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<front>
<journal-meta>
<journal-id journal-id-type="publisher-id">Front. Cardiovasc. Med.</journal-id>
<journal-title>Frontiers in Cardiovascular Medicine</journal-title>
<abbrev-journal-title abbrev-type="pubmed">Front. Cardiovasc. Med.</abbrev-journal-title>
<issn pub-type="epub">2297-055X</issn>
<publisher>
<publisher-name>Frontiers Media S.A.</publisher-name>
</publisher>
</journal-meta>
<article-meta>
<article-id pub-id-type="doi">10.3389/fcvm.2021.702920</article-id>
<article-categories>
<subj-group subj-group-type="heading">
<subject>Cardiovascular Medicine</subject>
<subj-group>
<subject>Review</subject>
</subj-group>
</subj-group>
</article-categories>
<title-group>
<article-title>The Role of Metabolism in Heart Failure and Regeneration</article-title>
</title-group>
<contrib-group>
<contrib contrib-type="author">
<name><surname>Bae</surname> <given-names>Jiyoung</given-names></name>
<uri xlink:href="http://loop.frontiersin.org/people/1323895/overview"/>
</contrib>
<contrib contrib-type="author">
<name><surname>Paltzer</surname> <given-names>Wyatt G.</given-names></name>
<uri xlink:href="http://loop.frontiersin.org/people/1331508/overview"/>
</contrib>
<contrib contrib-type="author" corresp="yes">
<name><surname>Mahmoud</surname> <given-names>Ahmed I.</given-names></name>
<xref ref-type="corresp" rid="c001"><sup>&#x0002A;</sup></xref>
<uri xlink:href="http://loop.frontiersin.org/people/1162241/overview"/>
</contrib>
</contrib-group>
<aff><institution>Department of Cell and Regenerative Biology, University of Wisconsin-Madison School of Medicine and Public Health</institution>, <addr-line>Madison, WI</addr-line>, <country>United States</country></aff>
<author-notes>
<fn fn-type="edited-by"><p>Edited by: Monika Gladka, Academic Medical Center, Netherlands</p></fn>
<fn fn-type="edited-by"><p>Reviewed by: Yuka Morikawa, Texas Heart Institute, United States; Paula Alexandra Da Costa Martins, Maastricht University, Netherlands; Olaf Bergmann, Karolinska Institutet (KI), Sweden; Hashim Ali, King&#x00027;s College London, United Kingdom</p></fn>
<corresp id="c001">&#x0002A;Correspondence: Ahmed I. Mahmoud <email>aimahmoud&#x00040;wisc.edu</email></corresp>
<fn fn-type="other" id="fn001"><p>This article was submitted to Cardiovascular Biologics and Regenerative Medicine, a section of the journal Frontiers in Cardiovascular Medicine</p></fn></author-notes>
<pub-date pub-type="epub">
<day>16</day>
<month>07</month>
<year>2021</year>
</pub-date>
<pub-date pub-type="collection">
<year>2021</year>
</pub-date>
<volume>8</volume>
<elocation-id>702920</elocation-id>
<history>
<date date-type="received">
<day>30</day>
<month>04</month>
<year>2021</year>
</date>
<date date-type="accepted">
<day>23</day>
<month>06</month>
<year>2021</year>
</date>
</history>
<permissions>
<copyright-statement>Copyright &#x000A9; 2021 Bae, Paltzer and Mahmoud.</copyright-statement>
<copyright-year>2021</copyright-year>
<copyright-holder>Bae, Paltzer and Mahmoud</copyright-holder>
<license xlink:href="http://creativecommons.org/licenses/by/4.0/"><p>This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.</p></license> </permissions>
<abstract><p>Heart failure is the leading cause of death worldwide. The inability of the adult mammalian heart to regenerate following injury results in the development of systolic heart failure. Thus, identifying novel approaches toward regenerating the adult heart has enormous therapeutic potential for adult heart failure. Mitochondrial metabolism is an essential homeostatic process for maintaining growth and survival. The emerging role of mitochondrial metabolism in controlling cell fate and function is beginning to be appreciated. Recent evidence suggests that metabolism controls biological processes including cell proliferation and differentiation, which has profound implications during development and regeneration. The regenerative potential of the mammalian heart is lost by the first week of postnatal development when cardiomyocytes exit the cell cycle and become terminally differentiated. This inability to regenerate following injury is correlated with the metabolic shift from glycolysis to fatty acid oxidation that occurs during heart maturation in the postnatal heart. Thus, understanding the mechanisms that regulate cardiac metabolism is key to unlocking metabolic interventions during development, disease, and regeneration. In this review, we will focus on the emerging role of metabolism in cardiac development and regeneration and discuss the potential of targeting metabolism for treatment of heart failure.</p></abstract>
<kwd-group>
<kwd>heart regeneration</kwd>
<kwd>development</kwd>
<kwd>metabolism</kwd>
<kwd>heart failure</kwd>
<kwd>cell cycle</kwd>
</kwd-group>
<counts>
<fig-count count="2"/>
<table-count count="1"/>
<equation-count count="0"/>
<ref-count count="110"/>
<page-count count="11"/>
<word-count count="8585"/>
</counts>
</article-meta>
</front>
<body>
<sec sec-type="intro" id="s1">
<title>Introduction</title>
<p>Heart failure is the leading cause of morbidity and mortality worldwide. In the United States alone, there are over 6,000,000 people with heart failure (<xref ref-type="bibr" rid="B1">1</xref>). This is largely due to the inability of the adult mammalian heart to replenish the lost myocardial tissue following injury, which results in the progressive weakening of the heart muscle and the development of heart failure (<xref ref-type="bibr" rid="B2">2</xref>). Current therapies are focused on preventing further remodeling of the remaining myocardial tissue. Heart transplantations are the only treatment in patients with severe heart failure (<xref ref-type="bibr" rid="B3">3</xref>). Due to the complexity and complications associated with heart transplants they are not always a suitable treatment; therefore, identifying novel therapeutic approaches to promote adult heart regeneration provides immense opportunities to advance heart failure therapy. Endogenous heart regeneration following injury has been demonstrated in some non-mammalian vertebrates (<xref ref-type="bibr" rid="B4">4</xref>, <xref ref-type="bibr" rid="B5">5</xref>). Interestingly, neonatal mice are also capable of regenerating their heart tissue following injury, however this regenerative ability is lost within a few days following birth (<xref ref-type="bibr" rid="B6">6</xref>, <xref ref-type="bibr" rid="B7">7</xref>). These models of endogenous regeneration provide us with a platform to elucidate the mechanisms that guide heart regeneration to reactivate these processes to promote adult heart regeneration.</p>
<p>Embryonic and neonatal cardiomyocytes produce energy primarily <italic>via</italic> glycolysis, where postnatal maturation is accompanied with a metabolic switch to fatty acid oxidation to meet the energy demands of adult cardiomyocytes (<xref ref-type="bibr" rid="B8">8</xref>) (<xref ref-type="fig" rid="F1">Figure 1</xref>). This metabolic switch contributes to the postnatal cardiomyocyte cell cycle exit and loss of the regenerative potential of the mammalian heart. This underscores the potential role of cardiac metabolism as a target to promote adult heart regeneration.</p>
<fig id="F1" position="float">
<label>Figure 1</label>
<caption><p>Schematic representation of the energy utilization in neonatal and adult mouse hearts. The neonatal mouse heart generates energy through glucose metabolism, while the adult mouse heart generates energy through fatty acid oxidation.</p></caption>
<graphic xlink:href="fcvm-08-702920-g0001.tif"/>
</fig>
<p>In this review, we highlight major studies of cardiac metabolism including fatty acid oxidation, glucose, and amino acid metabolism (<xref ref-type="fig" rid="F2">Figure 2</xref>). We also discuss key metabolic targets that may play an important role during cardiomyocyte development and regeneration and their potential as a therapeutic target for adult heart disease.</p>
<fig id="F2" position="float">
<label>Figure 2</label>
<caption><p>Schematic of the major metabolic pathways that modulate the cardiac regenerative response following injury. Glucose metabolism (blue), fatty acid metabolism (purple), and BCAA metabolism (red). Acetyl CoA from these major metabolic pathways is required for the TCA cycle. GLUT, glucose transporter type; HK, hexokinase; G-6-P, glucose-6-phosphate; F-1,6-BP, fructose-1,6-biphosphate; PFK, phosphofructokinase; PDK, pyruvate dehydrogenase kinase; PDH, pyruvate dehydrogenase; CD36, cluster of differentiation; CPT1, carnitine palmitoyltransferase; MCD, malonyl CoA dehydrogenase; ACC, acetyl CoA carboxylase; BCAAs, branched-chain amino acids; AA, amino acid; BCAT, branched-chain amino-transferase; BCKA, branched-chain alpha keto acids; BCKDH, branched-chain alpha-keto acid dehydrogenase; PP2Cm, protein phosphatase 2Cm; mTOR, the mechanistic target of rapamycin; AMPK, 5&#x02032; adenosine monophosphate-activated protein kinase; TCA, tricarboxylic acid cycle; SDH, succinate dehydrogenase. Yellow star induces regeneration and red lightning bolt inhibits regeneration.</p></caption>
<graphic xlink:href="fcvm-08-702920-g0002.tif"/>
</fig>
</sec>
<sec id="s2">
<title>Energy Metabolism and Heart Regeneration</title>
<p>The heart is the most energy-consuming tissue (per gram) in the human body (<xref ref-type="bibr" rid="B9">9</xref>), and energy production takes place in the mitochondria. The main function of the mitochondria is generating energy as adenosine triphosphate (ATP); thus, mitochondria play an essential role during development, cellular proliferation, and tissue regeneration, all of which are energy demanding processes (<xref ref-type="bibr" rid="B10">10</xref>&#x02013;<xref ref-type="bibr" rid="B12">12</xref>).</p>
<p>Heart regenerative capacity differs by model organisms from vertebrates to human. Zebrafish and newts have a remarkable capability to regenerate their hearts after injury. Zebrafish heart regeneration is primarily derived from the proliferation of the pre-existing cardiomyocytes (<xref ref-type="bibr" rid="B13">13</xref>, <xref ref-type="bibr" rid="B14">14</xref>). Following injury, cardiomyocyte dedifferentiation and proliferation are required to regenerate the heart following injury. Interestingly, single-cell transcriptional analysis of regenerating zebrafish hearts demonstrate that proliferating border zone cardiomyocytes undergo metabolic reprogramming to glycolysis from oxidative phosphorylation following cryoinjury (<xref ref-type="bibr" rid="B15">15</xref>). In contrast, glycolysis inhibitors including 2-deoxyglucose and lonidamine impair cardiomyocyte proliferation and heart regeneration (<xref ref-type="bibr" rid="B15">15</xref>). These results suggest that the glycolytic metabolic state mediates cardiomyocyte proliferation and regeneration following injury in zebrafish.</p>
<p>Like zebrafish, embryonic and neonatal mice can regenerate their heart after injury. Both zebrafish and neonatal mouse hearts have lower mitochondrial DNA copy numbers compared to postnatal and adult mice (<xref ref-type="bibr" rid="B16">16</xref>). This increase in cardiomyocyte mitochondrial number in the adult heart is due to the switch from glycolytic metabolism in neonatal cardiomyocytes to oxygen-dependent mitochondrial oxidative phosphorylation in adult cardiomyocytes (<xref ref-type="bibr" rid="B17">17</xref>). This metabolic switch and increase mitochondrial DNA results in a significant rise in reactive oxygen species (ROS) production from mitochondria which plays an essential role in regulating heart development and regeneration (<xref ref-type="bibr" rid="B16">16</xref>). This increase in ROS production contributes to postnatal cardiomyocyte cell cycle arrest. Interestingly, the increased sarcomere contraction in the postnatal heart promotes mitochondrial metabolism, which results in ROS production and DNA damage response activation <italic>via</italic> p53. As a result, inhibition of sarcomeres in cardiac troponin T knockout cardiomyocytes prevents cell cycle arrest and polyploidy resulting in increased cardiomyocyte proliferation (<xref ref-type="bibr" rid="B18">18</xref>). Furthermore, ROS scavengers such as N-acetyl cysteine (NAC) prolongs the postnatal window of cardiomyocyte proliferation and regeneration following ischemia reperfusion (I/R) injury (<xref ref-type="bibr" rid="B16">16</xref>).</p>
<p>Significant metabolic shifts occur in response to abnormal heart conditions. A healthy adult heart generates energy through fatty acid oxidation, however conditions such as pressure overload, hypertrophy, and ischemia results in a metabolic transition toward anaerobic glycolytic metabolism to be protect against damage (<xref ref-type="bibr" rid="B19">19</xref>). A recent study elegantly demonstrates the different metabolite utilization in human hearts by using arterio-venous metabolomics, which is a powerful tool to measure metabolite utilization in humans by measuring the metabolite intake and release in the blood from human hearts. Similar to mouse studies, healthy human hearts mostly uptake fatty acids as a fuel source while they only uptake limited amounts of glucose. Interestingly, the healthy heart releases amino acids, specifically essential amino acids. In contrast, the failing heart utilizes more ketones and lactate, but less fatty acids (<xref ref-type="bibr" rid="B20">20</xref>). These results are consistent with previous animal studies demonstrating that ketones and &#x003B2;-hydroxybutyrate are protective in the failing heart (<xref ref-type="bibr" rid="B21">21</xref>, <xref ref-type="bibr" rid="B22">22</xref>). Collectively, these studies demonstrate that cardiac metabolism is dynamic and can switch to different states during development, disease, and regeneration.</p>
</sec>
<sec id="s3">
<title>Fatty Acid Oxidation in the Heart</title>
<p>The heart requires high amounts of energy to maintain adult cardiac physiology (<xref ref-type="bibr" rid="B9">9</xref>). The adult human heart generates ATP <italic>via</italic> fatty acid oxidation (<xref ref-type="bibr" rid="B23">23</xref>&#x02013;<xref ref-type="bibr" rid="B25">25</xref>). Fatty acids are oxidized through the tricarboxylic acid (TCA) cycle in the mitochondria, and the intermediate electrons from the TCA cycle flow through the electron transport chain (ETC) and produce a proton gradient to generate energy through ATP synthesis (<xref ref-type="bibr" rid="B26">26</xref>).</p>
<p>The first step for transporting long chain fatty acids from the cytosol into the mitochondria for initiating mitochondrial fatty acid oxidation occurs by carnitine palmitoyltransferase I (CPT1) in the outer mitochondrial membrane. CoA in acyl-CoA, which is derived from fatty acids, is converted to carnitine through CPT1. Thus, CPT1 is a key enzyme in regulating fatty acid oxidation. There are three tissue-specific isoforms of CPT1 that exist in mammalian tissues: CPT1A is expressed in the liver, lung, spleen, pancreas, and kidney; CPT1B is expressed in the heart, skeletal muscle, and adipose tissue; and CPT1C is expressed in the brain (<xref ref-type="bibr" rid="B27">27</xref>). Mitochondrial CPT1 activity is very low in the neonatal rat heart. Interestingly, CPT1 level is significantly increased in 7-day-old juvenile mice, which is the timepoint when the majority of mammalian cardiomyocytes have already exited the cell cycle (<xref ref-type="bibr" rid="B28">28</xref>). CPT1 expression is increased in adolescent (6 months) sheep hearts compared to fetus (105 days) hearts (<xref ref-type="bibr" rid="B29">29</xref>). Thus, CPT1 could be a key regulator of cardiomyocyte proliferation.</p>
<p>CPT1 inhibition reduces fatty acid oxidation due to the blockade of fatty acid transfer into the mitochondria. Inhibition of CPT1 by etomoxir promotes neonatal mouse cardiomyocyte proliferation (<xref ref-type="bibr" rid="B30">30</xref>). However, inhibition or activation of CPT1 does not induce cardiomyocyte proliferation in the adult mouse heart (<xref ref-type="bibr" rid="B31">31</xref>). Ventricular cardiomyocytes isolated from neonatal mice injected with the CPT1 inhibitor etomoxir show a reduction in fatty acid oxidation genes (<xref ref-type="bibr" rid="B30">30</xref>). These results demonstrate that disruption of fatty acid oxidation by inhibition of CPT1 extends neonatal cardiomyocyte proliferation and heart regeneration but is not sufficient to promote adult heart regeneration.</p>
<p>Another metabolite that regulates fatty acid oxidation <italic>via</italic> CPT1 inhibition is malonyl-CoA (<xref ref-type="bibr" rid="B32">32</xref>). Inhibition of malonyl-CoA decarboxylase (MCD), which is responsible for malonyl-CoA decarboxylation, results in increased malonyl-CoA levels which reduces fatty acid oxidation and increases glucose oxidation (<xref ref-type="bibr" rid="B33">33</xref>). As a consequence, short-term pharmacological inhibition of MCD increases malonyl-CoA levels in ischemic conditions resulting in improving cardiac function during ischemia/reperfusion (I/R) injury in the swine heart (<xref ref-type="bibr" rid="B34">34</xref>) and following myocardial infarction (MI) in the rat heart (<xref ref-type="bibr" rid="B35">35</xref>). Genetically MCD deficient mouse hearts show increased glucose oxidation and improved cardiac function following I/R injury (<xref ref-type="bibr" rid="B36">36</xref>). These results demonstrate that malonyl-CoA improves cardiac function following injury through CPT1 inhibition.</p>
<p>CPT1 is also regulated by peroxisome proliferator-activated receptors (PPARs), which are lipid receptors that play a critical role in regulating energy metabolism. There are three subtypes of PPAR: PPAR&#x003B1;, PPAR&#x003B2;/&#x003B4;, and PPAR&#x003B3; (<xref ref-type="bibr" rid="B37">37</xref>). PPAR&#x003B1;, &#x003B2;/&#x003B4;, &#x003B3; gene expression levels are lower in the developing mouse heart compared to 14- and 28-day-old mouse hearts (<xref ref-type="bibr" rid="B38">38</xref>, <xref ref-type="bibr" rid="B39">39</xref>). The levels of PPARs change during aging, as cardiac PPAR&#x003B1; is significantly reduced in aged mice (<xref ref-type="bibr" rid="B40">40</xref>). PPARs play multiple roles in cardiac function in several disease states. It has been shown that expression of PPAR&#x003B1; and CPT1 is notably reduced in adult mouse hearts following transverse aortic constriction (TAC) injury (<xref ref-type="bibr" rid="B41">41</xref>) as well as following I/R injury (<xref ref-type="bibr" rid="B42">42</xref>). However, activation of PPAR&#x003B1; using the PPAR&#x003B1; agonist GW7647 increased CPT1 gene expression which increased fatty acid oxidation and enhanced oxygen consumption rate in the presence of the fatty acid palmitate in isolated mouse cardiomyocytes (<xref ref-type="bibr" rid="B30">30</xref>).</p>
<p>However, the role of PPAR in cardiomyocyte proliferation and regeneration remains unclear. The PPAR&#x003B1; agonist GW7647 does not promote cardiomyocyte proliferation and cardiac function following MI in adult mouse hearts (<xref ref-type="bibr" rid="B31">31</xref>). Furthermore, PPAR&#x003B1; activation by agonist WY-14643 reduced cardiac function following I/R injury (<xref ref-type="bibr" rid="B42">42</xref>). Moreover, larger infarct size is observed in PPAR&#x003B1; knockout mouse heart following I/R injury (<xref ref-type="bibr" rid="B43">43</xref>). In contrast, another study showed that PPAR&#x003B1; transgenic mouse hearts showed improved cardiac function and reduced left ventricular dilation following TAC injury (<xref ref-type="bibr" rid="B41">41</xref>).</p>
<p>Another PPAR family receptor, PPAR&#x003B4;, has been shown to play a role during cardiac injury. The PPAR&#x003B4; ligand, GW501516, has been shown to inhibit cardiac fibroblast proliferation and transdifferentiation to myofibroblasts (<xref ref-type="bibr" rid="B44">44</xref>). Furthermore, inhibition of PPAR&#x003B4; reduced cardiomyocyte proliferation following injury in zebrafish hearts, whereas cardiomyocyte-specific PPAR&#x003B4; overexpression induced proliferation and reduced scar size following MI in mouse hearts (<xref ref-type="bibr" rid="B45">45</xref>).</p>
<p>Despite the important role of PPAR receptors in a variety of heart disease models, the exact role of these receptors in regulating cardiomyocyte proliferation and heart regeneration remains to be fully defined.</p>
</sec>
<sec id="s4">
<title>Glucose Metabolism in Heart</title>
<p>Although the adult mammalian heart utilizes fatty acids as a main source of energy in the heart, glucose plays an important role as an energy source (<xref ref-type="bibr" rid="B46">46</xref>&#x02013;<xref ref-type="bibr" rid="B49">49</xref>). Under healthy conditions the heart mostly uses fatty acids to produce energy, however, it will switch to glucose as an energy source during heart failure (<xref ref-type="bibr" rid="B50">50</xref>&#x02013;<xref ref-type="bibr" rid="B52">52</xref>). Glucose metabolism is initiated by glucose uptake. In the heart, glucose enters cardiomyocytes <italic>via</italic> glucose transporters (GLUTs) which are expressed by various cell types. Among 14 members of the GLUT family (<xref ref-type="bibr" rid="B53">53</xref>), the most abundant GLUTs in the human heart are the insulin-sensitive glucose transporter GLUT4 (<xref ref-type="bibr" rid="B54">54</xref>, <xref ref-type="bibr" rid="B55">55</xref>), and the insulin-independent glucose transporter GLUT1 (<xref ref-type="bibr" rid="B54">54</xref>, <xref ref-type="bibr" rid="B56">56</xref>).</p>
<p>Under physiological conditions, GLUT1 is the main glucose transporter in embryonic and neonatal hearts, while GLUT4 is the primary glucose transporter in adult hearts (<xref ref-type="bibr" rid="B57">57</xref>, <xref ref-type="bibr" rid="B58">58</xref>). In heart failure, GLUT4 expression is reduced while the levels of GLUT1 increase (<xref ref-type="bibr" rid="B59">59</xref>). This results in an increase in GLUT1-mediated glycolysis in heart failure, suggesting that GLUT1 plays an important role in cardiac protection during heart failure. GLUT1 expression is also increased in the heart under hypoxic conditions (<xref ref-type="bibr" rid="B60">60</xref>), which is mediated <italic>via</italic> hypoxia-inducible factor-1&#x003B1; (HIF-1&#x003B1;) (<xref ref-type="bibr" rid="B61">61</xref>). Cardiac-specific overexpression of GLUT1 results in increased glucose uptake and glycolysis in the mouse heart (<xref ref-type="bibr" rid="B62">62</xref>, <xref ref-type="bibr" rid="B63">63</xref>), whereas cardiac-specific GLUT1 deletion reduces glucose uptake and glycolysis in isolated mouse cardiomyocytes following TAC injury (<xref ref-type="bibr" rid="B59">59</xref>). Interestingly, GLUT1 overexpression enhanced the regenerative response of neonatal mice following cryoinjury by increasing the levels of glucose metabolites (<xref ref-type="bibr" rid="B64">64</xref>). These results provide new evidence that increased GLUT1 expression promotes cardiomyocyte proliferation and heart regeneration through increased glucose metabolism.</p>
<p>Once glucose enters cardiomyocytes through GLUTs, glucose is phosphorylated and metabolized by key glycolytic enzymes such as hexokinase (HK) and phosphofructokinase (PFK) to form two pyruvate molecules (<xref ref-type="bibr" rid="B65">65</xref>). Pyruvate is then oxidized to acetyl CoA by pyruvate dehydrogenase (PDH), a key regulator in pyruvate metabolism (<xref ref-type="bibr" rid="B66">66</xref>), to enter the TCA cycle in the mitochondria. These glycolytic enzymes have been demonstrated to play a role in cardiac repair and regeneration following injury. In adult zebrafish, increased glycolysis has been shown to promote cardiomyocyte proliferation through increased cell cycle gene expression following injury (<xref ref-type="bibr" rid="B67">67</xref>). In addition, inhibition of glycolysis by 2-deoxyglucose reduced cardiomyocyte proliferation in the injured zebrafish heart (<xref ref-type="bibr" rid="B15">15</xref>). Thus, key components of glycolysis play an important role during cardiomyocyte proliferation and heart regeneration.</p>
<p>Hexokinase (HK) is the first enzyme of glycolysis that phosphorylates glucose to glucose-6-phosphate. Among the four distinct HK isozymes (HK 1, 2, 3, and 4) (<xref ref-type="bibr" rid="B68">68</xref>), HK-1 and -2 are expressed in the heart and regulate cardiac glucose metabolism (<xref ref-type="bibr" rid="B69">69</xref>, <xref ref-type="bibr" rid="B70">70</xref>). Cardiac-specific HK-2 overexpression decreased cardiac hypertrophy in isoproterenol-induced mouse hearts and reduced cardiomyocyte size in neonatal rat ventricular cardiomyocytes (<xref ref-type="bibr" rid="B71">71</xref>). In addition, HK-2 overexpression reduced ROS accumulation which is upregulated during cardiac hypertrophy (<xref ref-type="bibr" rid="B71">71</xref>). In contrast, reduced HK-2 expression in HK-2<sup>&#x0002B;/&#x02212;</sup> mice results in increased cardiac dysfunction due to increase in cell death and fibrosis and reduction of angiogenesis following I//R injury (<xref ref-type="bibr" rid="B72">72</xref>). Whether HK plays a role during heart regeneration remains to be determined.</p>
<p>Another important enzyme that regulates glycolysis is phosphofructokinase (PFK) which has two isoforms: PFK-1 and PFK-2. PFK-2 regulates PFK-1 activity since PFK-2 regulates the synthesis of fructose-2,6-biphosphate, which activates PFK1 that promotes glycolysis. Thus, PFK-2 is a crucial enzyme that regulates glycolysis (<xref ref-type="bibr" rid="B65">65</xref>). PFK-2 is activated upon insulin stimulation which promotes glycolysis, where PFK-2 is reduced in the insulin-deficient streptozotocin-induced diabetic mice and high-fat diet-induced obese mice (<xref ref-type="bibr" rid="B73">73</xref>). Glycolysis and insulin sensitivity are decreased in cardiac-specific kinase-deficient PFK-2 mutant mouse hearts (<xref ref-type="bibr" rid="B74">74</xref>, <xref ref-type="bibr" rid="B75">75</xref>). As a result, glycolysis is not increased in cardiac-specific kinase-deficient PFK-2 mice in contrast to wild type mice following TAC surgery (<xref ref-type="bibr" rid="B75">75</xref>). On the other hand, overexpression of kinase-active PFK-2 enhances contractility in hypoxic mouse cardiomyocytes (<xref ref-type="bibr" rid="B76">76</xref>). Thus, PFK-2 regulates glycolysis and may play a role in cardiac protection following injury.</p>
<p>A key glycolysis enzyme is pyruvate dehydrogenase kinase (PDK). There are four PDK isoforms (PDK 1, 2, 3, and 4). PDKs expression is significantly increased during heart development and is further increased in the adult heart (<xref ref-type="bibr" rid="B58">58</xref>). PDKs expression is also increased in the infarct zone following cardiac cryoinjury in zebrafish (<xref ref-type="bibr" rid="B67">67</xref>). Among the PDK isoforms, cardiac PDK4 is the most significantly upregulated enzyme in 7-day-old mice, where the majority of mammalian cardiomyocytes exit the cell cycle (<xref ref-type="bibr" rid="B58">58</xref>). PDKs play in a role in glycolysis <italic>via</italic> inhibition of pyruvate dehydrogenase (PDH), which is a limiting step in glucose oxidation. PDK inhibition by dichloroacetate induces PDH activation which promotes cardiac function following KCl-induced cardiac arrest (<xref ref-type="bibr" rid="B77">77</xref>). A recent study demonstrated that cardiac-specific deletion of PDK4 promotes adult cardiomyocyte proliferation and heart regeneration following adult MI (<xref ref-type="bibr" rid="B78">78</xref>). In summary, PDK plays an important role in glycolysis <italic>via</italic> inhibition of PDH activity, suggesting that PDKs may be an important therapeutic target to increase glycolysis and promote cardiac repair and regeneration.</p>
<p>Pyruvate kinase muscle isoenzyme 2 (PKM2), a rate-limiting enzyme in the final step of glycolysis, is expressed in embryonic and neonatal mouse hearts; however, it is significantly reduced beyond postnatal day 7 when cardiomyocytes exit the cell cycle (<xref ref-type="bibr" rid="B79">79</xref>). Interestingly, overexpression of PKM2 in cardiomyocytes promotes cell cycle and glucose-6-phosphate dehydrogenase expression (<xref ref-type="bibr" rid="B79">79</xref>). Cardiomyocyte-specific PKM2 expression by modified RNA (modRNA) promotes adult cardiomyocyte proliferation and cardiac regeneration following adult MI (<xref ref-type="bibr" rid="B79">79</xref>). Conversely, loss of PKM2 reduces cardiomyocyte proliferation following injury in zebrafish hearts (<xref ref-type="bibr" rid="B67">67</xref>). Moreover, cardiomyocyte-specific deletion of PKM2 impairs heart development as they exhibit smaller heart size and low levels of cardiomyocyte proliferation (<xref ref-type="bibr" rid="B79">79</xref>).</p>
<p>Taken together, these studies demonstrate that glycolysis plays an important role in regulating cardiomyocyte proliferation and heart regeneration following injury. Thus, targeting glucose metabolism is a promising approach to promote adult heart regeneration.</p>
</sec>
<sec id="s5">
<title>Amino Acid Metabolism in the Heart</title>
<p>Amino acids are key molecules for cell growth and survival. Amino acids are used as the building blocks for protein synthesis as well as inhibiting proteolysis (<xref ref-type="bibr" rid="B80">80</xref>). In addition, amino acids serve as precursors to key metabolites (<xref ref-type="bibr" rid="B81">81</xref>). Remarkably, amino acids can act as a signaling molecule, such as leucine, which stimulates muscle protein synthesis <italic>via</italic> the mechanistic target of rapamycin (mTOR) signaling pathway (<xref ref-type="bibr" rid="B82">82</xref>&#x02013;<xref ref-type="bibr" rid="B84">84</xref>). The levels of cellular amino acids fluctuate throughout development, increasing in postnatal stages until reaching peak levels around P9 and then decreasing into adult stages suggesting a dynamic role for amino acids during development and maturation (<xref ref-type="bibr" rid="B85">85</xref>).</p>
<p>A recent study demonstrated that circulating arterial amino acid levels are reduced in patients with heart failure in comparison to healthy patients (<xref ref-type="bibr" rid="B86">86</xref>). Decreasing levels of arterial amino acids correlated with reduced heart function, demonstrating the potential use for arterial amino acid levels as a biomarker of heart failure (<xref ref-type="bibr" rid="B86">86</xref>). To understand if this reduction of circulating arterial amino acids was the heart reducing its energy consumption of amino acids a recent study aimed to quantify fuel consumption of the failing and non-failing human heart (<xref ref-type="bibr" rid="B20">20</xref>). This study demonstrated that energy consumption of amino acids was unchanged between the non-failing and failing hearts (<xref ref-type="bibr" rid="B20">20</xref>), suggesting that the role amino acids play in heart failure is not tied to their function as an energy source.</p>
<p>To further understand the role of amino acid metabolism in heart failure, a main focus was placed on a subset of amino acids, the branched chain amino acids (BCAAs), which are utilized differently than the other amino acids. BCAAs consist of leucine, isoleucine, and valine (<xref ref-type="bibr" rid="B87">87</xref>). BCAAs account for nearly 5% of total carbon used within the heart, and they also act as regulatory components for other metabolic processes (<xref ref-type="bibr" rid="B20">20</xref>, <xref ref-type="bibr" rid="B88">88</xref>). BCAA catabolism has been shown to play a role in heart failure. This is seen in both humans and rodents where all components in BCAA catabolism have altered expression levels in heart failure (<xref ref-type="bibr" rid="B87">87</xref>). A study using a mouse model deficient in protein phosphatase 2Cm (PP2Cm), which is a critical component in the conversion of branch chain ketone acids to acyl-CoA derivatives <italic>via</italic> the branched-chain alpha-keto acid dehydrogenase complex (BCKDH), demonstrated that the knockout mice have a higher susceptibility to heart failure in response to pressure overload stress (<xref ref-type="bibr" rid="B87">87</xref>). This was due to the higher levels of BCAAs in the PP2Cm deficient mice, which reduced glucose breakdown <italic>via</italic> direct inhibition of pyruvate dehydrogenase (<xref ref-type="bibr" rid="B89">89</xref>).</p>
<p>The mechanistic target of rapamycin (mTOR) signaling pathway has been demonstrated to play an important role during heart development and growth (<xref ref-type="bibr" rid="B90">90</xref>, <xref ref-type="bibr" rid="B91">91</xref>). Interestingly, BCAAs stimulate mTOR activation which promotes metabolic reprogramming to glycolysis from fatty acid oxidation through HIF-1&#x003B1; (<xref ref-type="bibr" rid="B92">92</xref>). In contrast, inhibition of mTOR promotes human iPSC-derived cardiomyocyte maturation and impairs zebrafish heart regeneration following injury (<xref ref-type="bibr" rid="B93">93</xref>, <xref ref-type="bibr" rid="B94">94</xref>). mTOR is also inhibited by 5&#x02032; adenosine monophosphate-activated protein kinase (AMPK) through tuberous sclerosis complex 2 (TSC2) (<xref ref-type="bibr" rid="B95">95</xref>). Pharmacological activation of AMPK by metformin inhibits mTOR pathway activation following TAC injury (<xref ref-type="bibr" rid="B96">96</xref>). In addition, AMPK activation by AICAR promotes human iPSC-derived cardiomyocyte maturation (<xref ref-type="bibr" rid="B97">97</xref>). Thus, downstream pathways of BCAAs including mTOR and AMPK can regulate cardiomyocyte proliferation and regeneration.</p>
<p>Conversely, stimulating BCAA catabolism can be protective against heart injury and failure. BCAA catabolism can be activated by inhibition of the branched chain ketoacid dehydrogenase kinase (BCKDK), which results in BCKDH activation (<xref ref-type="bibr" rid="B87">87</xref>). BCKDK inhibition increased BCAA catabolism, which increased cardiac function following TAC compared to controls (<xref ref-type="bibr" rid="B98">98</xref>). In addition, adenoviral overexpression of PP2Cm in infarcted diabetic mice resulted in a significantly smaller scar size compared to controls (<xref ref-type="bibr" rid="B99">99</xref>). These studies demonstrate that enhanced BCAA catabolism can be protective against cardiac injury.</p>
<p>This relationship between BCAA catabolism and heart failure demonstrate that amino acid metabolism plays a role in heart disease and repair. Future studies to dissect the role of amino acids in the heart will establish their role as an important therapeutic target in cardiovascular disease.</p>
</sec>
<sec id="s6">
<title>TCA Cycle Metabolites in the Heart</title>
<p>The metabolic switch from glycolysis in neonatal mice to fatty acid oxidation in adult cardiomyocytes is accompanied by a significant increase in mitochondrial number and high levels of ROS production (<xref ref-type="bibr" rid="B16">16</xref>). This increase in ROS levels in the postnatal heart induces cardiomyocyte DNA damage, which contributes to cardiomyocyte cell cycle exit in the adult mammalian heart (<xref ref-type="bibr" rid="B16">16</xref>). Thus, elucidating the role of mitochondrial metabolites in regulating this metabolic switch is critical to identify metabolic targets to promote adult heart regeneration.</p>
<p>Succinate dehydrogenase (SDH), also known as mitochondrial complex II, is an important enzyme in regulating cell cycle and metabolic reprogramming in cancer because SDH plays a role in both the TCA cycle and the electron transport chain (<xref ref-type="bibr" rid="B100">100</xref>). Metabolic reprogramming has been recognized as a hallmark of various cancers due to the unique metabolic signature of cancer (<xref ref-type="bibr" rid="B101">101</xref>). In the presence of oxygen, pyruvate is converted to acetyl-CoA which enters the mitochondrial TCA cycle. However, in the absence of oxygen very limited oxidative phosphorylation takes place, instead lactate production increases aerobic glycolysis (<xref ref-type="bibr" rid="B101">101</xref>). Interestingly, pyruvate is mostly converted to lactate in cancer cells regardless of the oxygen levels. This metabolic switch promotes cancer cell survival and cell proliferation (<xref ref-type="bibr" rid="B100">100</xref>&#x02013;<xref ref-type="bibr" rid="B102">102</xref>).</p>
<p>Recent studies demonstrated that reverse activity of SDH during ischemia results in succinate accumulation (<xref ref-type="bibr" rid="B103">103</xref>, <xref ref-type="bibr" rid="B104">104</xref>). The accumulated succinate is then rapidly oxidized following reperfusion and results in a burst of ROS production <italic>via</italic> reverse activity of the mitochondrial complex I (<xref ref-type="bibr" rid="B105">105</xref>). These studies suggest that ROS production due to reverse activity of SDH and succinate accumulation is a hallmark of I/R injury (<xref ref-type="bibr" rid="B105">105</xref>). Interestingly, SDH inhibition reduces infarct size during ischemia in Langendorff-perfused mouse hearts (<xref ref-type="bibr" rid="B106">106</xref>). Furthermore, the SDH competitive inhibitor malonate reduces infarct size during I/R injury in pig hearts (<xref ref-type="bibr" rid="B107">107</xref>). These results demonstrate that SDH inhibition during I/R injury blocks the SDH-mediated succinate accumulation, thus protecting the heart against the redox insult during I/R injury. Interestingly, a recent study demonstrated that succinate accumulation in ischemia/reperfusion is not due to the reverse activity of SDH, but rather due to canonical TCA cycle activity (<xref ref-type="bibr" rid="B108">108</xref>). Thus, although succinate accumulation during ischemia is conserved across vertebrates, the proposed mechanism of succinate accumulation remains to be further understood.</p>
<p>SDH knockdown induces cell proliferation and migration in human hepatocellular carcinoma cell lines and leads to a metabolic shift to glycolysis as demonstrated by increased level of glycolytic enzymes (<xref ref-type="bibr" rid="B109">109</xref>). Interestingly, a recent study demonstrated that metabolic reprogramming to glycolysis promotes cardiomyocyte proliferation and heart regeneration following injury in zebrafish (<xref ref-type="bibr" rid="B15">15</xref>). Remarkably, SDH inhibition by malonate promotes adult cardiomyocyte proliferation, revascularization, and heart regeneration following adult myocardial infarction (<xref ref-type="bibr" rid="B110">110</xref>). In contrast to the cardioprotective role of malonate during I/R injury in mouse and pig hearts (<xref ref-type="bibr" rid="B105">105</xref>, <xref ref-type="bibr" rid="B107">107</xref>); malonate did not protect against infarction post-MI but rather promoted regeneration following infarction (<xref ref-type="bibr" rid="B110">110</xref>). Furthermore, SDH inhibition by malonate following adult MI was accompanied by increased succinate levels as a consequence of TCA cycle inhibition, which is distinct from the cardioprotective role of malonate that prevents succinate accumulation during I/R injury (<xref ref-type="bibr" rid="B105">105</xref>, <xref ref-type="bibr" rid="B110">110</xref>). Interestingly, metabolic profiling of the adult heart demonstrated an increase in glucose metabolism and a decrease in TCA cycle metabolism following SDH inhibition by malonate, consistent with a metabolic reprogramming from oxidative phosphorylation to glycolysis in the adult heart. These results demonstrate that SDH inhibition by malonate promotes adult heart regeneration <italic>via</italic> metabolic reprogramming (<xref ref-type="bibr" rid="B110">110</xref>).</p>
<p>Collectively, these studies demonstrate an important role for mitochondrial metabolites in regulating the cardiac metabolic state, and targeting metabolism has an important therapeutic potential to promote adult heart regeneration.</p>
</sec>
<sec sec-type="discussion" id="s7">
<title>Discussion</title>
<p>The role of the complex metabolic interactions in the heart and their potential to promote cardiac repair and regeneration are beginning to be appreciated. The shift in metabolism from glycolysis to fatty acid oxidation after birth coincides with the loss of regenerative potential in the neonatal mouse heart. The studies that are highlighted throughout this review demonstrate that manipulation of metabolic pathways is an area of immense potential for identifying new therapeutics to treat heart diseases (<xref ref-type="table" rid="T1">Table 1</xref>). Targeting these metabolic pathways can promote or inhibit regeneration depending upon the specific component that is modulated (<xref ref-type="fig" rid="F2">Figure 2</xref>).</p>
<table-wrap position="float" id="T1">
<label>Table 1</label>
<caption><p>Summary of recent studies demonstrating a central role for metabolism in heart failure and regeneration.</p></caption>
<table frame="hsides" rules="groups">
<thead><tr>
<th valign="top" align="left"><bold>Metabolism</bold></th>
<th valign="top" align="left"><bold>Target gene</bold></th>
<th valign="top" align="left"><bold>Function</bold></th>
<th valign="top" align="left"><bold>Application</bold></th>
<th valign="top" align="left"><bold>Results</bold></th>
<th valign="top" align="center"><bold>References</bold></th>
</tr>
</thead>
<tbody>
<tr>
<td valign="top" align="left">Fatty acid oxidation</td>
<td valign="top" align="left">Carnitine palmitoyltransferase 1 (CPT1)</td>
<td valign="top" align="left">Induces fatty acid oxidation</td>
<td valign="top" align="left">CPT1 inhibition</td>
<td valign="top" align="left">Increased proliferation of isolated neonatal cardiomyocytes</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B30">30</xref>)</td>
</tr>
<tr>
<td/>
<td/>
<td/>
<td/>
<td valign="top" align="left">Reduced in fatty acid oxidation gene expression</td>
<td/>
</tr>
<tr>
<td/>
<td/>
<td/>
<td/>
<td valign="top" align="left">No change in adult mouse cardiomyocyte proliferation</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B31">31</xref>)</td>
</tr>
<tr>
<td/>
<td valign="top" align="left">Malonyl-CoA decarboxylase (MCD)</td>
<td valign="top" align="left">Reduces fatty acid oxidation</td>
<td valign="top" align="left">MCD inhibition</td>
<td valign="top" align="left">Increased malonyl-CoA levels in ischemic swine heart</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B33">33</xref>, <xref ref-type="bibr" rid="B34">34</xref>)</td>
</tr>
<tr>
<td/>
<td/>
<td/>
<td/>
<td valign="top" align="left">Improved cardiac function following rat heart myocardial infarction (MI)</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B35">35</xref>)</td>
</tr>
<tr>
<td/>
<td/>
<td/>
<td/>
<td valign="top" align="left">Increased glucose oxidation in MCD deficient mouse heart</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B36">36</xref>)</td>
</tr>
<tr>
<td/>
<td/>
<td/>
<td/>
<td valign="top" align="left">Improved cardiac function in ischemic MCD deficient mouse heart</td>
<td/>
</tr>
<tr>
<td/>
<td valign="top" align="left">Peroxisome proliferator-activated receptor (PPAR) &#x003B1;</td>
<td valign="top" align="left">Induces fatty acid oxidation</td>
<td valign="top" align="left">PPAR&#x003B1; activation</td>
<td valign="top" align="left">Increased CPT1 gene expression and oxygen consumption rate in the presence of the fatty acid palmitate in isolated mouse cardiomyocytes</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B30">30</xref>)</td>
</tr>
<tr>
<td/>
<td/>
<td/>
<td/>
<td valign="top" align="left">No change in adult cardiomyocyte proliferation and cardiac function following MI</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B31">31</xref>)</td>
</tr>
<tr>
<td/>
<td/>
<td/>
<td/>
<td valign="top" align="left">Cardiac function decreased following I/R injury</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B42">42</xref>)</td>
</tr>
<tr>
<td/>
<td valign="top" align="left">PPAR&#x003B4;</td>
<td valign="top" align="left">Induces fatty acid oxidation</td>
<td valign="top" align="left">PPAR&#x003B4; activation</td>
<td valign="top" align="left">Decreased cardiac fibroblast proliferation and myofibroblast transdifferentiation</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B44">44</xref>)</td>
</tr>
<tr>
<td/>
<td/>
<td/>
<td/>
<td valign="top" align="left">Reduced cardiomyocyte proliferation and increased scar size following MI in mouse heart</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B45">45</xref>)</td>
</tr>
<tr>
<td/>
<td/>
<td/>
<td valign="top" align="left">PPAR&#x003B4; inhibition</td>
<td valign="top" align="left">Reduced cardiomyocyte proliferation following cardiac injury in zebrafish</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B45">45</xref>)</td>
</tr>
<tr>
<td valign="top" align="left">Glucose metabolism</td>
<td valign="top" align="left">GLUT1</td>
<td valign="top" align="left">Increases glucose uptake</td>
<td valign="top" align="left">GLUT1 overexpression</td>
<td valign="top" align="left">Increased glucose uptake and glycolysis in the mouse heart</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B62">62</xref>, <xref ref-type="bibr" rid="B63">63</xref>)</td>
</tr>
<tr>
<td/>
<td/>
<td/>
<td/>
<td valign="top" align="left">Increased regenerative response and glucose metabolites in neonatal mouse heart following cryoinjury</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B64">64</xref>)</td>
</tr>
<tr>
<td/>
<td/>
<td valign="top" align="left">Decreases glucose uptake</td>
<td valign="top" align="left">GLUT1 inhibition</td>
<td valign="top" align="left">Reduced glucose uptake and glycolysis in isolated mouse cardiomyocytes following TAC injury</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B59">59</xref>)</td>
</tr>
<tr>
<td/>
<td valign="top" align="left">Hexokinase (HK) 2</td>
<td valign="top" align="left">Increases glycolysis</td>
<td valign="top" align="left">HK-2 overexpression</td>
<td valign="top" align="left">Decreased cardiac hypertrophy in isoproterenol-induced mouse hearts</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B71">71</xref>)</td>
</tr>
<tr>
<td/>
<td/>
<td/>
<td/>
<td valign="top" align="left">Reduced cardiomyocyte size in neonatal rat ventricular cardiomyocytes</td>
<td/>
</tr>
<tr>
<td/>
<td/>
<td/>
<td/>
<td valign="top" align="left">Reduced ROS accumulation</td>
<td/>
</tr>
<tr>
<td/>
<td/>
<td valign="top" align="left">Decreases glycolysis</td>
<td valign="top" align="left">HK-2 inhibition</td>
<td valign="top" align="left">Increased cardiac dysfunction and cell death and fibrosis</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B72">72</xref>)</td>
</tr>
<tr>
<td/>
<td/>
<td/>
<td/>
<td valign="top" align="left">Decreased angiogenesis following I/R injury</td>
<td/>
</tr>
<tr>
<td/>
<td valign="top" align="left">Phosphofructokinase (PFK) 2</td>
<td valign="top" align="left">Increases glycolysis</td>
<td valign="top" align="left">PFK-2 inhibition</td>
<td valign="top" align="left">Reduced glycolysis and insulin sensitivity in mice</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B74">74</xref>, <xref ref-type="bibr" rid="B75">75</xref>)</td>
</tr>
<tr>
<td/>
<td/>
<td/>
<td valign="top" align="left">PFK-2 overexpression</td>
<td valign="top" align="left">Increased contractility in hypoxic mouse cardiomyocytes</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B76">76</xref>)</td>
</tr>
<tr>
<td/>
<td valign="top" align="left">Pyruvate dehydrogenase kinase (PDK)</td>
<td valign="top" align="left">Increases glycolysis</td>
<td valign="top" align="left">PDK inhibition</td>
<td valign="top" align="left">Increased cardiac function following KCI-induced cardiac arrest</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B77">77</xref>)</td>
</tr>
<tr>
<td/>
<td/>
<td/>
<td valign="top" align="left">PDK-4 inhibition</td>
<td valign="top" align="left">Promoted mouse cardiomyocyte proliferation and heart regeneration following adult MI</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B78">78</xref>)</td>
</tr>
<tr>
<td/>
<td valign="top" align="left">Pyruvate kinase muscle isoenzyme 2 (PKM2)</td>
<td valign="top" align="left">Increases glycolysis</td>
<td valign="top" align="left">PKM2 overexpression</td>
<td valign="top" align="left">Increased cardiomyocyte proliferation and cardiac regeneration following adult MI</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B79">79</xref>)</td>
</tr>
<tr>
<td/>
<td/>
<td/>
<td valign="top" align="left">PKM2 inhibition</td>
<td valign="top" align="left">Reduced cardiomyocyte proliferation following injury in zebrafish hearts</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B67">67</xref>)</td>
</tr>
<tr>
<td/>
<td/>
<td/>
<td/>
<td valign="top" align="left">Impaired heart development and reduced cardiomyocyte proliferation</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B79">79</xref>)</td>
</tr>
<tr>
<td valign="top" align="left">Amino acid metabolism</td>
<td valign="top" align="left">Protein Phosphatase 2cm (PP2 cm)/Protein Phosphatase 1 k (PPM1K)</td>
<td valign="top" align="left">Reduced BCAA oxidation</td>
<td valign="top" align="left">PP2cm inhibition</td>
<td valign="top" align="left">Increased BCAA and BCKA levels</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B87">87</xref>)</td>
</tr>
<tr>
<td/>
<td/>
<td/>
<td/>
<td valign="top" align="left">Reduced cardiac function and increased heart failure</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B87">87</xref>, <xref ref-type="bibr" rid="B89">89</xref>)</td>
</tr>
<tr>
<td/>
<td/>
<td/>
<td/>
<td valign="top" align="left">Decrease in glucose uptake and utilization</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B89">89</xref>)</td>
</tr>
<tr>
<td/>
<td/>
<td valign="top" align="left">Increased BCAA oxidation</td>
<td valign="top" align="left">PP2cm overexpression</td>
<td valign="top" align="left">Decreased DNA damage and cell death, leading to a smaller scar size post-MI</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B99">99</xref>)</td>
</tr>
<tr>
<td/>
<td valign="top" align="left">BCKDK</td>
<td valign="top" align="left">Increased BCAA oxidation</td>
<td valign="top" align="left">BCKDK inhibition</td>
<td valign="top" align="left">Decreased free BCAAs, leading to improved heart function post-TAC</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B98">98</xref>)</td>
</tr>
<tr>
<td valign="top" align="left">TCA cycle metabolism</td>
<td valign="top" align="left">Succinate dehydrogenase (SDH)</td>
<td valign="top" align="left">Reduced succinate accumulation</td>
<td valign="top" align="left">SDH inhibition</td>
<td valign="top" align="left">Reduced infarct size during ischemia in I/R mouse hearts</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B106">106</xref>)</td>
</tr>
<tr>
<td/>
<td/>
<td/>
<td/>
<td valign="top" align="left">Reduced infarct size during I/R injury in pig hearts</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B107">107</xref>)</td>
</tr>
<tr>
<td/>
<td/>
<td/>
<td/>
<td valign="top" align="left">Induced glucose metabolism in adult mouse hearts</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B110">110</xref>)</td>
</tr>
<tr>
<td/>
<td/>
<td/>
<td/>
<td valign="top" align="left">Promoted adult cardiomyocyte proliferation, revascularization, and heart regeneration following MI</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B110">110</xref>)</td>
</tr>
</tbody>
</table>
</table-wrap>
<p>Manipulating metabolic components in ways that can stimulate glucose metabolism has been implicated in promoting regeneration, as this shifts the heart&#x00027;s metabolic landscape closer to the metabolic state of the regenerative neonatal heart. This was demonstrated with deletion of PDK4, overexpression of PP2cm, as well as SDH inhibition <italic>via</italic> malonate, which promoted regeneration by inducing glucose metabolism <italic>via</italic> modulating their respective metabolic pathways (<xref ref-type="bibr" rid="B78">78</xref>, <xref ref-type="bibr" rid="B99">99</xref>, <xref ref-type="bibr" rid="B110">110</xref>).</p>
<p>In contrast, increased fatty acid oxidation has been demonstrated to reduce the cardiac regenerative response following injury. Inducing fatty acid oxidation <italic>via</italic> treatment with the PPAR&#x003B1; agonist WY-14643 results in reduced cardiac function after injury (<xref ref-type="bibr" rid="B42">42</xref>). Similarly, inhibition of glycolysis exacerbates cardiac injury, as demonstrated by reduced HK-2 expression (<xref ref-type="bibr" rid="B72">72</xref>) and PP2cm deletion (<xref ref-type="bibr" rid="B87">87</xref>).</p>
<p>The dynamic role of glycolysis and fatty acid oxidation following injury demonstrates a central role for cardiac metabolism during regeneration. Although multiple key components have already been identified that can be targeted therapeutically, these metabolic pathways play an important role in cardiac homeostasis. Thus, elucidating the mechanisms of these pathways during homeostasis, disease, and regeneration is an essential step prior to targeting these pathways for therapeutic development. For example, targeting succinate dehydrogenase post-MI promoted adult heart regeneration, yet the mechanisms by which succinate dehydrogenase inhibition promotes regeneration needs to be fully understood prior to clinical use (<xref ref-type="bibr" rid="B110">110</xref>). Furthermore, harnessing the potential of known pharmacological agents that have been demonstrated to target these metabolic pathways needs to be explored as candidates to induce adult heart regeneration.</p>
<p>Elucidating the role of cardiac metabolism in health and disease will provide us with novel avenues with significant therapeutic potential that could aid in promoting heart repair and regeneration. Advancements in this area of research will provide a better understanding of heart disease and regeneration.</p>
</sec>
<sec id="s8">
<title>Author Contributions</title>
<p>JB and AM contributed to conception and design of the manuscript. JB, WP, and AM wrote the manuscript. All authors contributed to manuscript revision, read, and approved the submitted manuscript.</p>
</sec>
<sec sec-type="COI-statement" id="conf1">
<title>Conflict of Interest</title>
<p>The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.</p>
</sec>
</body>
<back>
<ack><p>We apologize to any authors of studies that we might have not discussed.</p>
</ack>
<ref-list>
<title>References</title>
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<fn fn-type="financial-disclosure"><p><bold>Funding.</bold> Funding for this project was provided by the UW School of Medicine and Public Health from the Wisconsin Partnership Program (AM), an American Heart Association Career Development Award 19CDA34660169 (AM), NIH/NCATS through CTSA award UL1TR002373 to the UW Institute for Clinical and Translational Research, a post-doctoral training award from the Stem Cell and Regenerative Medicine Center at UW-Madison (JB) and NIH/NHLBI under Ruth L. Kirschstein NRSA T32 HL007936 to the UW Cardiovascular Research Center (JB).</p>
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