bims-carmet 2021-12-26 papers

bims-carmet

Biomed News

on Cardiac metabolism

Issue of 2021–12–26
eleven papers selected by
Mikky Atsér, University of British Columbia

A roadmap for the characterization of energy metabolism in human cardiomyocytes derived from induced pluripotent stem cells.
Disruption of the TCA cycle reveals an ATF4-dependent integration of redox and amino acid metabolism.
Cardiac Metabolism and Contractile Function in Mice with Reduced Trans-Endothelial Fatty Acid Transport.
Changes in TCA cycle and TCA cycle-related metabolites in plasma upon citric acid administration in rats.
Mitochondrial dysfunction and mitochondrial therapies in heart failure.
Cardiac Metabolism in Sepsis.
Physiological and Pathophysiological Roles of Mitochondrial Na+-Ca2+ Exchanger, NCLX, in Hearts.
Reduced Fatty Acid Use from CD36 Deficiency Deteriorates Streptozotocin-Induced Diabetic Cardiomyopathy in Mice.
Acetyl-CoA production by specific metabolites promotes cardiac repair after myocardial infarction via histone acetylation.
Traditional Chinese medicine enhances myocardial metabolism during heart failure.
Ketone Body Metabolism in the Ischemic Heart.

J Mol Cell Cardiol. 2021 Dec 16. pii: S0022-2828(21)00228-5. [Epub ahead of print]164 136-147

A roadmap for the characterization of energy metabolism in human cardiomyocytes derived from induced pluripotent stem cells.

Giulia Emanuelli, Anna Zoccarato, Christina M Reumiller, Angelos Papadopoulos, Mei Chong, Sabine Rebs, Kai Betteridge, Matteo Beretta, Katrin Streckfuss-Bömeke, Ajay M Shah.

  Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) are an increasingly employed model in cardiac research and drug discovery. As cellular metabolism plays an integral role in determining phenotype, the characterization of the metabolic profile of hiPSC-CM during maturation is crucial for their translational application. In this study we employ a combination of methods including extracellular flux, 13C-glucose enrichment and targeted metabolomics to characterize the metabolic profile of hiPSC-CM during their maturation in culture from 6 weeks, up to 12 weeks. Results show a progressive remodeling of pathways involved in energy metabolism and substrate utilization along with an increase in sarcomere regularity. The oxidative capacity of hiPSC-CM and particularly their ability to utilize fatty acids increased with time. In parallel, relative glucose oxidation was reduced while glutamine oxidation was maintained at similar levels. There was also evidence of increased coupling of glycolysis to mitochondrial respiration, and away from glycolytic branch pathways at later stages of maturation. The rate of glycolysis as assessed by lactate production was maintained at both stages but with significant alterations in proximal glycolytic enzymes such as hexokinase and phosphofructokinase. We observed a progressive maturation of mitochondrial oxidative capacity at comparable levels of mitochondrial content between these time-points with enhancement of mitochondrial network structure. These results show that the metabolic profile of hiPSC-CM is progressively restructured, recapitulating aspects of early post-natal heart development. This would be particularly important to consider when employing these cell model in studies where metabolism plays an important role.

Keywords:  Cardiac cell models; Energy metabolism; Metabolic maturation; Metabolic shift; iPSC-derived cardiomyocytes

DOI:  https://doi.org/10.1016/j.yjmcc.2021.12.001
Elife. 2021 Dec 23. pii: e72593. [Epub ahead of print]10

Disruption of the TCA cycle reveals an ATF4-dependent integration of redox and amino acid metabolism.

Dylan Gerard Ryan, Ming Yang, Hiran A Prag, Giovanny Rodriguez Blanco, Efterpi Nikitopoulou, Marc Segarra-Mondejar, Christopher A Powell, Tim Young, Nils Burger, Jan Lj Miljkovic, Michal Minczuk, Michael P Murphy, Alex von Kriegsheim, Christian Frezza.

  The Tricarboxylic Acid Cycle (TCA) cycle is arguably the most critical metabolic cycle in physiology and exists as an essential interface coordinating cellular metabolism, bioenergetics, and redox homeostasis. Despite decades of research, a comprehensive investigation into the consequences of TCA cycle dysfunction remains elusive. Here, we targeted two TCA cycle enzymes, fumarate hydratase (FH) and succinate dehydrogenase (SDH), and combined metabolomics, transcriptomics, and proteomics analyses to fully appraise the consequences of TCA cycle inhibition (TCAi) in murine kidney epithelial cells. Our comparative approach shows that TCAi elicits a convergent rewiring of redox and amino acid metabolism dependent on the activation of ATF4 and the integrated stress response (ISR). Furthermore, we also uncover a divergent metabolic response, whereby acute FHi, but not SDHi, can maintain asparagine levels via reductive carboxylation and maintenance of cytosolic aspartate synthesis. Our work highlights an important interplay between the TCA cycle, redox biology and amino acid homeostasis.

Keywords:  biochemistry; cell biology; chemical biology; mouse

DOI:  https://doi.org/10.7554/eLife.72593
Metabolites. 2021 Dec 19. pii: 889. [Epub ahead of print]11(12):

Cardiac Metabolism and Contractile Function in Mice with Reduced Trans-Endothelial Fatty Acid Transport.

Tatsuya Iso, Masahiko Kurabayashi.

  The heart is a metabolic omnivore that combusts a considerable amount of energy substrates, mainly long-chain fatty acids (FAs) and others such as glucose, lactate, ketone bodies, and amino acids. There is emerging evidence that muscle-type continuous capillaries comprise the rate-limiting barrier that regulates FA uptake into cardiomyocytes. The transport of FAs across the capillary endothelium is composed of three major steps-the lipolysis of triglyceride on the luminal side of the endothelium, FA uptake by the plasma membrane, and intracellular FA transport by cytosolic proteins. In the heart, impaired trans-endothelial FA (TEFA) transport causes reduced FA uptake, with a compensatory increase in glucose use. In most cases, mice with reduced FA uptake exhibit preserved cardiac function under unstressed conditions. When the workload is increased, however, the total energy supply relative to its demand (estimated with pool size in the tricarboxylic acid (TCA) cycle) is significantly diminished, resulting in contractile dysfunction. The supplementation of alternative fuels, such as medium-chain FAs and ketone bodies, at least partially restores contractile dysfunction, indicating that energy insufficiency due to reduced FA supply is the predominant cause of cardiac dysfunction. Based on recent in vivo findings, this review provides the following information related to TEFA transport: (1) the mechanisms of FA uptake by the heart, including TEFA transport; (2) the molecular mechanisms underlying the induction of genes associated with TEFA transport; (3) in vivo cardiac metabolism and contractile function in mice with reduced TEFA transport under unstressed conditions; and (4) in vivo contractile dysfunction in mice with reduced TEFA transport under diseased conditions, including an increased afterload and streptozotocin-induced diabetes.

Keywords:  TCA cycle; capillary endothelium; cardiac metabolism; contractile function; fatty acid; glucose; pool size; trans-endothelial fatty acid transport

DOI:  https://doi.org/10.3390/metabo11120889
Heliyon. 2021 Dec;7(12): e08501

Changes in TCA cycle and TCA cycle-related metabolites in plasma upon citric acid administration in rats.

Yurie Hara, Satoshi Kume, Yosky Kataoka, Nakamichi Watanabe.

  Recent studies have reported that plasma levels of tricarboxylic acid (TCA) cycle metabolites and TCA cycle-related metabolite change in patients with chronic fatigue syndrome (CFS) and in healthy humans after exercise. Exogenous dietary citric acid has been reported to alleviate fatigue during daily activities and after exercise. However, it is unknown whether dietary citric acid affects the plasma levels of these metabolites. Therefore, the present study aimed to investigate the effects of exogenously administered citric acid on TCA cycle metabolites and TCA cycle-related metabolites in plasma. Sprague-Dawley rats were divided into control and citric acid groups. We evaluated the effect of exogenous dietary citric acid on the plasma TCA cycle and TCA cycle-related metabolites by metabolome analysis using liquid chromatography-tandem mass spectrometry (LC-MS/MS). TCA cycle metabolites, including plasma citrate, cis-aconitate, and isocitrate, were significantly elevated after exogenous administration of citric acid. Anaplerotic amino acids, which are converted to TCA cycle metabolites, such as serine, glycine, tryptophan, lysine, leucine, histidine, glutamine, arginine, isoleucine, methionine, valine, and phenylalanine, also showed significantly elevated levels. Citric acid administration significantly increased the levels of initial TCA cycle metabolites in the plasma. This increase after administration of citric acid was shown to be opposite to the metabolic changes observed in patients with CFS. These results contribute novel insight into the fatigue alleviation mechanism of citric acid.

Keywords:  Amino acid; Anaplerotic substrates; Citric acid; Fatigue; Metabolome analysis; Tricarboxylic acid cycle

DOI:  https://doi.org/10.1016/j.heliyon.2021.e08501
Pharmacol Res. 2021 Dec 17. pii: S1043-6618(21)00622-8. [Epub ahead of print]175 106038

Mitochondrial dysfunction and mitochondrial therapies in heart failure.

Chennan Wu, Zhen Zhang, Weidong Zhang, Xia Liu.

  Cardiovascular diseases remain the leading cause of death worldwide in the last decade, accompanied by immense health and economic burdens. Heart failure (HF), as the terminal stage of many cardiovascular diseases, is a common, intractable, and costly medical condition. Despite significant improvements in pharmacologic and device therapies over the years, life expectancy for this disease remains poor. Current therapies have not reversed the trends in morbidity and mortality as expected. Thus, there is an urgent need for novel potential therapeutic agents. Although the pathophysiology of the failing heart is extraordinarily complex, targeting mitochondrial dysfunction can be an effective approach for potential treatment. Increasing evidence has shown that mitochondrial abnormalities, including altered metabolic substrate utilization, impaired mitochondrial oxidative phosphorylation (OXPHOS), increased reactive oxygen species (ROS) formation, and aberrant mitochondrial dynamics, are closely related to HF. Here, we reviewed the findings on the role of mitochondrial dysfunction in HF, along with novel mitochondrial therapeutics and their pharmacological effects.

Keywords:  Energy metabolism; Heart failure; Mitochondrial dynamics; Mitochondrial dysfunction; Oxidative phosphorylation

DOI:  https://doi.org/10.1016/j.phrs.2021.106038
Metabolites. 2021 Dec 06. pii: 846. [Epub ahead of print]11(12):

Cardiac Metabolism in Sepsis.

Satoshi Kawaguchi, Motoi Okada.

  The mechanism of sepsis-induced cardiac dysfunction is believed to be different from that of myocardial ischemia. In sepsis, chemical mediators, such as endotoxins, cytokines, and nitric oxide, cause metabolic abnormalities, mitochondrial dysfunction, and downregulation of β-adrenergic receptors. These factors inhibit the production of ATP, essential for myocardial energy metabolism, resulting in cardiac dysfunction. This review focuses on the metabolic changes in sepsis, particularly in the heart. In addition to managing inflammation, interventions focusing on metabolism may be a new therapeutic strategy for cardiac dysfunction due to sepsis.

Keywords:  ATP; SICM; metabolic switch; sepsis; β-adrenergic receptor

DOI:  https://doi.org/10.3390/metabo11120846
Biomolecules. 2021 Dec 14. pii: 1876. [Epub ahead of print]11(12):

Physiological and Pathophysiological Roles of Mitochondrial Na+-Ca2+ Exchanger, NCLX, in Hearts.

Ayako Takeuchi, Satoshi Matsuoka.

  It has been over 10 years since SLC24A6/SLC8B1, coding the Na+/Ca2+/Li+ exchanger (NCLX), was identified as the gene responsible for mitochondrial Na+-Ca2+ exchange, a major Ca2+ efflux system in cardiac mitochondria. This molecular identification enabled us to determine structure-function relationships, as well as physiological/pathophysiological contributions, and our understandings have dramatically increased. In this review, we provide an overview of the recent achievements in relation to NCLX, focusing especially on its heart-specific characteristics, biophysical properties, and spatial distribution in cardiomyocytes, as well as in cardiac mitochondria. In addition, we discuss the roles of NCLX in cardiac functions under physiological and pathophysiological conditions-the generation of rhythmicity, the energy metabolism, the production of reactive oxygen species, and the opening of mitochondrial permeability transition pores.

Keywords:  Ca2+ signaling; NCLX; heart; metabolism; mitochondria; mitochondrial Na+-Ca2+ exchanger

DOI:  https://doi.org/10.3390/biom11121876
Metabolites. 2021 Dec 17. pii: 881. [Epub ahead of print]11(12):

Reduced Fatty Acid Use from CD36 Deficiency Deteriorates Streptozotocin-Induced Diabetic Cardiomyopathy in Mice.

Yogi Umbarawan, Ryo Kawakami, Mas Rizky A A Syamsunarno, Hideru Obinata, Aiko Yamaguchi, Hirofumi Hanaoka, Takako Hishiki, Noriyo Hayakawa, Norimichi Koitabashi, Hiroaki Sunaga, Hiroki Matsui, Masahiko Kurabayashi, Tatsuya Iso.

  Cardiac dysfunction is induced by multifactorial mechanisms in diabetes. Deranged fatty acid (FA) utilization, known as lipotoxicity, has long been postulated as one of the upstream events in the development of diabetic cardiomyopathy. CD36, a transmembrane glycoprotein, plays a major role in FA uptake in the heart. CD36 knockout (CD36KO) hearts exhibit reduced rates of FA transport with marked enhancement of glucose use. In this study, we explore whether reduced FA use by CD36 ablation suppresses the development of streptozotocin (STZ)-induced diabetic cardiomyopathy. We found that cardiac contractile dysfunction had deteriorated 16 weeks after STZ treatment in CD36KO mice. Although accelerated glucose uptake was not reduced in CD36KO-STZ hearts, the total energy supply, estimated by the pool size in the TCA cycle, was significantly reduced. The isotopomer analysis with 13C6-glucose revealed that accelerated glycolysis, estimated by enrichment of 13C2-citrate and 13C2-malate, was markedly suppressed in CD36KO-STZ hearts. Levels of ceramides, which are cardiotoxic lipids, were not elevated in CD36KO-STZ hearts compared to wild-type-STZ ones. Furthermore, increased energy demand by transverse aortic constriction resulted in synergistic exacerbation of contractile dysfunction in CD36KO-STZ mice. These findings suggest that CD36KO-STZ hearts are energetically compromised by reduced FA use and suppressed glycolysis; therefore, the limitation of FA utilization is detrimental to cardiac energetics in this model of diabetic cardiomyopathy.

Keywords:  CD36; ceramide; diabetic cardiomyopathy; fatty acid; glucose; metabolomics; streptozotocin

DOI:  https://doi.org/10.3390/metabo11120881
Elife. 2021 Dec 23. pii: e60311. [Epub ahead of print]10

Acetyl-CoA production by specific metabolites promotes cardiac repair after myocardial infarction via histone acetylation.

Ienglam Lei, Shuo Tian, Wenbin Gao, Liu Liu, Yijing Guo, Paul Tang, Eugene Chen, Zhong Wang.

  Myocardial infarction (MI) is accompanied by severe energy deprivation and extensive epigenetic changes. However, how energy metabolism and chromatin modifications are interlinked during MI and heart repair has been poorly explored. Here, we examined the effect of different carbon sources that are involved in the major metabolic pathways of acetyl-CoA synthesis on myocardial infarction and found that elevation of acetyl-CoA by sodium octanoate (8C) significantly improved heart function in ischemia reperfusion (I/R) rats. Mechanistically, 8C reduced I/R injury by promoting histone acetylation which in turn activated the expression of antioxidant genes and inhibited cardiomyocyte (CM) apoptosis. Furthermore, we elucidated that 8C-promoted histone acetylation and heart repair were carried out by metabolic enzyme medium-chain acyl-CoA dehydrogenase (MCAD) and histone acetyltransferase Kat2a, suggesting that 8C dramatically improves cardiac function mainly through metabolic acetyl-CoA-mediated histone acetylation. Therefore, our study uncovers an interlinked metabolic/epigenetic network comprising 8C, acetyl-CoA, MCAD, and Kat2a to combat heart injury.

Keywords:  cell biology; mouse

DOI:  https://doi.org/10.7554/eLife.60311
Biomed Pharmacother. 2021 Dec 15. pii: S0753-3322(21)01325-1. [Epub ahead of print]146 112538

Traditional Chinese medicine enhances myocardial metabolism during heart failure.

Wang Shao-Mei, Ye Li-Fang, Wang Li-Hong.

  The prognosis of various cardiovascular diseases eventually leads to heart failure (HF). An energy metabolism disorder of cardiomyocytes is important in explaining the molecular basis of HF; this will aid global research regarding treatment options for HF from the perspective of myocardial metabolism. There are many drugs to improve myocardial metabolism for the treatment of HF, including angiotensin receptor blocker-neprilysin inhibitor (ARNi) and sodium glucose cotransporter 2 (SGLT-2) inhibitors. Although Western medicine has made considerable progress in HF therapy, the morbidity and mortality of the disease remain high. Therefore, HF has attracted attention from researchers worldwide. In recent years, the application of traditional Chinese medicine (TCM) in HF treatment has been gradually accepted, and many studies have investigated the mechanism whereby TCM improves myocardial metabolism; the TCMs studied include Danshen yin, Fufang Danshen dripping pill, and Shenmai injection. This enables the clinical application of TCM in the treatment of HF by improving myocardial metabolism. We systematically reviewed the efficacy of TCM for improving myocardial metabolism during HF as well as the pharmacological effects of active TCM ingredients on the cardiovascular system and the potential mechanisms underlying their ability to improve myocardial metabolism. The results indicate that TCM may serve as a complementary and alternative approach for the prevention of HF. However, further rigorously designed randomized controlled trials are warranted to assess the effect of TCM on long-term hard endpoints in patients with cardiovascular disease.

Keywords:  Energy metabolism; Heart failure; Traditional Chinese medicine

DOI:  https://doi.org/10.1016/j.biopha.2021.112538
Front Cardiovasc Med. 2021 ;8 789458

Ketone Body Metabolism in the Ischemic Heart.

Stephen C Kolwicz.

  Ketone bodies have been identified as an important, alternative fuel source in heart failure. In addition, the use of ketone bodies as a fuel source has been suggested to be a potential ergogenic aid for endurance exercise performance. These findings have certainly renewed interest in the use of ketogenic diets and exogenous supplementation in an effort to improve overall health and disease. However, given the prevalence of ischemic heart disease and myocardial infarctions, these strategies may not be ideal for individuals with coronary artery disease. Although research studies have clearly defined changes in fatty acid and glucose metabolism during ischemia and reperfusion, the role of ketone body metabolism in the ischemic and reperfused myocardium is less clear. This review will provide an overview of ketone body metabolism, including the induction of ketosis via physiological or nutritional strategies. In addition, the contribution of ketone body metabolism in healthy and diseased states, with a particular emphasis on ischemia-reperfusion (I-R) injury will be discussed.

Keywords:  beta-hydroxybutyrate; hypoxia; ischemia; ketosis; reperfusion

DOI:  https://doi.org/10.3389/fcvm.2021.789458