Exploring the Effects of Chronic Remote Ischemic Preconditioning Versus High-Intensity Exercise on Improving Peak Exercise Capacity and Cardiac Energy Metabolism: a Randomized, Crossover Clinical Trial

Dramatic maturational changes in cardiac energy metabolism occur in the newborn period, with a shift from glycolysis to fatty acid oxidation. Acetylation and succinylation of lysyl residues are novel posttranslational modifications involved in the control of cardiac energy metabolism. We investigated the impact of changes in protein acetylation/succinylation on the maturational changes in energy metabolism of 1-, 7-, and 21-day-old rabbit hearts. Cardiac fatty acid β-oxidation rates increased in 21-day vs. 1- and 7-day-old hearts, whereas glycolysis and glucose oxidation rates decreased in 21-day-old hearts. The fatty acid oxidation enzymes, long-chain acyl-CoA dehydrogenase (LCAD) and β-hydroxyacyl-CoA dehydrogenase (β-HAD), were hyperacetylated with maturation, positively correlated with their activities and fatty acid β-oxidation rates. This alteration was associated with increased expression of the mitochondrial acetyltransferase, general control of amino acid synthesis 5 like 1 (GCN5L1), since silencing GCN5L1 mRNA in H9c2 cells significantly reduced acetylation and activity of LCAD and β-HAD. An increase in mitochondrial ATP production rates with maturation was associated with the decreased acetylation of peroxisome proliferator-activated receptor-γ coactivator-1α, a transcriptional regulator for mitochondrial biogenesis. In addition, hypoxia-inducible factor-1α, hexokinase, and phosphoglycerate mutase expression declined postbirth, whereas acetylation of these glycolytic enzymes increased. Phosphorylation rather than acetylation of pyruvate dehydrogenase (PDH) increased in 21-day-old hearts, accounting for the low glucose oxidation postbirth. A maturational increase was also observed in succinylation of PDH and LCAD. Collectively, our data are the first suggesting that acetylation and succinylation of the key metabolic enzymes in newborn hearts play a crucial role in cardiac energy metabolism with maturation. Listen to this article’s corresponding podcast at http://ajpheart.podbean.com/e/acetylation-control-of-energy-metabolism-in-newborn-hearts/ .

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Six weeks of a polarized training-intensity distribution leads to greater physiological and performance adaptations than a threshold model in trained cyclists

Journal of Applied Physiology ◽

10.1152/japplphysiol.00652.2012 ◽

2013 ◽

Vol 114 (4) ◽

pp. 461-471 ◽

Cited By ~ 45

Author(s):

Craig M. Neal ◽

Angus M. Hunter ◽

Lorraine Brennan ◽

Aifric O'Sullivan ◽

D. Lee Hamilton ◽

...

Keyword(s):

Exercise Capacity ◽

Intensity Distribution ◽

High Intensity ◽

Threshold Model ◽

Endurance Performance ◽

High Intensity Exercise ◽

Metabolic Adaptation ◽

Mitochondrial Enzyme ◽

Training Intensity ◽

Metabolomics Analysis

This study was undertaken to investigate physiological adaptation with two endurance-training periods differing in intensity distribution. In a randomized crossover fashion, separated by 4 wk of detraining, 12 male cyclists completed two 6-wk training periods: 1) a polarized model [6.4 (±1.4 SD) h/wk; 80%, 0%, and 20% of training time in low-, moderate-, and high-intensity zones, respectively]; and 2) a threshold model [7.5 (±2.0 SD) h/wk; 57%, 43%, and 0% training-intensity distribution]. Before and after each training period, following 2 days of diet and exercise control, fasted skeletal muscle biopsies were obtained for mitochondrial enzyme activity and monocarboxylate transporter (MCT) 1 and 4 expression, and morning first-void urine samples were collected for NMR spectroscopy-based metabolomics analysis. Endurance performance (40-km time trial), incremental exercise, peak power output (PPO), and high-intensity exercise capacity (95% maximal work rate to exhaustion) were also assessed. Endurance performance, PPOs, lactate threshold (LT), MCT4, and high-intensity exercise capacity all increased over both training periods. Improvements were greater following polarized rather than threshold for PPO [mean (±SE) change of 8 (±2)% vs. 3 (±1)%, P < 0.05], LT [9 (±3)% vs. 2 (±4)%, P < 0.05], and high-intensity exercise capacity [85 (±14)% vs. 37 (±14)%, P < 0.05]. No changes in mitochondrial enzyme activities or MCT1 were observed following training. A significant multilevel, partial least squares-discriminant analysis model was obtained for the threshold model but not the polarized model in the metabolomics analysis. A polarized training distribution results in greater systemic adaptation over 6 wk in already well-trained cyclists. Markers of muscle metabolic adaptation are largely unchanged, but metabolomics markers suggest different cellular metabolic stress that requires further investigation.

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Cardiac Energy Metabolism in Heart Failure Associated with Obesity and Diabetes

Cardiac Energy Metabolism in Health and Disease ◽

10.1007/978-1-4939-1227-8_5 ◽

2014 ◽

pp. 69-88

Author(s):

Gary D. Lopaschuk

Keyword(s):

Heart Failure ◽

Energy Metabolism ◽

Obesity And Diabetes ◽

Cardiac Energy Metabolism ◽

Cardiac Energy

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Abstract 15649: Pharmacological Inhibition of Aldose Reductase by AT001 Prevents Abnormal Cardiac Energy Metabolism and Improves Heart Function in an Animal Model of Diabetic Cardiomyopathy

Circulation ◽

10.1161/circ.142.suppl_3.15649 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Keshav Gopal ◽

Qutuba Karwi ◽

Seyed Amirhossein Tabatabaei Dakhili ◽

Riccardo Perfetti ◽

Ravichandran Ramasamy ◽

...

Keyword(s):

Fatty Acid ◽

Energy Metabolism ◽

Fatty Acid Oxidation ◽

Diabetic Cardiomyopathy ◽

Acid Oxidation ◽

Cardiac Energetics ◽

Cardiac Efficiency ◽

Oxidation Rates ◽

Cardiac Energy Metabolism ◽

Cardiac Energy

Introduction: Diabetic Cardiomyopathy (DCM) is a major cause of death in people with type 2 diabetes (T2D). Alterations in cardiac energy metabolism including increased fatty acid oxidation rates and reduced glucose oxidation rates are key contributing factors to the development of DCM. Studies have shown that Aldose Reductase (AR), an enzyme activated under hyperglycemic conditions, can modulate myocardial glucose and fatty acid oxidation, and promotes cardiac dysfunction. Hypothesis: Pharmacological inhibition of AR using a next-generation inhibitor AT-001, can mitigate DCM in mice by modulating cardiac energy metabolism and improving cardiac efficiency. Methods: Male human AR overexpressing (hAR-Tg) and C57BL/6J (Control) mice were subjected to experimental T2D (high-fat diet [60% kcal from lard] for 10-wk with a single intraperitoneal streptozotocin injection of 75 mg/kg) and treated for the last 3-wk with AT-001 (40mg/kg/day) or vehicle via oral gavage. Cardiac energy metabolism and in vivo cardiac function were assessed via isolated working heart perfusions and ultrasound echocardiography, respectively. Results: AT-001 treatment significantly improved cardiac energetics in a murine model of DCM (hAR-Tg mice with T2D). Particularly, AT-001-treated mice exhibited decreased cardiac fatty acid oxidation rates compared to the vehicle-treated mice (342 ± 53 vs 964 ± 130 nmol/min/g dry wt.). Concurrently, there was a significant decrease in cardiac oxygen consumption in the AT-001-treated compared to the vehicle-treated mice (41 ± 12 vs 60 ± 11 μmol/min/g dry wt.), suggesting increased cardiac efficiency. Furthermore, treatment with AT-001 prevented cardiac structural and functional abnormalities present in DCM, including diastolic dysfunction as reflected by an increase in the tissue Doppler E’/A’ ratio and decrease in E/E’ ratio. Moreover, AT-001 treatment prevented cardiac hypertrophy as reflected by a decrease in LV mass in AT-001-treated mice. Conclusions: AR inhibition with AT-001 prevents cardiac structural and functional abnormalities in a mouse model of DCM, and normalizes cardiac energetics by shifting cardiac metabolism towards a non-diabetic metabolic state.

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