Malonyl-CoA and carnitine in regulation of fat oxidation in human skeletal muscle during exercise

2005 ◽  
Vol 288 (1) ◽  
pp. E133-E142 ◽  
Author(s):  
Carsten Roepstorff ◽  
Nils Halberg ◽  
Thore Hillig ◽  
Asish K. Saha ◽  
Neil B. Ruderman ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Glycogen ◽  
Human Skeletal Muscle ◽  
Fat Oxidation ◽  
Free Carnitine ◽  
Carbohydrate Diet ◽  
Acetyl Coa ◽  
Low Carbohydrate Diet ◽  
Malonyl Coa ◽  
Amp Activated Protein Kinase

Intracellular mechanisms regulating fat oxidation were investigated in human skeletal muscle during exercise. Eight young, healthy, moderately trained men performed bicycle exercise (60 min, 65% peak O2 consumption) on two occasions, where they ingested either 1) a high-carbohydrate diet (H-CHO) or 2) a low-carbohydrate diet (L-CHO) before exercise to alter muscle glycogen content as well as to induce, respectively, low and high rates of fat oxidation. Leg fat oxidation was 122% higher during exercise in L-CHO than in H-CHO ( P < 0.001). In keeping with this, the activity of α2-AMP-activated protein kinase (α2-AMPK) was increased twice as much in L-CHO as in H-CHO ( P < 0.01) at 60 min of exercise. However, acetyl-CoA carboxylase (ACC)β Ser221 phosphorylation was increased to the same extent (6-fold) under the two conditions. The concentration of malonyl-CoA was reduced 13% by exercise in both conditions ( P < 0.05). Pyruvate dehydrogenase activity was higher during exercise in H-CHO than in L-CHO ( P < 0.01). In H-CHO only, the concentrations of acetyl-CoA and acetylcarnitine were increased ( P < 0.001), and the concentration of free carnitine was decreased ( P < 0.01), by exercise. The data suggest that a decrease in the concentration of malonyl-CoA, secondary to α2-AMPK activation and ACC inhibition (by phosphorylation), contributes to the increase in fat oxidation observed at the onset of exercise regardless of muscle glycogen levels. They also suggest that, with high muscle glycogen, the availability of free carnitine may limit fat oxidation during exercise, due to its increased use for acetylcarnitine formation.

Effect of phosphorylation by AMP-activated protein kinase on palmitoyl-CoA inhibition of skeletal muscle acetyl-CoA carboxylase

2005 ◽  
Vol 98 (4) ◽  
pp. 1221-1227 ◽  
Author(s):  
D. S. Rubink ◽  
W. W. Winder
Keyword(s):  
Skeletal Muscle ◽  
Fatty Acid ◽  
Protein Kinase ◽  
Fatty Acid Oxidation ◽  
Acid Oxidation ◽  
Acetyl Coa Carboxylase ◽  
Acetyl Coa ◽  
Oxidation Rates ◽  
Malonyl Coa ◽  
Amp Activated Protein Kinase

AMP-activated protein kinase (AMPK) has previously been demonstrated to phosphorylate and inactivate skeletal muscle acetyl-CoA carboxylase (ACC), the enzyme responsible for synthesis of malonyl-CoA, an inhibitor of carnitine palmitoyltransferase 1 and fatty acid oxidation. Contraction-induced activation of AMPK with subsequent phosphorylation/inactivation of ACC has been postulated to be responsible in part for the increase in fatty acid oxidation that occurs in muscle during exercise. These studies were designed to answer the question: Does phosphorylation of ACC by AMPK make palmitoyl-CoA a more effective inhibitor of ACC? Purified rat muscle ACC was subjected to phosphorylation by AMPK. Activity was determined on nonphosphorylated and phosphorylated ACC preparations at acetyl-CoA concentrations ranging from 2 to 500 μM and at palmitoyl-CoA concentrations ranging from 0 to 100 μM. Phosphorylation resulted in a significant decline in the substrate saturation curve at all palmitoyl-CoA concentrations. The inhibitor constant for palmitoyl-CoA inhibition of ACC was reduced from 1.7 ± 0.25 to 0.85 ± 0.13 μM as a consequence of phosphorylation. At 0.5 mM citrate, ACC activity was reduced to 13% of control values in response to the combination of phosphorylation and 10 μM palmitoyl-CoA. Skeletal muscle ACC is more potently inhibited by palmitoyl-CoA after having been phosphorylated by AMPK. This may contribute to low-muscle malonyl-CoA values and increasing fatty acid oxidation rates during long-term exercise when plasma fatty acid concentrations are elevated.

Influence of malonyl-CoA and palmitate concentration on rate of palmitate oxidation in rat muscle

1998 ◽  
Vol 85 (5) ◽  
pp. 1909-1914 ◽  
Author(s):  
G. F. Merrill ◽  
E. J. Kurth ◽  
B. B. Rasmussen ◽  
W. W. Winder
Keyword(s):  
Skeletal Muscle ◽  
Fatty Acid ◽  
Protein Kinase ◽  
Fatty Acid Oxidation ◽  
Acid Oxidation ◽  
Acetyl Coa Carboxylase ◽  
Acetyl Coa ◽  
Palmitate Oxidation ◽  
Malonyl Coa ◽  
Amp Activated Protein Kinase

5-Aminoimidazole-4-carboxamide 1-β-d-ribofuranoside (AICAR) is taken up by perfused skeletal muscle and phosphorylated to form 5-aminoimidazole-4-carboxamide-1-β-d-ribofuraosyl-5′-monophosphate (analog of 5′-AMP) with consequent activation of AMP-activated protein kinase, phosphorylation of acetyl-CoA carboxylase, decrease in malonyl-CoA, and increase in fatty acid oxidation. This study was designed to determine the effect of increasing levels of palmitate on the rate of fatty acid oxidation. Malonyl-CoA concentration was manipulated with AICAR at different palmitate concentrations. Rat hindlimbs were perfused with Krebs-Henseleit bicarbonate containing 4% bovine serum albumin, washed bovine red cells, 200 μU/ml insulin, 10 mM glucose, and different concentrations of palmitate (0.1–1.0 mM) without or with AICAR (2.0 mM). Perfusion with medium containing AICAR was found to activate AMP-activated protein kinase in skeletal muscle, inactivate acetyl-CoA carboxylase, and decrease malonyl-CoA at all concentrations of palmitate. The rate of palmitate oxidation increased as a function of palmitate concentration in both the presence and absence of AICAR but was always higher in the presence of AICAR. These results provide additional evidence that malonyl-CoA is an important regulator of the rate of fatty acid oxidation at palmitate concentrations in the physiological range.

Sensitivity of CPT I to malonyl-CoA in trained and untrained human skeletal muscle

2000 ◽  
Vol 278 (3) ◽  
pp. E462-E468 ◽  
Author(s):  
Emma C. Starritt ◽  
Richard A. Howlett ◽  
George J. F. Heigenhauser ◽  
Lawrence L. Spriet
Keyword(s):  
Skeletal Muscle ◽  
Human Skeletal Muscle ◽  
Aerobic Training ◽  
Fat Metabolism ◽  
Acetyl Coa ◽  
Malonyl Coa ◽  
Metabolic Conditions ◽  
Carnitine Palmitoyltransferase I ◽  
Cpt I ◽  
Rest And Exercise

The present study examined the sensitivity of carnitine palmitoyltransferase I (CPT I) activity to its inhibitor malonyl-CoA (M-CoA), and simulated metabolic conditions of rest and exercise, in aerobically trained and untrained humans. Maximal CPT I activity was measured in mitochondria isolated from resting human skeletal muscle. Mean CPT I activity was 492.8 ± 72.8 and 260.8 ± 33.6 μmol ⋅ min−1 ⋅ kg wet muscle−1 in trained and untrained subjects, respectively (pH 7.0, 37°C). The sensitivity to M-CoA was greater in trained muscle; the IC50 for M-CoA was 0.17 ± 0.04 and 0.49 ± 0.17 μM in trained and untrained muscle, respectively. The presence of acetyl-CoA, free coenzyme A (CoASH), and acetylcarnitine, in concentrations simulating rest and exercise conditions did not release the M-CoA-induced inhibition of CPT I activity. However, CPT I activity was reduced at pH 6.8 vs. pH 7.0 in both trained and untrained muscle in the presence of physiological concentrations of M-CoA. The results of this study indicate that aerobic training is associated with an increase in the sensitivity of CPT I to M-CoA. Accumulations of acetyl-CoA, CoASH, and acetylcarnitine do not counteract the M-CoA-induced inhibition of CPT I activity. However, small decreases in pH produce large reductions in the activity of CPT I and may contribute to the decrease in fat metabolism that occurs during moderate and intense aerobic exercise intensities.

scholarly journals Effects of Oral Resveratrol Supplementation on Glycogen Replenishment and Mitochondria Biogenesis in Exercised Human Skeletal Muscle

Nutrients ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3721
Author(s):  
Chun-Ching Huang ◽  
Chia-Chen Liu ◽  
Jung-Piao Tsao ◽  
Chin-Lin Hsu ◽  
I-Shiung Cheng
Keyword(s):  
Skeletal Muscle ◽  
Glucose Uptake ◽  
Muscle Glycogen ◽  
Human Skeletal Muscle ◽  
Young Male ◽  
Gene Expressions ◽  
Plasma Parameters ◽  
Post Exercise ◽  
Glycogen Resynthesis ◽  
Mitochondria Biogenesis

The present study aimed to investigate the effect of oral resveratrol supplementation on the key molecular gene expressions involved in mitochondria biogenesis and glycogen resynthesis in human skeletal muscle. Nine young male athletes participated in the single-blind and crossover designed study. All subjects completed a 4-day resveratrol and placebo supplement in a randomized order while performing a single bout of cycling exercise. Immediately after the exercise challenge, the subjects consumed a carbohydrate (CHO) meal (2 g CHO/Kg body mass) with either resveratrol or placebo capsules. Biopsied muscle samples, blood samples and expired gas samples were obtained at 0 h and 3 h after exercise. The muscle samples were measured for gene transcription factor expression by real-time PCR for glucose uptake and mitochondria biogenesis. Plasma glucose, insulin, glycerol, non-esterified fatty acid concentrations and respiratory exchange ratio were analyzed during post-exercise recovery periods. The results showed that the muscle glycogen concentrations were higher at 3 h than at 0 h; however, there were no difference between resveratrol trial and placebo trial. There were no significantly different concentrations in plasma parameters between the two trials. Similarly, no measured gene expressions were significant between the two trials. The evidence concluded that the 4-day oral resveratrol supplementation did not improve post-exercise muscle glycogen resynthesis and related glucose uptake and mitochondrial biosynthesis gene expression in men.

scholarly journals Endurance training reduces the contraction-induced interleukin-6 mRNA expression in human skeletal muscle

2004 ◽  
Vol 287 (6) ◽  
pp. E1189-E1194 ◽  
Author(s):  
Christian P. Fischer ◽  
Peter Plomgaard ◽  
Anne K. Hansen ◽  
Henriette Pilegaard ◽  
Bengt Saltin ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Mrna Expression ◽  
Muscle Glycogen ◽  
Human Skeletal Muscle ◽  
Acute Exercise ◽  
Glycogen Content ◽  
Knee Extensor ◽  
Exercise Induced ◽  
Response To Exercise ◽  
Resting Muscle

Contracting skeletal muscle expresses large amounts of IL-6. Because 1) IL-6 mRNA expression in contracting skeletal muscle is enhanced by low muscle glycogen content, and 2) IL-6 increases lipolysis and oxidation of fatty acids, we hypothesized that regular exercise training, associated with increased levels of resting muscle glycogen and enhanced capacity to oxidize fatty acids, would lead to a less-pronounced increase of skeletal muscle IL-6 mRNA in response to acute exercise. Thus, before and after 10 wk of knee extensor endurance training, skeletal muscle IL-6 mRNA expression was determined in young healthy men ( n = 7) in response to 3 h of dynamic knee extensor exercise, using the same relative workload. Maximal power output, time to exhaustion during submaximal exercise, resting muscle glycogen content, and citrate synthase and 3-hydroxyacyl-CoA dehydrogenase enzyme activity were all significantly enhanced by training. IL-6 mRNA expression in resting skeletal muscle did not change in response to training. However, although absolute workload during acute exercise was 44% higher ( P < 0.05) after the training period, skeletal muscle IL-6 mRNA content increased 76-fold ( P < 0.05) in response to exercise before the training period, but only 8-fold ( P < 0.05, relative to rest and pretraining) in response to exercise after training. Furthermore, the exercise-induced increase of plasma IL-6 ( P < 0.05, pre- and posttraining) was not higher after training despite higher absolute work intensity. In conclusion, the magnitude of the exercise-induced IL-6 mRNA expression in contracting human skeletal muscle was markedly reduced by 10 wk of training.

Oral glucose ingestion attenuates exercise-induced activation of 5′-AMP-activated protein kinase in human skeletal muscle

2006 ◽  
Vol 342 (3) ◽  
pp. 949-955 ◽  
Author(s):  
Thorbjorn C.A. Akerstrom ◽  
Jesper B. Birk ◽  
Ditte K. Klein ◽  
Christian Erikstrup ◽  
Peter Plomgaard ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Protein Kinase ◽  
Human Skeletal Muscle ◽  
Oral Glucose ◽  
Glucose Ingestion ◽  
Exercise Induced ◽  
Amp Activated Protein Kinase

Skeletal muscle basal AMP-activated protein kinase activity is chronically elevated in alloxan-diabetic dogs: impact of exercise

2003 ◽  
Vol 95 (4) ◽  
pp. 1523-1530 ◽  
Author(s):  
Michael J. Christopher ◽  
Zhi-Ping Chen ◽  
Christian Rantzau ◽  
Bruce E. Kemp ◽  
Frank P. Alford
Keyword(s):  
Skeletal Muscle ◽  
Protein Kinase ◽  
Vastus Lateralis ◽  
Glucose Disposal ◽  
Protein Kinase Activity ◽  
Acetyl Coa Carboxylase ◽  
Acetyl Coa ◽  
Peripheral Tissues ◽  
Diabetic Dogs ◽  
Amp Activated Protein Kinase

The effect of diabetes and exercise on skeletal muscle (SkM) AMP-activated protein kinase (AMPK)α1 and -α2 activities and site-specific phosphorylation of acetyl-CoA carboxylase was examined in the same six dogs before alloxan (35 mg/kg)-induced diabetes (C) and after 4-5 wk of suboptimally controlled hyperglycemic and hypoinsulinemic diabetes (DHG) in the presence and absence of 300-min phlorizin (50 μg·kg-1·min-1)-induced “normoglycemia” (DNG). In each study, the dog underwent a 150-min [3-3H]glucose infusion period, followed by a 30-min treadmill exercise test (60-70% maximal oxygen capacity) to measure the rate of glucose disposal into peripheral tissues (Rdtissue). SkM biopsies were taken from the thigh (vastus lateralis) before and immediately after exercise. In the C and DHG states, the rise in plasma free fatty acids (FFA) with exercise (∼40%) was similar. In the DNG group, preexercise FFA were significantly higher, but the absolute rise in FFA with exercise was similar. However, the exercise-induced increment in Rdtissue was significantly blunted (by ∼40-50%) in the DNG group compared with the other states. In SkM, preexercise AMPKα1 and -α2 activities were significantly elevated (by ∼60-125%) in both diabetic states, but unlike the C group these activities did not rise further with exercise. Additionally, preexercise acetyl-CoA carboxylase phosphorylation in both diabetic states was elevated by ∼70-80%, but the increases with exercise were similar to the C group. Preexercise AMPKα1 and -α2 activities were negatively correlated with Rdtissue during exercise for the combined groups (both P < 0.02). In conclusion, the elevated preexercise SkM AMPKα1 and -α2 activities contribute to the ongoing basal supply of glucose and fatty acid metabolism in suboptimally controlled hypoinsulinemic diabetic dogs; but whether they also play a permissive role in the metabolic stress response to exercise remains uncertain.

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