scholarly journals Pyruvate dehydrogenase kinase-4 contributes to the recirculation of gluconeogenic precursors during postexercise glycogen recovery

2014 ◽  
Vol 306 (2) ◽  
pp. R102-R107 ◽  
Author(s):  
Eric A. F. Herbst ◽  
Rebecca E. K. MacPherson ◽  
Paul J. LeBlanc ◽  
Brian D. Roy ◽  
Nam Ho Jeoung ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Glycogen ◽  
Pyruvate Dehydrogenase ◽  
Liver Glycogen ◽  
Pyruvate Dehydrogenase Kinase ◽  
Muscle Lactate ◽  
Pyruvate Dehydrogenase Kinase 4 ◽  
Mrna Content ◽  
Caloric Consumption ◽  
Glycogen Stores

During recovery from glycogen-depleting exercise, there is a shift from carbohydrate oxidation to glycogen resynthesis. The activity of the pyruvate dehydrogenase (PDH) complex may decrease to reduce oxidation of carbohydrates in favor of increasing gluconeogenic recycling of carbohydrate-derived substrates for this process. The precise mechanism behind this has yet to be elucidated; however, research examining mRNA content has suggested that the less-abundant pyruvate dehydrogenase kinase-4 (PDK4) may reduce PDH activation during exercise recovery. To investigate this, skeletal muscle and liver of wild-type (WT) and PDK4-knockout (PDK4-KO) mice were analyzed at rest (Rest), after exercise to exhaustion (Exh), and after 2 h of recovery with ad libitum feeding (Rec). Although there were no differences in exercise tolerance between genotypes, caloric consumption was doubled by PDK4-KO mice during Rec. Because of this, PDK4-KO mice at Rec supercompensated muscle glycogen to 120% of resting stores. Therefore, an extra group of PDK4-KO mice were pair-fed (PF) with WT mice during Rec for comparison. PF mice fully replenished muscle glycogen but recovered only 50% of liver glycogen stores. Concentrations of muscle lactate and alanine were also lower in PF than in WT mice, indicating that this decrease may lead to a potential reduction of recycled gluconeogenic substrates, due to oxidation of their carbohydrate precursors in skeletal muscle, leading to observed reductions in hepatic glucose and glycogen concentrations. Because of the impairments seen in PF PDK4-KO mice, these results suggest a role for PDK4 in regulating the PDH complex in muscle and promoting gluconeogenic precursor recirculation during recovery from exhaustive exercise.

scholarly journals Pyruvate dehydrogenase kinase-4 deficiency lowers blood glucose and improves glucose tolerance in diet-induced obese mice

2008 ◽  
Vol 295 (1) ◽  
pp. E46-E54 ◽  
Author(s):  
Nam Ho Jeoung ◽  
Robert A. Harris
Keyword(s):  
Skeletal Muscle ◽  
Blood Glucose ◽  
Glucose Tolerance ◽  
Pyruvate Dehydrogenase ◽  
High Fat Diet ◽  
Pyruvate Dehydrogenase Kinase ◽  
Wild Type ◽  
High Fat ◽  
Pyruvate Dehydrogenase Kinase 4 ◽  
Liver And Kidney

The effect of pyruvate dehydrogenase kinase-4 (PDK4) deficiency on glucose homeostasis was studied in mice fed a high-fat diet. Expression of PDK4 was greatly increased in skeletal muscle and diaphragm but not liver and kidney of wild-type mice fed the high-fat diet. Wild-type and PDK4−/− mice consumed similar amounts of the diet and became equally obese. Insulin resistance developed in both groups. Nevertheless, fasting blood glucose levels were lower, glucose tolerance was slightly improved, and insulin sensitivity was slightly greater in the PDK4−/− mice compared with wild-type mice. When the mice were killed in the fed state, the actual activity of the pyruvate dehydrogenase complex (PDC) was higher in the skeletal muscle and diaphragm but not in the liver and kidney of PDK4−/− mice compared with wild-type mice. When the mice were killed after overnight fasting, the actual PDC activity was higher only in the kidney of PDK4−/− mice compared with wild-type mice. The concentrations of gluconeogenic substrates were lower in the blood of PDK4−/− mice compared with wild-type mice, consistent with reduced formation in peripheral tissues. Diaphragms isolated from PDK4−/− mice oxidized glucose faster and fatty acids slower than diaphragms from wild-type mice. Fatty acid oxidation inhibited glucose oxidation by diaphragms from wild-type but not PDK4−/− mice. NEFA, ketone bodies, and branched-chain amino acids were elevated more in PDK4−/− mice, consistent with slower rates of oxidation. These findings show that PDK4 deficiency lowers blood glucose and slightly improves glucose tolerance and insulin sensitivity in mice with diet-induced obesity.

scholarly journals Role of NADH/NAD+ transport activity and glycogen store on skeletal muscle energy metabolism during exercise: in silico studies

2009 ◽  
Vol 296 (1) ◽  
pp. C25-C46 ◽  
Author(s):  
Yanjun Li ◽  
Ranjan K. Dash ◽  
Jaeyeon Kim ◽  
Gerald M. Saidel ◽  
Marco E. Cabrera
Keyword(s):  
Skeletal Muscle ◽  
Energy Metabolism ◽  
Muscle Glycogen ◽  
Redox State ◽  
Muscle Lactate ◽  
Mitochondrial Redox State ◽  
Muscle Energy ◽  
Muscle Energy Metabolism ◽  
Glycogen Stores ◽  
Muscle Glycogen Concentration

Skeletal muscle can maintain ATP concentration constant during the transition from rest to exercise, whereas metabolic reaction rates may increase substantially. Among the key regulatory factors of skeletal muscle energy metabolism during exercise, the dynamics of cytosolic and mitochondrial NADH and NAD+ have not been characterized. To quantify these regulatory factors, we have developed a physiologically based computational model of skeletal muscle energy metabolism. This model integrates transport and reaction fluxes in distinct capillary, cytosolic, and mitochondrial domains and investigates the roles of mitochondrial NADH/NAD+ transport (shuttling) activity and muscle glycogen concentration (stores) during moderate intensity exercise (60% maximal O2 consumption). The underlying hypothesis is that the cytosolic redox state (NADH/NAD+) is much more sensitive to a metabolic disturbance in contracting skeletal muscle than the mitochondrial redox state. This hypothesis was tested by simulating the dynamic metabolic responses of skeletal muscle to exercise while altering the transport rate of reducing equivalents (NADH and NAD+) between cytosol and mitochondria and muscle glycogen stores. Simulations with optimal parameter estimates showed good agreement with the available experimental data from muscle biopsies in human subjects. Compared with these simulations, a 20% increase (or ∼20% decrease) in mitochondrial NADH/NAD+ shuttling activity led to an ∼70% decrease (or ∼3-fold increase) in cytosolic redox state and an ∼35% decrease (or ∼25% increase) in muscle lactate level. Doubling (or halving) muscle glycogen concentration resulted in an ∼50% increase (or ∼35% decrease) in cytosolic redox state and an ∼30% increase (or ∼25% decrease) in muscle lactate concentration. In both cases, changes in mitochondrial redox state were minimal. In conclusion, the model simulations of exercise response are consistent with the hypothesis that mitochondrial NADH/NAD+ shuttling activity and muscle glycogen stores affect primarily the cytosolic redox state. Furthermore, muscle lactate production is regulated primarily by the cytosolic redox state.

scholarly journals Transcriptional regulation of pyruvate dehydrogenase kinase 4 in skeletal muscle during and after exercise

2004 ◽  
Vol 63 (2) ◽  
pp. 221-226 ◽  
Author(s):  
Henriette Pilegaard ◽  
P. Darrell Neufer
Keyword(s):  
Skeletal Muscle ◽  
Muscle Glycogen ◽  
Pyruvate Dehydrogenase ◽  
High Fat Diet ◽  
Prolonged Exercise ◽  
Pyruvate Dehydrogenase Kinase ◽  
High Fat ◽  
Low Intensity ◽  
Low Intensity Exercise ◽  
The Impact

The pyruvate dehydrogenase complex (PDC) has a key position in skeletal muscle metabolism as it represents the entry of carbohydrate-derived fuel into the mitochondria for oxidation. PDC is regulated by a phosphorylation–dephosphorylation cycle, in which the pyruvate dehydrogenase kinase (PDK) phosphorylates and inactivates the complex. PDK exists in four isoforms, of which the PDK4 isoform is predominantly expressed in skeletal and heart muscle. PDK4 transcription and PDK4 mRNA are markedly increased in human skeletal muscle during prolonged exercise and after both short-term high-intensity and prolonged low-intensity exercise. The exercise-induced transcriptional response of PDK4 is enhanced when muscle glycogen is lowered before the exercise, and intake of a low-carbohydrate high-fat diet during recovery from exercise results in increased transcription and mRNA content of PDK4 when compared with intake of a high-carbohydrate diet. The activity of pyruvate dehydrogenase (PDH) is increased during the first 2 h of low-intensity exercise, followed by a decrease towards resting levels, which is in line with the possibility that the increased PDK4 expressed influences the PDH activity already during prolonged exercise. PDK4 expression is also increased in response to fasting and a high-fat diet. Thus, increased PDK4 expression when carbohydrate availability is low seems to contribute to the sparing of carbohydrates by preventing carbohydrate oxidation. The impact of substrate availability on PDK4 expression during recovery from exercise also underlines the high metabolic priority given to replenishing muscle glycogen stores and re-establishing intracellular homeostasis after exercise.

Effect of epinephrine on glycogen stores

1959 ◽  
Vol 196 (6) ◽  
pp. 1253-1257 ◽  
Author(s):  
Joseph E. Sokal ◽  
Edward J. Sarcione
Keyword(s):  
Skeletal Muscle ◽  
Muscle Glycogen ◽  
Intraperitoneal Injection ◽  
Liver Glycogen ◽  
Blood Levels ◽  
Glucagon Release ◽  
Control Value ◽  
High Concentrations ◽  
Glycogen Stores ◽  
Stimulation Of

Subcutaneous epinephrine doses of 0.1 mg/kg or more consistently produced declines in muscle glycogen of rats. Transient declines (30%) in liver glycogen, followed by net resynthesis to levels above the control value, were observed after subcutaneous doses 0.2–0.4 mg/kg. Subcutaneous doses of 6.0 mg/kg were required to produce progressive depletion of liver glycogen (82%), over a 3-hour period. However, such depletion was uniformly obtained by intraperitoneal injection of much smaller doses (0.4 mg/kg/hr.). High blood levels of lactate and glucose did not reverse glycogenolysis in liver or in muscle when adequate concentrations of epinephrine were maintained. Although intraperitoneal injection of epinephrine leads to high concentrations at the liver and lower concentrations at skeletal muscle, intraperitoneal doses of 0.1 mg/kg/hr. produced declines in muscle glycogen but not in liver glycogen. It is concluded that the concentration of epinephrine required to produce glycogenolysis in the liver is at least 5–10 times as high as that effective in the muscle. The transient hepatic glycogenolysis observed after relatively small subcutaneous doses of epinephrine may be due to stimulation of endogenous glucagon release.

scholarly journals Activation of Liver X Receptor Regulates Substrate Oxidation in White Adipocytes

Endocrinology ◽  
2009 ◽  
Vol 150 (9) ◽  
pp. 4104-4113 ◽  
Author(s):  
Britta M. Stenson ◽  
Mikael Rydén ◽  
Knut R. Steffensen ◽  
Kerstin Wåhlén ◽  
Amanda T. Pettersson ◽  
...  
Keyword(s):  
Pyruvate Dehydrogenase ◽  
Pyruvate Dehydrogenase Complex ◽  
Substrate Oxidation ◽  
Pyruvate Dehydrogenase Kinase ◽  
Tissue Mass ◽  
Metabolic Complications ◽  
Pyruvate Dehydrogenase Kinase 4 ◽  
White Adipocytes ◽  
X Receptors

Abstract Liver X receptors (LXRs) are nuclear receptors with established roles in cholesterol, lipid, and carbohydrate metabolism, although their function in adipocytes is not well characterized. Increased adipose tissue mass in obesity is associated with increased adipocyte lipolysis. Fatty acids (FA) generated by lipolysis can be oxidized by mitochondrial β-oxidation, reesterified, or released from the adipocyte. The latter results in higher circulating levels of free FAs, in turn causing obesity-related metabolic complications. However, mitochondrial β-oxidation can at least in part counteract an increased output of FA into circulation. In this study, we provide evidence that activation of LXRs up-regulates mitochondrial β-oxidation in both human and murine white adipocytes. We also show that the expression of a kinase regulating the cellular fuel switch, pyruvate dehydrogenase kinase 4 (PDK4), is up-regulated by the LXR agonist GW3965 in both in vitro differentiated human primary adipocytes and differentiated murine 3T3-L1 cells. Moreover, activation of LXR causes PDK4-dependent phosphorylation of the pyruvate dehydrogenase complex, thereby decreasing its activity and attenuating glucose oxidation. The specificity of the GW3965 effect on oxidation was confirmed by RNA interference targeting LXRs. We propose that LXR has an important role in the regulation of substrate oxidation and the switch between lipids and carbohydrates as cellular fuel in both human and murine white adipocytes.

scholarly journals Transforming Growth Factor β Mediates Drug Resistance by Regulating the Expression of Pyruvate Dehydrogenase Kinase 4 in Colorectal Cancer

2016 ◽  
Vol 291 (33) ◽  
pp. 17405-17416 ◽  
Author(s):  
Yang Zhang ◽  
Yi Zhang ◽  
Liying Geng ◽  
Haowei Yi ◽  
Wei Huo ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Colon Cancer ◽  
Drug Resistance ◽  
Cancer Cells ◽  
Pyruvate Dehydrogenase ◽  
Pyruvate Dehydrogenase Kinase ◽  
Dependent Manner ◽  
Colon Cancer Cells ◽  
Pyruvate Dehydrogenase Kinase 4 ◽  
Mouse Xenograft Model

Drug resistance is one of the main causes of colon cancer recurrence. However, our understanding of the underlying mechanisms and availability of therapeutic options remains limited. Here we show that expression of pyruvate dehydrogenase kinase 4 (PDK4) is positively correlated with drug resistance of colon cancer cells and induced by 5-fluorouracil (5-FU) treatment in drug-resistant but not drug-sensitive cells. Knockdown of PDK4 expression sensitizes colon cancer cells to 5-FU or oxaliplatin-induced apoptosis in vitro and increases the effectiveness of 5-FU in the inhibition of tumor growth in a mouse xenograft model in vivo. In addition, we demonstrate for the first time that TGFβ mediates drug resistance by regulating PDK4 expression and that 5-FU induces PDK4 expression in a TGFβ signaling-dependent manner. Mechanistically, knockdown or inhibition of PDK4 significantly increases the inhibitory effect of 5-FU on expression of the anti-apoptotic factors Bcl-2 and survivin. Importantly, studies of patient samples indicate that expression of PDK4 and phosphorylation of Smad2, an indicator of TGFβ pathway activation, show a strong correlation and that both positively associate with chemoresistance in colorectal cancer. These findings indicate that the TGFβ/PDK4 signaling axis plays an important role in the response of colorectal cancer to chemotherapy. A major implication of our studies is that inhibition of PDK4 may have considerable therapeutic potential to overcome drug resistance in colorectal cancer patients, which warrants the development of PDK4-specific inhibitors.

Skeletal muscle pyruvate dehydrogenase activity during maximal exercise in humans

1995 ◽  
Vol 269 (3) ◽  
pp. E458-E468 ◽  
Author(s):  
C. T. Putman ◽  
N. L. Jones ◽  
L. C. Lands ◽  
T. M. Bragg ◽  
M. G. Hollidge-Horvat ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Pyruvate Dehydrogenase ◽  
Maximal Exercise ◽  
Vastus Lateralis ◽  
Active Form ◽  
Lactate Production ◽  
Glycolytic Flux ◽  
Muscle Lactate ◽  
Mitochondrial Oxidation ◽  
Exercise In Humans

The regulation of the active form of pyruvate dehydrogenase (PDHa) and related metabolic events were examined in human skeletal muscle during repeated bouts of maximum exercise. Seven subjects completed three consecutive 30-s bouts of maximum isokinetic cycling, separated by 4 min of recovery. Biopsies of the vastus lateralis were taken before and immediately after each bout. PDHa increased from 0.45 +/- 0.15 to 2.96 +/- 0.38, 1.10 +/- 0.11 to 2.91 +/- 0.11, and 1.28 +/- 0.18 to 2.82 +/- 0.32 mmol.min-1.kg wet wt-1 during bouts 1, 2, and 3, respectively. Glycolytic flux was 13-fold greater than PDHa in bouts 1 and 2 and 4-fold greater during bout 3. This discrepancy between the rate of pyruvate production and oxidation resulted in substantial lactate accumulation to 89.5 +/- 11.6 in bout 1, 130.8 +/- 13.8 in bout 2, and 106.6 +/- 10.1 mmol/kg dry wt in bout 3. These events coincided with an increase in the mitochondrial oxidation state, as reflected by a fall in mitochondrial NADH/NAD, indicating that muscle lactate production during exercise was not an O2-dependent process in our subjects. During exercise the primary factor regulating PDHa transformation was probably intracellular Ca2+. In contrast, the primary regulatory factors causing greater PDHa during recovery were lower ATP/ADP and NADH/NAD and increased concentrations of pyruvate and H+. Greater PDHa during recovery facilitated continued oxidation of the lactate load between exercise bouts.

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