Academia.eduAcademia.edu

Figure 8 – uploaded by Daniel Kane

See full PDFdownloadDownload figure
Fig. 7 Intracellular PO, (P;O2) versus metabolic rate using com- bined data of Molé et al. [(1999); solid squares] and Richardson et al. [(2001); solid circles]. Data from Richardson et al. (2006) working in Carlier’s lab were used as the resting value for both sets of data, so the square is overlying a circle. In addition, note that the reported PO, value at 100% of VOomax was the same for both data sets, so again, the square is overlying the circle. Reprinted with permission from Clanton et al. (2013)

Figure 7 Intracellular PO, (P;O2) versus metabolic rate using com- bined data of Molé et al. [(1999); solid squares] and Richardson et al. [(2001); solid circles]. Data from Richardson et al. (2006) working in Carlier’s lab were used as the resting value for both sets of data, so the square is overlying a circle. In addition, note that the reported PO, value at 100% of VOomax was the same for both data sets, so again, the square is overlying the circle. Reprinted with permission from Clanton et al. (2013)

Related Figures (11)

Fig.1 Enantiomers of lactate. Enantiomers are a pair of stereoi- somers which are mirror images of each other. While there is some d(—)La_ in human tissues and blood from both endogenous and exog- omers are a pair of stereoisomers which are mirror image: of each other. In the case of La (Fig. 1), the C2 carbon
Fig.1 Enantiomers of lactate. Enantiomers are a pair of stereoi- somers which are mirror images of each other. While there is some d(—)La_ in human tissues and blood from both endogenous and exog- omers are a pair of stereoisomers which are mirror image: of each other. In the case of La (Fig. 1), the C2 carbon
Fig. 2 Carl Wilhelm Scheele (1742-1786), discoverer of lactic acid and oxygen. Retrieved from (Lundgren 2014). Encyclopedia Britan- nica, _ https://www.britannica.com/biography/Carl-Wilhelm-Scheele. Access data August 04, 2017
Fig. 2 Carl Wilhelm Scheele (1742-1786), discoverer of lactic acid and oxygen. Retrieved from (Lundgren 2014). Encyclopedia Britan- nica, _ https://www.britannica.com/biography/Carl-Wilhelm-Scheele. Access data August 04, 2017
Fig. 4 Idealized blood [La] response to progressive incremental exercise plotted against oxygen uptake (VO,). Also illustrated are three single point measures often used to describe the response: the visually determined lactate threshold (LT) (Gladden et al. 1985), LT as determined by the D,,,, method (LTp) (Cheng et al. 1992), and the onset of blood La’ accumulation (OBLA=4 mM) (Heck et al. 1985). Reprinted with permission from Gladden (2004a) Lactate metabolism during exercise. In Principles of Exercise Biochemistry, 3rd edn, ed. Poortmans JR, pp. 152-196. Karger, Basel Fig. 3 V-slope method for determining the gas exchange threshold, redrawn with permission from (Beaver et al. 1986). Carbon dioxide output (VCO) is plotted against simultaneously determined oxy- gen uptake (VO>) in a progressive incremental exercise test. The gas exchange threshold is detected by a mathematical algorithm that determines the intersection of the two straight lines that provide the best fit to the overall data set
Fig. 4 Idealized blood [La] response to progressive incremental exercise plotted against oxygen uptake (VO,). Also illustrated are three single point measures often used to describe the response: the visually determined lactate threshold (LT) (Gladden et al. 1985), LT as determined by the D,,,, method (LTp) (Cheng et al. 1992), and the onset of blood La’ accumulation (OBLA=4 mM) (Heck et al. 1985). Reprinted with permission from Gladden (2004a) Lactate metabolism during exercise. In Principles of Exercise Biochemistry, 3rd edn, ed. Poortmans JR, pp. 152-196. Karger, Basel Fig. 3 V-slope method for determining the gas exchange threshold, redrawn with permission from (Beaver et al. 1986). Carbon dioxide output (VCO) is plotted against simultaneously determined oxy- gen uptake (VO>) in a progressive incremental exercise test. The gas exchange threshold is detected by a mathematical algorithm that determines the intersection of the two straight lines that provide the best fit to the overall data set
Fig.5 Blood [La] response to constant work rate exercise at dif- ferent intensities. Idealized data based on the reports of Wasserman et al. (1967, 1986) and Pringle and Jones (Pringle and Jones 2002) are plotted. Blood [La ] responses for work rates below (< MLSS), at (=MLSS) and greater than (> MLSS) the maximal lactate steady state intensity are shown. Although the usual blood [La ] at the MLSS is approximately 4 mM, this concentration can vary widely among individuals (Pedersen et al. 2001). Reprinted with permission from Gladden (2004a) Lactate metabolism during exercise. In Prin- ciples of Exercise Biochemistry, 3rd edn, ed. Poortmans JR, pp. 152- 196. Karger, Basel
Fig.5 Blood [La] response to constant work rate exercise at dif- ferent intensities. Idealized data based on the reports of Wasserman et al. (1967, 1986) and Pringle and Jones (Pringle and Jones 2002) are plotted. Blood [La ] responses for work rates below (< MLSS), at (=MLSS) and greater than (> MLSS) the maximal lactate steady state intensity are shown. Although the usual blood [La ] at the MLSS is approximately 4 mM, this concentration can vary widely among individuals (Pedersen et al. 2001). Reprinted with permission from Gladden (2004a) Lactate metabolism during exercise. In Prin- ciples of Exercise Biochemistry, 3rd edn, ed. Poortmans JR, pp. 152- 196. Karger, Basel
Fig.6 Net La output and uptake across an isolated, blood-perfused, contracting skeletal muscle (canine gastrocnemius-superficial digital flexor complex; N=5) at rest and during contractions at 5 twitches per sec over a period of 1 hour, followed by 30 min of recovery. Net La output is positive on the y-axis and net La uptake is negative. Note that net La output during contractions peaks at approximately 10 min and then declines and often becomes net uptake as the con- tractions continue. See text for additional details. Redrawn with per- mission from Welch and Stainsby (1967)
Fig.6 Net La output and uptake across an isolated, blood-perfused, contracting skeletal muscle (canine gastrocnemius-superficial digital flexor complex; N=5) at rest and during contractions at 5 twitches per sec over a period of 1 hour, followed by 30 min of recovery. Net La output is positive on the y-axis and net La uptake is negative. Note that net La output during contractions peaks at approximately 10 min and then declines and often becomes net uptake as the con- tractions continue. See text for additional details. Redrawn with per- mission from Welch and Stainsby (1967)
Fig. 8 Hypothetical pattern of metabolic dependence (La produc- tion) on intracellular PO, (PiO,) during the transition from one exercise work rate to another. With increase in work rate (arrow 1), [ADP]-[Pi]/[ATP] increases. However, intracellular PO, will likely also decrease with increased work rate (arrow 2). As a result, O» uptake would be transiently insufficient to supply ATP at the required rate, leading to a further increase in [ADP]-[Pi]/[ATP] (arrow 3, from open circle to solid square) for adequate stimulation of oxida- tive phosphorylation. The connection to La metabolism is that the increases in [ADP]-[Pi]/[ATP] simultaneously accelerate glyco- lysis and, therefore, La production (see text for additional details).
Fig. 8 Hypothetical pattern of metabolic dependence (La produc- tion) on intracellular PO, (PiO,) during the transition from one exercise work rate to another. With increase in work rate (arrow 1), [ADP]-[Pi]/[ATP] increases. However, intracellular PO, will likely also decrease with increased work rate (arrow 2). As a result, O» uptake would be transiently insufficient to supply ATP at the required rate, leading to a further increase in [ADP]-[Pi]/[ATP] (arrow 3, from open circle to solid square) for adequate stimulation of oxida- tive phosphorylation. The connection to La metabolism is that the increases in [ADP]-[Pi]/[ATP] simultaneously accelerate glyco- lysis and, therefore, La production (see text for additional details).
Fig. 9 Cell-to-cell lactate shuttle, and the astrocyte—neuron lactate shuttle. Based on (Pellerin et al. 1998, Brooks 2002). As the rate of demand for ATP increases in exercising skeletal muscle, La accu- mulates and efflux from muscle fibers increases by means of MCTs (lower left). Within the exercising muscle, La is shuttled among het- erogeneous fiber types, from glycolytic to oxidative fibers via MCTs (small blue squares in lower right). Alternatively, La may be carried in circulation to less, or slightly active skeletal muscle, where it is oxidized (CO, +H,O) in oxidative fibers. In inactive glycolytic skel- etal muscle fibers, La is converted chiefly to glycogen, with some oxidized in oxidative fibers. La is also carried in the blood to the liver, where it is either oxidized, or converted to glucose via gluco- neogenesis. The newly formed glucose is either stored as glycogen, or released back into circulation (Cori cycle), where it can return to, for example, exercising muscle. Circulating La is also readily oxidized in cardiac fibers and brain. Within the brain, the astrocyte—neuron lactate shuttle (upper right panel) is the process by which astrocytes take up glucose from the microcirculation, converting the glucose to La via glycolysis. This astrocytic La diffuses from the astrocyte to an adjacent neuron by means of MCTs. In the neuron, the La is oxi- dized at the mitochondria (CO,+H,O) to resynthesize ATP, and/or used for the cataplerotic production of amino acid neurotransmitters (NTs; e.g., glutamate, aspartate, and GABA)
Fig. 9 Cell-to-cell lactate shuttle, and the astrocyte—neuron lactate shuttle. Based on (Pellerin et al. 1998, Brooks 2002). As the rate of demand for ATP increases in exercising skeletal muscle, La accu- mulates and efflux from muscle fibers increases by means of MCTs (lower left). Within the exercising muscle, La is shuttled among het- erogeneous fiber types, from glycolytic to oxidative fibers via MCTs (small blue squares in lower right). Alternatively, La may be carried in circulation to less, or slightly active skeletal muscle, where it is oxidized (CO, +H,O) in oxidative fibers. In inactive glycolytic skel- etal muscle fibers, La is converted chiefly to glycogen, with some oxidized in oxidative fibers. La is also carried in the blood to the liver, where it is either oxidized, or converted to glucose via gluco- neogenesis. The newly formed glucose is either stored as glycogen, or released back into circulation (Cori cycle), where it can return to, for example, exercising muscle. Circulating La is also readily oxidized in cardiac fibers and brain. Within the brain, the astrocyte—neuron lactate shuttle (upper right panel) is the process by which astrocytes take up glucose from the microcirculation, converting the glucose to La via glycolysis. This astrocytic La diffuses from the astrocyte to an adjacent neuron by means of MCTs. In the neuron, the La is oxi- dized at the mitochondria (CO,+H,O) to resynthesize ATP, and/or used for the cataplerotic production of amino acid neurotransmitters (NTs; e.g., glutamate, aspartate, and GABA)
(ETS). The electrons are then passed to the mobile electron carrier Q, transported through Complex III, and then to Complex IV/COX via cytochrome c. The final electron acceptor at Complex IV in this schematic is molecular O5. The drops in free energy occurring across the ETS at complexes I, III, and IV are sufficient to drive the extru- sion of H* from the matrix into the intermembrane space, generating the proton motive force necessary to drive the synthesis of ATP at Complex V/ATP synthase. Omitted for clarity: Complex I/succinate dehydrogenase of the TCA/ETS, the glycerol 3-phosphate shuttle, the NAD(P) transhydrogenase, and stoichiometries of reactants and prod- ucts for all reactions. ADP adenosine diphosphate, ATP adenosine triphosphate, C cytochrome c, CD147 chaperone protein for MCT1, cLDH cytosolic 1-lactate dehydrogenase, CO2 carbon dioxide, CoA coenzyme A, H* hydrogen ion, H2O water, I! Complex I/NADH oxi- doreductase of the mitochondrial electron system, //J Complex III of the mitochondrial electron transport system, /V/COX complex IV/ cytochrome c oxidase, La’ 1-lactate; MAS malate—aspartate shuttle, MCT monocarboxylate transporter, mLDH mitochondrial 1-lactate dehydrogenase, MPC mitochondrial pyruvate carrier, NAD* oxidized nicotinamide adenine dinucleotide, NADH reduced nicotinamide adenine dinucleotide, O2 molecular oxygen, PDH pyruvate dehydro- genase complex, Pyr pyruvate, Q quinone, TCA tricarboxylic acid cycle, V Complex V/ATP synthase Fig. 10 Cytosol-to-mitochondria lactate shuttle (Rogatzki et al. 2015). Based on (Stainsby and Brooks 1990; Hashimoto et al. 2006; Gladden 2008a; Rogatzki et al. 2015) and combined from (Kane 2014; Rogatzki et al. 2015). The prominent activity of the near- equilibrium LDH ensures cytosolic La formation during most con- ditions, with rates increasing in parallel with increased glycolytic activity. The figure depicts a skeletal muscle, and not all cells nec- essarily exhibit all the processes depicted in the upper right. Com- partmentations with glycolytic activity include association with the sarcolemmal Na*/K* ATPase, glycolysis-related reactions, and the Ca**-ATPase of the sarcoplasmic reticulum. La enters the mitochon- drial intermembrane space through porins in the outer mitochondrial membrane. Here, mLDH oxidizes La to Pyr , reducing NAD* to NADH. Pyr crosses the mitochondrial inner membrane via the MPC and/or MCT1, stabilized by CD147. Note: arguments against mito- chondrial MCT have been made; see (Halestrap and Wilson 2012). The NADH generated by mLDH is reoxidized by the MAS, which shuttles reducing power across the inner mitochondrial membrane. This is necessary, because the inner mitochondrial membrane is impermeable to NAD* and NADH. In the matrix, Pyr is oxidized by PDH to acetyl coA, which enters the TCA cycle, generating addi- tional NADH. Oxidation of NADH at Complex I is a primary entry point of electrons into the mitochondrial electron transport system
(ETS). The electrons are then passed to the mobile electron carrier Q, transported through Complex III, and then to Complex IV/COX via cytochrome c. The final electron acceptor at Complex IV in this schematic is molecular O5. The drops in free energy occurring across the ETS at complexes I, III, and IV are sufficient to drive the extru- sion of H* from the matrix into the intermembrane space, generating the proton motive force necessary to drive the synthesis of ATP at Complex V/ATP synthase. Omitted for clarity: Complex I/succinate dehydrogenase of the TCA/ETS, the glycerol 3-phosphate shuttle, the NAD(P) transhydrogenase, and stoichiometries of reactants and prod- ucts for all reactions. ADP adenosine diphosphate, ATP adenosine triphosphate, C cytochrome c, CD147 chaperone protein for MCT1, cLDH cytosolic 1-lactate dehydrogenase, CO2 carbon dioxide, CoA coenzyme A, H* hydrogen ion, H2O water, I! Complex I/NADH oxi- doreductase of the mitochondrial electron system, //J Complex III of the mitochondrial electron transport system, /V/COX complex IV/ cytochrome c oxidase, La’ 1-lactate; MAS malate—aspartate shuttle, MCT monocarboxylate transporter, mLDH mitochondrial 1-lactate dehydrogenase, MPC mitochondrial pyruvate carrier, NAD* oxidized nicotinamide adenine dinucleotide, NADH reduced nicotinamide adenine dinucleotide, O2 molecular oxygen, PDH pyruvate dehydro- genase complex, Pyr pyruvate, Q quinone, TCA tricarboxylic acid cycle, V Complex V/ATP synthase Fig. 10 Cytosol-to-mitochondria lactate shuttle (Rogatzki et al. 2015). Based on (Stainsby and Brooks 1990; Hashimoto et al. 2006; Gladden 2008a; Rogatzki et al. 2015) and combined from (Kane 2014; Rogatzki et al. 2015). The prominent activity of the near- equilibrium LDH ensures cytosolic La formation during most con- ditions, with rates increasing in parallel with increased glycolytic activity. The figure depicts a skeletal muscle, and not all cells nec- essarily exhibit all the processes depicted in the upper right. Com- partmentations with glycolytic activity include association with the sarcolemmal Na*/K* ATPase, glycolysis-related reactions, and the Ca**-ATPase of the sarcoplasmic reticulum. La enters the mitochon- drial intermembrane space through porins in the outer mitochondrial membrane. Here, mLDH oxidizes La to Pyr , reducing NAD* to NADH. Pyr crosses the mitochondrial inner membrane via the MPC and/or MCT1, stabilized by CD147. Note: arguments against mito- chondrial MCT have been made; see (Halestrap and Wilson 2012). The NADH generated by mLDH is reoxidized by the MAS, which shuttles reducing power across the inner mitochondrial membrane. This is necessary, because the inner mitochondrial membrane is impermeable to NAD* and NADH. In the matrix, Pyr is oxidized by PDH to acetyl coA, which enters the TCA cycle, generating addi- tional NADH. Oxidation of NADH at Complex I is a primary entry point of electrons into the mitochondrial electron transport system
Fig.11 Demonstration of lactate-protected hypoglycemia (LPH) in anesthetized dogs. A Experimental manipulation of [glucose] in anesthetized dogs (n = 3) as described in the text. Once blood [glu- cose] was reduced to <1 mM, time to brain isoelectricity (death) was ~0.5 h. In B, the same protocol was repeated (n = 2) but with prior and continued infusion of exogenous La to almost ten times normal and clamped there (~ 10 mM). Subsequently, time to isoelec- tricity was increased 10-fold (>5.5 h), substantiating for the first time in whole animals what had been suspected from clinical case reports (Oldenbeuving et al. 2014) and decades of data demonstrating La ’s ability to be transported and utilized as a fuel throughout almost all tissues of the body (Gladden 2004b). This proposed LPH (Nijsten and van Dam 2009; Goodwin et al. 2015) might function for at least a period of hours. Note different scales on x- and y-axes in Pan- els A versus B. Data are from unpublished results of Goodwin ML, Rogatzki MJ, Sun Y, McDonald JR, Lee K, Oldenbeuving G, Nijsten MWN, Gladden LB
Fig.11 Demonstration of lactate-protected hypoglycemia (LPH) in anesthetized dogs. A Experimental manipulation of [glucose] in anesthetized dogs (n = 3) as described in the text. Once blood [glu- cose] was reduced to <1 mM, time to brain isoelectricity (death) was ~0.5 h. In B, the same protocol was repeated (n = 2) but with prior and continued infusion of exogenous La to almost ten times normal and clamped there (~ 10 mM). Subsequently, time to isoelec- tricity was increased 10-fold (>5.5 h), substantiating for the first time in whole animals what had been suspected from clinical case reports (Oldenbeuving et al. 2014) and decades of data demonstrating La ’s ability to be transported and utilized as a fuel throughout almost all tissues of the body (Gladden 2004b). This proposed LPH (Nijsten and van Dam 2009; Goodwin et al. 2015) might function for at least a period of hours. Note different scales on x- and y-axes in Pan- els A versus B. Data are from unpublished results of Goodwin ML, Rogatzki MJ, Sun Y, McDonald JR, Lee K, Oldenbeuving G, Nijsten MWN, Gladden LB
580 California St., Suite 400
San Francisco, CA, 94104
© 2025 Academia. All rights reserved