Why Lactate is a Friend to Exercise

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

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.

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

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

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 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

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

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

Redox Reaction

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

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

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).

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

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

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