont’d ILS Lactate major product of glycolysis Direct uptake & oxidation of lactate by isolated mitochondria w/o extra-mito conversion 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

12. Visual…

13. 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

14. 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

15. 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