The relationship between human skeletal muscle pyruvate dehydrogenase phosphatase activity and muscle aerobic capacity

2011 ◽  
Vol 111 (2) ◽  
pp. 427-434 ◽  
Author(s):  
Lorenzo K. Love ◽  
Paul J. LeBlanc ◽  
J. Greig Inglis ◽  
Nicolette S. Bradley ◽  
Jon Choptiany ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Protein Content ◽  
Endurance Training ◽  
Aerobic Capacity ◽  
Pyruvate Dehydrogenase ◽  
Human Skeletal Muscle ◽  
Citrate Synthase ◽  
Tricarboxylic Acid Cycle ◽  
Carbohydrate Oxidation ◽  
Pyruvate Dehydrogenase Phosphatase

Pyruvate dehydrogenase (PDH) is a mitochondrial enzyme responsible for regulating the conversion of pyruvate to acetyl-CoA for use in the tricarboxylic acid cycle. PDH is regulated through phosphorylation and inactivation by PDH kinase (PDK) and dephosphorylation and activation by PDH phosphatase (PDP). The effect of endurance training on PDK in humans has been investigated; however, to date no study has examined the effect of endurance training on PDP in humans. Therefore, the purpose of this study was to examine differences in PDP activity and PDP1 protein content in human skeletal muscle across a range of muscle aerobic capacities. This association is important as higher PDP activity and protein content will allow for increased activation of PDH, and carbohydrate oxidation. The main findings of this study were that 1) PDP activity ( r2 = 0.399, P = 0.001) and PDP1 protein expression ( r2 = 0.153, P = 0.039) were positively correlated with citrate synthase (CS) activity as a marker for muscle aerobic capacity; 2) E1α ( r2 = 0.310, P = 0.002) and PDK2 protein ( r2 = 0.229, P =0.012) are positively correlated with muscle CS activity; and 3) although it is the most abundant isoform, PDP1 protein content only explained ∼18% of the variance in PDP activity ( r2 = 0.184, P = 0.033). In addition, PDP1 in combination with E1α explained ∼38% of the variance in PDP activity ( r2 = 0.383, P = 0.005), suggesting that there may be alternative regulatory mechanisms of this enzyme other than protein content. These data suggest that with higher muscle aerobic capacity (CS activity) there is a greater capacity for carbohydrate oxidation (E1α), in concert with higher potential for PDH activation (PDP activity).

Exercise training increases branched-chain oxoacid dehydrogenase kinase content in human skeletal muscle

2007 ◽  
Vol 293 (3) ◽  
pp. R1335-R1341 ◽  
Author(s):  
Krista R. Howarth ◽  
Kirsten A. Burgomaster ◽  
Stuart M. Phillips ◽  
Martin J. Gibala
Keyword(s):  
Skeletal Muscle ◽  
Exercise Training ◽  
Protein Content ◽  
Human Skeletal Muscle ◽  
Acute Exercise ◽  
Citrate Synthase ◽  
Muscle Protein ◽  
Moderate Intensity ◽  
Main Effect ◽  
Branched Chain

The branched-chain oxoacid dehydrogenase complex (BCOAD) is rate determining for the oxidation of branched-chain amino acids (BCAAs) in skeletal muscle. Exercise training blunts the acute exercise-induced activation of BCOAD (BCOADa) in human skeletal muscle (McKenzie S, Phillips SM, Carter SL, Lowther S, Gibala MJ, Tarnopolsky MA. Am J Physiol Endocrinol Metab 278: E580–E587, 2000); however, the mechanism is unknown. We hypothesized that training would increase the muscle protein content of BCOAD kinase, the enzyme responsible for inactivation of BCOAD by phosphorylation. Twenty subjects [23 ± 1 yr; peak oxygen uptake (V̇o2peak) = 41 ± 2 ml·kg−1·min−1] performed 6 wk of either high-intensity interval or continuous moderate-intensity training on a cycle ergometer ( n = 10/group). Before and after training, subjects performed 60 min of cycling at 65% of pretraining V̇o2peak, and needle biopsy samples (vastus lateralis) were obtained before and immediately after exercise. The effect of training was demonstrated by an increased V̇o2peak, increased citrate synthase maximal activity, and reduced muscle glycogenolysis during exercise, with no difference between groups (main effects, P < 0.05). BCOADa was lower after training (main effect, P < 0.05), and this was associated with a ∼30% increase in BCOAD kinase protein content (main effect, P < 0.05). We conclude that the increased protein content of BCOAD kinase may be involved in the mechanism for reduced BCOADa after exercise training in human skeletal muscle. These data also highlight differences in models used to study the regulation of skeletal muscle BCAA metabolism, since exercise training was previously reported to increase BCOADa during exercise and decrease BCOAD kinase content in rats (Fujii H, Shimomura Y, Murakami T, Nakai N, Sato T, Suzuki M, Harris RA. Biochem Mol Biol Int 44: 1211–1216, 1998).

scholarly journals Increased pyruvate dehydrogenase activity in skeletal muscle of growth-restricted ovine fetuses

2019 ◽  
Vol 317 (4) ◽  
pp. R513-R520 ◽  
Author(s):  
Alexander L. Pendleton ◽  
Laurel R. Humphreys ◽  
Melissa A. Davis ◽  
Leticia E. Camacho ◽  
Miranda J. Anderson ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Pyruvate Dehydrogenase ◽  
Intrauterine Growth Restriction ◽  
Citrate Synthase ◽  
Pyruvate Dehydrogenase Kinase ◽  
Semitendinosus Muscle ◽  
Fetal Sheep ◽  
Pyruvate Dehydrogenase Phosphatase ◽  
And Control ◽  
Fetal Muscle

Fetal sheep with placental insufficiency-induced intrauterine growth restriction (IUGR) have lower fractional rates of glucose oxidation and greater gluconeogenesis, indicating lactate shuttling between skeletal muscle and liver. Suppression of pyruvate dehydrogenase ( PDH) activity was proposed because of greater pyruvate dehydrogenase kinase (PDK) 4 and PDK1 mRNA concentrations in IUGR muscle. Although PDK1 and PDK4 inhibit PDH activity to reduce pyruvate metabolism, PDH protein concentrations and activity have not been examined in skeletal muscle from IUGR fetuses. Therefore, we evaluated the protein concentrations and activity of PDH and the kinases and phosphatases that regulate PDH phosphorylation status in the semitendinosus muscle from placenta insufficiency-induced IUGR sheep fetuses and control fetuses. Immunoblots were performed for PDH, phosphorylated PDH (E1α), PDK1, PDK4, and pyruvate dehydrogenase phosphatase 1 and 2 (PDP1 and PDP2, respectively). Additionally, the PDH, lactate dehydrogenase (LDH), and citrate synthase (CS) enzymatic activities were measured. Phosphorylated PDH concentrations were 28% lower (P < 0.01) and PDH activity was 67% greater (P < 0.01) in IUGR fetal muscle compared with control. PDK1, PDK4, PDP1, PDP2, and PDH concentrations were not different between groups. CS and LDH activities were also unaffected. Contrary to the previous speculation, PDH activity was greater in skeletal muscle from IUGR fetuses, which parallels lower phosphorylated PDH. Therefore, greater expression of PDK1 and PDK4 mRNA did not translate to greater PDK1 or PDK4 protein concentrations or inhibition of PDH as proposed. Instead, these findings show greater PDH activity in IUGR fetal muscle, which indicates that alternative regulatory mechanisms are responsible for lower pyruvate catabolism.

Skeletal muscle fiber type comparison of pyruvate dehydrogenase phosphatase activity and isoform expression in fed and food-deprived rats

2007 ◽  
Vol 292 (2) ◽  
pp. E571-E576 ◽  
Author(s):  
Paul J. LeBlanc ◽  
Robert A. Harris ◽  
Sandra J. Peters
Keyword(s):  
Skeletal Muscle ◽  
Protein Content ◽  
Food Deprivation ◽  
Pyruvate Dehydrogenase ◽  
Fiber Type ◽  
Fiber Types ◽  
Mitochondrial Volume ◽  
Coordinate Changes ◽  
Pyruvate Dehydrogenase Phosphatase ◽  
Fast Twitch

Fiber type specificity of pyruvate dehydrogenase (PDH) phosphatase (PDP) was determined in fed (CON) and 48-h food-deprived (FD) rats. PDP activity and isoform protein content were determined in soleus (slow-twitch oxidative), red gastrocnemius (RG; fast-twitch oxidative glycolytic), and white gastrocnemius (WG; fast-twitch glycolytic) muscles. When normalized for mitochondrial volume, there was no difference in PDP activity between muscle types or CON and FD. When expressed per gram wet tissue weight, PDP activity was higher in RG compared with soleus and WG in both CON and FD rats. PDP activities from CON muscles were 1.48 ± 0.19, 2.68 ± 0.65, and 1.20 ± 0.33 nmol·min−1·g wet tissue wt−1 in soleus, RG, and WG, respectively, and decreased in FD muscles (1.22 ± 0.22, 2.00 ± 0.57, and 0.84 ± 0.18 nmol·min−1·g wet tissue wt−1). This correlated with increased PDP2 protein, however, only in RG, as PDP2 was not detectable in soleus or WG. PDP1 protein was not responsive to food deprivation in all fiber types. In conclusion, PDP activity and protein content were higher in fast-twitch oxidative glycolytic muscles from CON and FD rats, identifying a unique inter- and intramuscular distribution. FD induced a small but significant decrease in PDP activity that was partially due to decreases in PDP2 protein. As a result, coordinate changes to PDP activity opposite to those of the other regulatory enzyme, PDH kinase, during food deprivation would maximize the inactivation of skeletal muscle PDH and enhance carbohydrate conservation during periods of limited carbohydrate supply.

scholarly journals Skeletal muscle pyruvate dehydrogenase phosphatase: effects of obesity and endurance training

2006 ◽  
Vol 20 (4) ◽  
Author(s):  
Paul J LeBlanc ◽  
Matt Mulligan ◽  
AnaMaria Antolic ◽  
Laura MacPherson ◽  
J. Greig Inglis ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Endurance Training ◽  
Pyruvate Dehydrogenase ◽  
Pyruvate Dehydrogenase Phosphatase

5′-AMP-activated protein kinase activity and protein expression are regulated by endurance training in human skeletal muscle

2004 ◽  
Vol 286 (3) ◽  
pp. E411-E417 ◽  
Author(s):  
Christian Frøsig ◽  
Sebastian B. Jørgensen ◽  
D. Grahame Hardie ◽  
Erik A. Richter ◽  
Jørgen F. P. Wojtaszewski
Keyword(s):  
Skeletal Muscle ◽  
Protein Kinase ◽  
Exercise Training ◽  
Protein Content ◽  
Endurance Training ◽  
Human Skeletal Muscle ◽  
Protein Kinase Activity ◽  
Local Contraction ◽  
Ampk Activity ◽  
Amp Activated Protein Kinase

The 5′-AMP-activated protein kinase (AMPK) is proposed to be involved in signaling pathways leading to adaptations in skeletal muscle in response to both a single exercise bout and exercise training. This study investigated the effect of endurance training on protein content of catalytic (α1, α2) and regulatory (β1, β2 and γ1, γ2, γ3) subunit isoforms of AMPK as well as on basal AMPK activity in human skeletal muscle. Eight healthy young men performed supervised one-legged knee extensor endurance training for 3 wk. Muscle biopsies were obtained before and 15 h after training in both legs. In response to training the protein content of α1, β2 and γ1 increased in the trained leg by 41, 34, and 26%, respectively (α1 and β2 P < 0.005, γ1 P < 0.05). In contrast, the protein content of the regulatory γ3-isoform decreased by 62% in the trained leg ( P = 0.01), whereas no effect of training was seen for α2, β1, and γ2. AMPK activity associated with the α1- and the α2-isoforms increased in the trained leg by 94 and 49%, respectively (both P < 0.005). In agreement with these observations, phosphorylation of α-AMPK-(Thr172) and of the AMPK target acetyl-CoA carboxylase-β(Ser221) increased by 74 and 180%, respectively (both P < 0.001). Essentially similar results were obtained in four additional subjects studied 55 h after training. This study demonstrates that protein content and basal AMPK activity in human skeletal muscle are highly susceptible to endurance exercise training. Except for the increase in γ1 protein, all observed adaptations to training could be ascribed to local contraction-induced mechanisms, since they did not occur in the contralateral untrained muscle.

Skeletal muscle type comparison of pyruvate dehydrogenase phosphatase activity and isoform expression: effects of obesity and endurance training

2008 ◽  
Vol 295 (4) ◽  
pp. R1224-R1230 ◽  
Author(s):  
Paul J. LeBlanc ◽  
Matthew Mulligan ◽  
AnaMaria Antolić ◽  
Laura MacPherson ◽  
J. Greig Inglis ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Endurance Training ◽  
Carbohydrate Metabolism ◽  
Pyruvate Dehydrogenase ◽  
Fold Increase ◽  
Zucker Rats ◽  
Relative Role ◽  
Concomitant Increase ◽  
Obese Rats ◽  
Pyruvate Dehydrogenase Phosphatase

Pyruvate dehydrogenase (PDH) plays an important role in regulating carbohydrate metabolism in skeletal muscle. PDH is activated by PDH phosphatase (PDP) and deactivated by PDH kinase (PDK). Obesity has a large negative impact on skeletal muscle carbohydrate metabolism, whereas endurance training has been shown to improve regulatory control of skeletal muscle carbohydrate metabolism, more so when coupled with obesity. A majority of this literature has focused on PDK, with little information available on PDP. To determine the relative role of PDP in regulating skeletal muscle PDH activity with obesity and endurance training, obese and lean Zucker rats remained sedentary or were endurance trained (1 h/day, 5 days/wk) for a period of 8 wk. Soleus, red gastrocnemius, (RG), and white gastrocnemius (WG) muscles were sampled after the training period. The main findings were 1) obesity resulted in a 46% decrease in PDP activity expressed per milligram extracted mitochondrial protein only in RG, while PDP isoform content was unchanged; 2) 8 wk of endurance training led to a significant 1.4–2.2-fold increase in PDP activity of all muscle examined from obese rats, and the concomitant increase in PDP1 protein was only seen in soleus and RG; 3) 8 wk of endurance training led to a trending 1.4–2.2-fold increase in PDP activity of all muscle examined from obese rats, and the concomitant increase in PDP1 protein was only seen in soleus and RG; and 4) PDP2 protein content was not affected by obesity or training. These results suggest that decreased PDP activity in oxidative skeletal muscles may play a role in the impairment of carbohydrate metabolism in obese rats, which is reversible with endurance training.

Superoxide dismutase gene expression in skeletal muscle: fiber-specific adaptation to endurance training

1999 ◽  
Vol 277 (3) ◽  
pp. R856-R862 ◽  
Author(s):  
J. Hollander ◽  
R. Fiebig ◽  
M. Gore ◽  
J. Bejma ◽  
T. Ookawara ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Superoxide Dismutase ◽  
Protein Content ◽  
Endurance Training ◽  
Citrate Synthase ◽  
Vastus Lateralis ◽  
Mrna Level ◽  
Treadmill Running ◽  
Type I ◽  
Sod Activity

The effects of endurance training on the enzyme activity, protein content, and mRNA abundance of Mn and CuZn superoxide dismutase (SOD) were studied in various phenotypes of rat skeletal muscle. Female Sprague-Dawley rats were randomly divided into trained (T, n = 8) and untrained (U, n = 8) groups. Training, consisting of treadmill running at 27 m/min and 12% grade for 2 h/day, 5 days/wk for 10 wk, significantly increased citrate synthase activity ( P < 0.01) in the type I (soleus), type IIa (deep vastus lateralis, DVL), and mixed type II (plantaris) muscles but not in type IIb (superficial vastus lateralis, SVL) muscle. Mitochondrial (Mn) SOD activity was elevated by 80% ( P < 0.05) with training in DVL. SVL and plantaris muscle in T rats showed 54 and 42% higher pooled immunoreactive Mn SOD protein content, respectively, than those in U rats. However, no change in Mn SOD mRNA level was found in any of the muscles. CuZn SOD activity, protein content, and mRNA level in general were not affected by training, except for a 160% increase in pooled CuZn SOD protein in SVL. Training also significantly increased glutathione peroxidase and catalase activities ( P < 0.05), but only in DVL muscle. These data indicate that training adaptations of Mn SOD and other antioxidant enzymes occur primarily in type IIa fibers, probably as a result of enhanced free radical generation and modest antioxidant capacity. Differential training responses of mRNA, enzyme protein, and activity suggest that separate cellular signals may control pre- and posttranslational regulation of SOD.

Human skeletal muscle pyruvate dehydrogenase kinase activity increases after a low-carbohydrate diet

1998 ◽  
Vol 275 (6) ◽  
pp. E980-E986 ◽  
Author(s):  
Sandra J. Peters ◽  
Timothy A. St. Amand ◽  
Richard A. Howlett ◽  
George J. F. Heigenhauser ◽  
Lawrence L. Spriet
Keyword(s):  
Skeletal Muscle ◽  
Pyruvate Dehydrogenase ◽  
Human Skeletal Muscle ◽  
Citrate Synthase ◽  
Vastus Lateralis ◽  
Active Form ◽  
Pyruvate Dehydrogenase Kinase ◽  
Acid Oxidation ◽  
Low Carbohydrate Diet ◽  
Low Carbohydrate

To characterize human skeletal muscle enzymatic adaptation to a low-carbohydrate, high-fat, and high-protein diet (LCD), subjects consumed a eucaloric diet consisting of 5% of the total energy intake from carbohydrate, 63% from fat, and 33% from protein for 6 days compared with their normal diet (52% carbohydrate, 33% fat, and 14% protein). Biopsies were taken from the vastus lateralis before and after 3 and 6 days on a LCD. Intact mitochondria were extracted from fresh muscle and analyzed for pyruvate dehydrogenase (PDH) kinase, total PDH, and carnitine palmitoyltransferase I activities and mitochondrial ATP production rate (using carbohydrate and fat substrates). β-Hydroxyacyl CoA dehydrogenase, active PDH (PDHa), and citrate synthase activities were also measured on whole muscle homogenates. PDH kinase (PDHK) was calculated as the absolute value of the apparent first-order rate constant of the inactivation of PDH in the presence of 0.3 mM Mg2+-ATP. PDHK increased dramatically from 0.10 ± 0.02 min−1 to 0.35 ± 0.09 min−1 at 3 days and 0.49 ± 0.06 min−1 after 6 days. Resting PDHa activity decreased from 0.63 ± 0.17 to 0.17 ± 0.04 mmol ⋅ min−1 ⋅ kg−1after 6 days on the diet, whereas total PDH activity did not change. Activities for all other enzymes were unaltered by the LCD. In summary, severe deficiency of dietary carbohydrate combined with a twofold increase in dietary fat and protein caused a rapid three- to fivefold increase in PDHK activity in human skeletal muscle. The increased PDHK activity downregulated the amount of PDH in its active form at rest and decreased carbohydrate metabolism. However, an increase in the activities of enzymes involved in fatty acid oxidation did not occur.

Bed rest reduces metabolic protein content and abolishes exercise-induced mRNA responses in human skeletal muscle

2011 ◽  
Vol 301 (4) ◽  
pp. E649-E658 ◽  
Author(s):  
Stine Ringholm ◽  
Rasmus S. Biensø ◽  
Kristian Kiilerich ◽  
Amelia Guadalupe-Grau ◽  
Niels Jacob Aachmann-Andersen ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Protein Content ◽  
Human Skeletal Muscle ◽  
Citrate Synthase ◽  
Bed Rest ◽  
Sirtuin 1 ◽  
Vastus Lateralis Muscle ◽  
Before And After ◽  
Exercise Induced ◽  
Muscle Biopsies

The aim was to test the hypothesis that 7 days of bed rest reduces mitochondrial number and expression and activity of oxidative proteins in human skeletal muscle but that exercise-induced intracellular signaling as well as mRNA and microRNA (miR) responses are maintained after bed rest. Twelve young, healthy male subjects completed 7 days of bed rest with vastus lateralis muscle biopsies taken before and after bed rest. In addition, muscle biopsies were obtained from six of the subjects prior to, immediately after, and 3 h after 45 min of one-legged knee extensor exercise performed before and after bed rest. Maximal oxygen uptake decreased by 4%, and exercise endurance decreased nonsignificantly, by 11%, by bed rest. Bed rest reduced skeletal muscle mitochondrial DNA/nuclear DNA content 15%, hexokinase II and sirtuin 1 protein content ∼45%, 3-hydroxyacyl-CoA dehydrogenase and citrate synthase activity ∼8%, and miR-1 and miR-133a content ∼10%. However, cytochrome c and vascular endothelial growth factor (VEGF) protein content as well as capillarization did not change significantly with bed rest. Acute exercise increased AMP-activated protein kinase phosphorylation, peroxisome proliferator activated receptor-γ coactivator-1α, and VEGF mRNA content in skeletal muscle before bed rest, but the responses were abolished after bed rest. The present findings indicate that only 7 days of physical inactivity reduces skeletal muscle metabolic capacity as well as abolishes exercise-induced adaptive gene responses, likely reflecting an interference with the ability of skeletal muscle to adapt to exercise.

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