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.

Elevated n-3 fatty acids in a high-fat diet attenuate the increase in PDH kinase activity but not PDH activity in human skeletal muscle

2005 ◽  
Vol 98 (1) ◽  
pp. 350-355 ◽  
Author(s):  
Erin A. Turvey ◽  
George J. F. Heigenhauser ◽  
Michelle Parolin ◽  
Sandra J. Peters
Keyword(s):  
Skeletal Muscle ◽  
Fatty Acids ◽  
Pyruvate Dehydrogenase ◽  
High Fat Diet ◽  
Human Skeletal Muscle ◽  
Fat Content ◽  
Pyruvate Dehydrogenase Kinase ◽  
High Fat ◽  
High Fat Diets ◽  
Fat Diets

We tested the hypothesis that a high-fat diet (75% fat; 5% carbohydrates; 20% protein), for which 15% of the fat content was substituted with n-3 fatty acids, would not exhibit the diet-induced increase in pyruvate dehydrogenase kinase (PDK) activity, which is normally observed in human skeletal muscle. The fat content was the same in both the regular high-fat diet (HF) and in the n-3-substituted diet (N3). PDK activity increased after both high-fat diets, but the increase was attenuated after the N3 diet (0.051 ± 0.007 and 0.218 ± 0.047 min−1 for pre- and post-HF, respectively; vs. 0.073 ± 0.016 and 0.133 ± 0.032 min−1 for pre- and post-N3, respectively). However, the active form of pyruvate dehydrogenase (PDHa) activity decreased to a similar extent in both conditions (0.93 ± 0.17 and 0.43 ± 0.09 mmol/kg wet wt pre- and post-HF; vs. 0.87 ± 0.19 and 0.39 ± 0.05 mmol/kg wet wt pre- and post-N3, respectively). This suggested that the difference in PDK activity did not affect PDHa activation in the basal state, and it was regulated by intramitochondrial effectors, primarily muscle pyruvate concentration. Muscle glycogen content was consistent throughout the study, before and after both diet conditions, whereas muscle glucose-6-phosphate, glycerol-3-phosphate, lactate, and pyruvate were decreased after the high-fat diets. Plasma triglycerides decreased after both high-fat diets but decreased to a greater extent after the N3, whereas plasma free fatty acids increased after both diets, but to a lesser extent after the N3. In summary, PDK activity is decreased after a high-fat diet that is rich in n-3 fatty acids, although PDHa activity was unaltered. In addition, our data demonstrated that the hypolipidemic effect of n-3 fatty acids occurs earlier (3 days) than previously reported and is evident even when the diet has 75% of its total energy derived from fat.

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 Effects of Steady Low-Intensity Exercise on High-Fat Diet Stimulated Breast Cancer Progression Via the Alteration of Macrophage Polarization

2020 ◽  
Vol 19 ◽  
pp. 153473542094967
Author(s):  
Min Kyoon Kim ◽  
Yesl Kim ◽  
SeungHwa Park ◽  
Eunju Kim ◽  
Yerin Kim ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Growth ◽  
High Fat Diet ◽  
Tumor Volume ◽  
Macrophage Polarization ◽  
M2 Macrophage ◽  
High Fat ◽  
Low Intensity ◽  
M2 Macrophage Polarization ◽  
Low Intensity Exercise

Physical inactivity and high-fat diet, especially high saturated fat containing diet are established risk factors for breast cancer that are amenable to intervention. High-fat diet has been shown to induce tumor growth and metastasis by alteration of inflammation but steady exercise has anti-tumorigenic effects. However, the mechanisms underlying the effects of physical activity on high-fat diet stimulated breast cancer initiation and progression are currently unclear. In this study, we examined how the intensity of physical activity influences high fat diet-stimulated breast cancer latency and progression outcomes, and the possible mechanisms behind these effects. Five-week-old female Balb/c mice were fed either a control diet or a high-fat diet for 8 weeks, and then 4T1 mouse mammary tumor cells were inoculated into the mammary fat pads. Exercise training occurred before tumor cell injection, and tumor latency and tumor volume were measured. Mice with a high-fat diet and low-intensity exercise (HFLE) had a longer tumor latency period, slower tumor growth, and smaller tumor volume in the final tumor assessment compared with the control, high-fat diet control (HFDC), and high-fat diet with moderate-intensity exercise (HFME) groups. Steady low- and moderate-intensity exercise had no effect on cell proliferation but induced apoptosis by activating caspase-3 through the alteration of Bcl-2, Bcl-xL, and Bax expression. Furthermore, steady exercise reduced M2 macrophage polarization in breast tumor tissue, which has been linked to tumor growth. The myokine, myostatin, reduced M2 macrophage polarization through the inhibition of the JAK-STAT signaling pathway. These results suggest that steady low-intensity exercise could delay breast cancer initiation and growth and reduce tumor volume through the induction of tumor cell apoptosis and the suppression of M2 macrophage polarization.

scholarly journals Defining the contribution of skeletal muscle pyruvate dehydrogenase α1 to exercise performance and insulin action

2018 ◽  
Vol 315 (5) ◽  
pp. E1034-E1045 ◽  
Author(s):  
Kristoffer Svensson ◽  
Jessica R. Dent ◽  
Shahriar Tahvilian ◽  
Vitor F. Martins ◽  
Abha Sathe ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Insulin Sensitivity ◽  
Energy Expenditure ◽  
Exercise Performance ◽  
Pyruvate Dehydrogenase ◽  
High Intensity ◽  
High Intensity Exercise ◽  
Low Intensity ◽  
Low Intensity Exercise ◽  
Muscle Contractile

The pyruvate dehydrogenase complex (PDC) converts pyruvate to acetyl-CoA and is an important control point for carbohydrate (CHO) oxidation. However, the importance of the PDC and CHO oxidation to muscle metabolism and exercise performance, particularly during prolonged or high-intensity exercise, has not been fully defined especially in mature skeletal muscle. To this end, we determined whether skeletal muscle-specific loss of pyruvate dehydrogenase alpha 1 ( Pdha1), which is a critical subunit of the PDC, impacts resting energy metabolism, exercise performance, or metabolic adaptation to high-fat diet (HFD) feeding. For this, we generated a tamoxifen (TMX)-inducible Pdha1 knockout (PDHmKO) mouse, in which PDC activity is temporally and specifically ablated in adult skeletal muscle. We assessed energy expenditure, ex vivo muscle contractile performance, and endurance exercise capacity in PDHmKO mice and wild-type (WT) littermates. Additionally, we studied glucose homeostasis and insulin sensitivity in muscle after 12 wk of HFD feeding. TMX administration largely ablated PDHα in skeletal muscle of adult PDHmKO mice but did not impact energy expenditure, muscle contractile function, or low-intensity exercise performance. Additionally, there were no differences in muscle insulin sensitivity or body composition in PDHmKO mice fed a control or HFD, as compared with WT mice. However, exercise capacity during high-intensity exercise was severely impaired in PDHmKO mice, in parallel with a large increase in plasma lactate concentration. In conclusion, although skeletal muscle PDC is not a major contributor to resting energy expenditure or long-duration, low-intensity exercise performance, it is necessary for optimal performance during high-intensity exercise.

Insulin sensitivity is independent of lipid binding protein trafficking at the plasma membrane in human skeletal muscle: effect of a 3-day, high-fat diet

2014 ◽  
Vol 307 (9) ◽  
pp. R1136-R1145 ◽  
Author(s):  
Andreas B. Jordy ◽  
Annette K. Serup ◽  
Kristian Karstoft ◽  
Henriette Pilegaard ◽  
Bente Kiens ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Insulin Sensitivity ◽  
Protein Trafficking ◽  
High Fat Diet ◽  
Human Skeletal Muscle ◽  
Lipid Binding ◽  
High Fat ◽  
Before And After ◽  
The Impact ◽  
Sarcolemmal Vesicles

The aim of the present study was to investigate lipid-induced regulation of lipid binding proteins in human skeletal muscle and the impact hereof on insulin sensitivity. Eleven healthy male subjects underwent a 3-day hypercaloric and high-fat diet regime. Muscle biopsies were taken before and after the diet intervention, and giant sarcolemmal vesicles were prepared. The high-fat diet induced decreased insulin sensitivity, but this was not associated with a relocation of FAT/CD36 or FABPpm protein to the sarcolemma. However, FAT/CD36 and FABPpm mRNA, but not the proteins, were upregulated by increased fatty acid availability. This suggests a time dependency in the upregulation of FAT/CD36 and FABPpm protein during high availability of plasma fatty acids. Furthermore, we did not detect FATP1 and FATP4 protein in giant sarcolemmal vesicles obtained from human skeletal muscle. In conclusion, this study shows that a short-term lipid-load increases mRNA content of key lipid handling proteins in human muscle. However, decreased insulin sensitivity after a high-fat diet is not accompanied with relocation of FAT/CD36 or FABPpm protein to the sarcolemma. Finally, FATP1 and FATP4 protein was located intracellularly but not at the sarcolemma in humans.

scholarly journals Pre-Exercise High-Fat Diet for 3 Days Affects Post-Exercise Skeletal Muscle Glycogen Repletion

2017 ◽  
Vol 63 (5) ◽  
pp. 323-330 ◽  
Author(s):  
Yumiko TAKAHASHI ◽  
Yutaka MATSUNAGA ◽  
Yuki TAMURA ◽  
Shin TERADA ◽  
Hideo HATTA
Keyword(s):  
Skeletal Muscle ◽  
Muscle Glycogen ◽  
High Fat Diet ◽  
High Fat ◽  
Post Exercise ◽  
Skeletal Muscle Glycogen ◽  
Glycogen Repletion
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