bims-hafaim 2023-02-19 papers

Issue of 2023–02–19
three papers selected by
Kyle McCommis, Saint Louis University

Curr Heart Fail Rep. 2023 Feb 17.

Sher May Ng, Stefan Neubauer, Oliver J Rider.

PURPOSE OF REVIEW: Myocardial metabolism is intricately linked to cardiac function. Perturbations of cardiac energy metabolism result in an energy-starved heart and the development of contractile dysfunction. In this review, we discuss alterations in myocardial energy supply, transcriptional changes in response to different energy demands, and mitochondrial function in the development of heart failure.
RECENT FINDINGS: Recent studies on substrate modulation through modifying energy substrate supply have shown cardioprotective properties. In addition, large cardiovascular outcome trials of anti-diabetic agents have demonstrated prognostic benefit, suggesting the importance of myocardial metabolism in cardiac function. Understanding molecular and transcriptional controls of cardiac metabolism promises new research avenues for metabolic treatment targets. Future studies assessing the impact of substrate modulation on cardiac energetic status and function will better inform development of metabolic therapies.

Keywords: Heart failure; Metabolic inflexibility; Myocardial metabolism; Substrate utilisation

DOI: https://doi.org/10.1007/s11897-023-00589-y

Nat Cardiovasc Res. 2022 Sep;1(9): 817-829

Integrated landscape of cardiac metabolism in end-stage human nonischemic dilated cardiomyopathy.

Emily Flam, Cholsoon Jang, Danielle Murashige, Yifan Yang, Michael P Morley, Sunhee Jung, Daniel S Kantner, Hannah Pepper, Kenneth C Bedi, Jeff Brandimarto, Benjamin L Prosser, Thomas Cappola, Nathaniel W Snyder, Joshua D Rabinowitz, Kenneth B Margulies, Zolt Arany.

Heart failure (HF) is a leading cause of mortality. Failing hearts undergo profound metabolic changes, but a comprehensive evaluation in humans is lacking. We integrate plasma and cardiac tissue metabolomics of 678 metabolites, genome-wide RNA-sequencing, and proteomic studies to examine metabolic status in 87 explanted human hearts from 39 patients with end-stage HF compared with 48 nonfailing donors. We confirm bioenergetic defects in human HF and reveal selective depletion of adenylate purines required for maintaining ATP levels. We observe substantial reductions in fatty acids and acylcarnitines in failing tissue, despite plasma elevations, suggesting defective import of fatty acids into cardiomyocytes. Glucose levels, in contrast, are elevated. Pyruvate dehydrogenase, which gates carbohydrate oxidation, is de-repressed, allowing increased lactate and pyruvate burning. Tricarboxylic acid cycle intermediates are significantly reduced. Finally, bioactive lipids are profoundly reprogrammed, with marked reductions in ceramides and elevations in lysoglycerophospholipids. These data unveil profound metabolic abnormalities in human failing hearts.

DOI: https://doi.org/10.1038/s44161-022-00117-6

J Physiol. 2023 Feb 17.

On the interdependence of ketone body oxidation,glycogen content, glycolysis and energy metabolism in the heart.

Azrul Abdul Kadir, Brianna J Stubbs, Cher-Rin Chong, Henry Lee, Mark Cole, Carolyn Carr, David Hauton, James McCullagh, Rhys D Evans, Kieran Clarke.

In heart, glucose and glycolysis are important for anaplerosis and potentially therefore for d-beta-hydroxybutyrate (βHB) oxidation. As a glucose store, glycogen may also furnish anaplerosis. We determined the effects of glycogen content on βHB oxidation and glycolytic rates, and their downstream effects on energetics, in the isolated rat heart. High glycogen (HG) and low glycogen (LG) containing hearts were perfused with 11 mM [5-3 H]-glucose and/or 4mM [14 C]-βHB to measure glycolytic rates or βHB oxidation, respectively, then freeze-clamped for glycogen and metabolomic analyses. Free cytosolic [NAD+ ]/[NADH] and mitochondrial [Q+ ]/[QH2 ] ratios were estimated using the lactate dehydrogenase and succinate dehydrogenase reactions, respectively. Phosphocreatine (PCr) and inorganic phosphate (Pi) concentrations were measured using 31 P-NMR spectroscopy. Rates of βHB oxidation in LG hearts were half that in HG hearts, with βHB oxidation directly proportional to glycogen content. βHB oxidation decreased glycolysis in all hearts. Glycogenolysis in glycogen-replete hearts perfused with βHB alone was twice that of hearts perfused with βHB and glucose, which had significantly higher levels of the glycolytic intermediates, fructose 1,6-bisphosphate and 3-phosphoglycerate, and higher free cytosolic [NAD+ ]/[NADH]. βHB oxidation increased the Krebs cycle intermediates citrate, 2-oxoglutarate and succinate, the total nicotinamide adenine dinucleotide phosphate (NADP/H) pool, reduced mitochondrial [Q+ ]/[QH2 ], and increased the calculated free energy of ATP hydrolysis (∆GATP ). Although βHB oxidation inhibited glycolysis, glycolytic intermediates were not depleted, and cytosolic free NAD remained oxidised. βHB oxidation alone increased Krebs cycle intermediates, reduced mitochondrial Q and increased ∆GATP . We conclude that glycogen facilitates cardiac βHB oxidation by anaplerosis. KEY POINTS: Ketone bodies (D-β-hydroxybutyrate; acetoacetate) are increasingly recognised as important cardiac energetic substrates, in both healthy and diseased hearts. As 2-carbon equivalents they are cataplerotic, causing depletion of Kreb's cycle intermediates; therefore their utilisation requires anaplerotic supplementation. Intra-myocardial glycogen has been suggested as a potential anaplerotic source during ketone oxidation. We demonstrate here that cardiac glycogen does indeed provide anaplerotic substrate to facilitate β-hydroxybutyrate oxidation in isolated perfused rat heart, and utilising a novel pulse-chase metabolic approach, quantify this contribution. Further, using metabolomics and 31 P-MR, we show that glycolytic flux from myocardial glycogen increased the heart's ability to oxidise βHB, and βHB oxidation increased the mitochondrial redox potential, ultimately increasing the free energy of ATP hydrolysis. Abstract figure legend Overview of relationship of glycogen to ketone body oxidation and cardiac energetics in isolated perfused rat hearts. Myocardial glycogen was pre-labelled with tritium and its metabolic fate tracked using a pulse-chase technique. Increased glycolytic flux from glycogen facilitated increased exogenous β-hydroxybutyrate (βHB) oxidation through anaplerosis, and the increased βHB oxidation increased mitochondrial redox potential, and hence increased free energy of ATP hydrolysis. This article is protected by copyright. All rights reserved.

Keywords: d-β-hydroxybutyrate oxidation; glycogen; glycolysis; metabolomics; redox states

DOI: https://doi.org/10.1113/JP284270