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+ concentration can impair PFK when enzyme isolated but not in whole body exercise
H+ ions: not just from Lactate, formed in glycolytic rxns w/ ATP hydrolysis
PFK – whole body exercise – various enzymes that may have a counteractive effect

3. Glycolysis  2 pyruvate, 2 H+ ions, 2 NADH, & 2 ATP
Glycolysis not only yields ATP, but 2 NADH +2 H+ ions, and 2 pyruvate + 2 H2O molecules.

4. Lactate/H+ and Fatigue
1st studies of fatigue, amphibian muscle more readily generates La/H+
Lactate may even counter force-depressing effects of high extracellular K+
EC – Excitation-contraction
amphibian studies – more readily generates than mammalian muscle

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, Mg2+, ROS, and  in ATP, PCr, glycogen in fibers
Force production  w/  in Ca2+ release from SR
Lactate ions – don’t impair EC coupling

6. 2nd: Acidosis
pH can drop by pH units to ~6.7 and only moderate loss of force. More severe acidosis: marked  in force = safety margin
only few, dynamic exercise involves a severe acidosis needed to cause a decrease in force and even here H+ is interacting with other cellular changes

7. 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

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 VO2  lactate = preferred fuel
Co-localization of MCT, CD-147, & COX
CCLS – cell to cell lactate shuttle
MCT4 – monocarboxylate transporter
MCT, CD-147, & COX - – positioned specifically to facilitate lactate shuttle

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
ILS – intracellular Lactate Shuttle
constant production of La- in cytosol w/ rate of production increasing w/ rate of glycolysis increasing

12. Visual…
Mitochondrion Lactate mLDH? NADH NAD+ Pyruvate TCA Pyruvate Lactate LDH (3) (2) (4) (6) (7) (7) Glucose 6-phosphate Glyceraldehyde 3-phosphate H+ NADH NAD+ Fig.·1. The processes involved in the lactate shuttle hypothesis (Brooks, 1986). The pathway proposes that (1) glucose enters the cell, where it is sequentially broken down to pyruvate (2). Pyruvate enters the mitochondrion, allowing respiration to continue in the tricarboxylic acid (TCA) cycle (3). Lactate is subsequently formed viathe lactate dehydrogenase (LDH) reaction (4) and is then exported from the cytosolic compartment viamonocarboxylate transporter (MCT) transport (5), where it is redistributed to a variety of functional sites. Note the suggested presence of mitochondrial lactate dehydrogenase (mLDH) (6), which forms the construct of the intracellular shuttle system (7) (see text for description).

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