scholarly journals Metabolic reprogramming from glycolysis to amino acid utilization in cardiac HIF1α deficient mice

2019 ◽  
Author(s):  
Ivan Menendez-Montes ◽  
Beatriz Escobar ◽  
Beatriz Palacios ◽  
Manuel J. Gomez ◽  
Elena Bonzon ◽  
...  
Keyword(s):  
Amino Acid ◽  
Heart Development ◽  
Cardiac Development ◽  
Building Blocks ◽  
Embryonic Heart ◽  
Metabolic Reprogramming ◽  
Acid Oxidation ◽  
Metabolic Switch ◽  
Cardiac Growth ◽  
Cardiac Progenitors

AbstractRationaleHypoxia is an important environmental cue implicated in several physiopathological processes, including heart development. Several mouse models of activation or inhibition of hypoxia have been previously described. While gain of function models have been extensively characterized and indicate that HIF1 signaling needs to be tightly regulated to ensure a proper cardiac development, there is lack of consensus in the field about the functional outcomes of HIF1α loss.ObjectiveIn this study, we aim to assess the consequences of cardiac deletion of HIF1α during heart development and identify the cardiac adaptations to HIF1 loss.Methods and ResultsHere, we used a conditional deletion model ofHif1ain NKX2.5+cardiac progenitors. By a combination of histology, electron microscopy, massive gene expression studies, proteomics, metabolomics and cardiac imaging, we found that HIF1α is dispensable for cardiac development.Hif1aloss results in glycolytic inhibition in the embryonic heart without affecting normal cardiac growth. However, together with a premature increase in mitochondrial number by E12.5, we found global upregulation of amino acid transport and catabolic processes. Interestingly, this amino acid catabolism activation is transient and does not preclude the normal cardiac metabolic switch towards fatty acid oxidation (FAO) after E14.5. Moreover,Hif1aloss is accompanied by an increase in ATF4, described as an important regulator of several amino acid transporters.ConclusionsOur data indicate that HIF1α is not required for normal cardiac development and suggest that additional mechanisms can compensateHif1aloss. Moreover, our results reveal the metabolic flexibility of the embryonic heart at early stages of development, showing the capacity of the myocardium to adapt its energy source to satisfy the energetic and building blocks demands to achieve normal cardiac growth and function. This metabolic reprograming might be relevant in the setting of adult cardiac failure.

Abstract 16335: Metabolic Reprogramming From Glycolysis to Amino Acid Utilization in Cardiac Hif1 Alpha Deficient Mice

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Ivan Menendez-Montes ◽  
Beatriz Escobar ◽  
Manuel J Gómez ◽  
Teresa Albendea-Gomez ◽  
Beatriz Palacios ◽  
...  
Keyword(s):  
Amino Acid ◽  
Heart Development ◽  
Alternative Fuels ◽  
Cardiac Injury ◽  
Cardiac Metabolism ◽  
Metabolic Reprogramming ◽  
Structural Defects ◽  
Acid Oxidation ◽  
Cardiac Progenitors ◽  
Knock Out

Introduction: Hypoxia is an important environmental cue implicated in several physiopathological processes, including cardiac development. Several gain of function models described before indicate that HIF1 signaling needs to be tightly regulated to ensure proper heart formation. However, there is lack of consensus about the functional outcomes of cardiac HIF1 elimination. We have previously reported that HIF1alpha expression is spatiotemporally regulated along cardiogenesis, establishing metabolic territories in the embryonic myocardium and controlling a switch from glycolysis to fatty acid oxidation (FAO) essential for chamber formation and cardiomyocyte maturation. Objectives and Hypothesis: We aim to assess the consequences of cardiac deletion of HIF1alpha during heart development and identify the adaptations to HIF1 signaling loss. Based on the tight regulation of HIF1alpha expression during cardiogenesis, we anticipated significant alterations of cardiac metabolism as well as functional and structural defects in HIF1alpha mutants. Methods and Results: A new conditional Hif1alpha knock out was generated in NKX2.5 cardiac progenitors. By means of histology, electron microscopy and high-throughput genomics, proteomics and metabolomics, we found that deletion of Hif1alpha leads to impaired embryonic glycolysis without influencing cardiomyocyte size or proliferation and results in increased mitochondrial number, transient activation of amino acid response and upregulation of HIF2alpha and ATF4. HIF1alpha mutants display normal FAO metabolic profile and do not show cardiac dysfunction in the adulthood. Conclusions: We demonstrated that HIF1 signaling is dispensable for heart development and uncovered the metabolic flexibility of the mammalian embryonic myocardium, able to utilize alternative fuels to carbohydrates in contrast to other vertebrates like zebrafish. This data highlights the importance of HIF in cardiac metabolic programing and could explain the distinct proliferative and regenerative capacity of cardiomyocytes from different species in response to cardiac injury.

scholarly journals Activation of amino acid metabolic program in response to impaired glycolysis in cardiac HIF1 deficient mice

2020 ◽  
Author(s):  
Ivan Menendez-Montes ◽  
Beatriz Escobar ◽  
Manuel J. Gomez ◽  
Teresa Albendea-Gomez ◽  
Beatriz Palacios ◽  
...  
Keyword(s):  
Amino Acid ◽  
Heart Development ◽  
Alternative Energy ◽  
Therapeutic Interventions ◽  
Acid Oxidation ◽  
Normal Fatty Acid ◽  
Loss Of Function ◽  
Cardiac Progenitors ◽  
Knock Out ◽  
The Impact

ABSTRACTHypoxia is an important environmental cue in heart development. Despite of extensive characterization of gain and loss of function models, there is disagreement about the impact of HIF1α elimination in cardiac tissue. Here, we used a new conditional knock out of Hif1a in NKX2.5 cardiac progenitors to assess the morphological and functional consequences of HIF1α loss in the developing heart. By combining histology, electron microscopy and high-throughout genomics, proteomics and metabolomics, we found that deletion of Hif1a leads to impaired embryonic glycolysis without influencing cardiomyocyte proliferation and results in an increased mitochondrial number, activation of a transient amino acid response and upregulation of HIF2α and ATF4 by E12.5. Hif1a mutants display normal fatty acid oxidation metabolic profile and do not show any sign of cardiac dysfunction in the adulthood. Our results demonstrate that HIF1 signaling is dispensable for heart development and reveal the metabolic flexibility of the embryonic myocardium, opening the potential application of alternative energy sources as therapeutic interventions during ischemic events.

Abstract 257: Clonal Analysis Of Multipotent Cardiovascular Progenitors That Generate Cardiomyocytes During Development

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Konstantina Ioanna Sereti ◽  
Paniz Kamran Rashani ◽  
Peng Zhao ◽  
Reza Ardehali
Keyword(s):  
Single Cell ◽  
Heart Development ◽  
Cardiac Development ◽  
Clonal Analysis ◽  
Cardiac Cells ◽  
Single Cell Level ◽  
Reporter System ◽  
Cell Level ◽  
Cardiac Progenitors

It has been proposed that cardiac development in lower vertebrates is driven by the proliferation of cardiomyocytes. Similarly, cycling myocytes have been suggested to direct cardiac regeneration in neonatal mice after injury. Although, the role of cardiomyocyte proliferation in cardiac tissue generation during development has been well documented, the extent of this contribution as well as the role of other cell types, such as progenitor cells, still remains controversial. Here we used a novel stochastic four-color Cre-dependent reporter system (Rainbow) that allows labeling at a single cell level and retrospective analysis of the progeny. Cardiac progenitors expressing Mesp1 or Nkx2.5 were shown to be a source of cardiomyocytes during embryonic development while the onset of αMHC expression marked the developmental stage where the capacity of cardiac cells to proliferate diminishes significantly. Through direct clonal analysis we provide strong evidence supporting that cardiac progenitors, as opposed to mature cardiomyocytes, are the main source of cardiomyocytes during cardiac development. Moreover, we have identified quadri-, tri-, bi, and uni-potent progenitors that at a single cell level can generate cardiomyocytes, fibroblasts, endothelial and smooth muscle cells. Although existing cardiomyocytes undergo limited proliferation, our data indicates that it is mainly the progenitors that contribute to heart development. Furthermore, we show that the limited proliferation capacity of cardiomyocytes observed during normal development was enhanced following neonatal cardiac injury allowing almost complete regeneration of the scared tissue. However, this ability was largely absent in adult injured hearts. Detailed characterization of dividing cardiomyocytes and proliferating progenitors would greatly benefit the development of novel therapeutic options for cardiovascular diseases.

scholarly journals From Stripes to a Beating Heart: Early Cardiac Development in Zebrafish

2021 ◽  
Vol 8 (2) ◽  
pp. 17
Author(s):  
Cassie L. Kemmler ◽  
Fréderike W. Riemslagh ◽  
Hannah R. Moran ◽  
Christian Mosimann
Keyword(s):  
Congenital Heart Defects ◽  
Heart Development ◽  
Congenital Heart ◽  
Cardiac Development ◽  
Heart Defects ◽  
Lineage Tracing ◽  
Genetic Lineage ◽  
Zebrafish Model ◽  
Lateral Plate ◽  
Cardiac Progenitors

The heart is the first functional organ to form during vertebrate development. Congenital heart defects are the most common type of human birth defect, many originating as anomalies in early heart development. The zebrafish model provides an accessible vertebrate system to study early heart morphogenesis and to gain new insights into the mechanisms of congenital disease. Although composed of only two chambers compared with the four-chambered mammalian heart, the zebrafish heart integrates the core processes and cellular lineages central to cardiac development across vertebrates. The rapid, translucent development of zebrafish is amenable to in vivo imaging and genetic lineage tracing techniques, providing versatile tools to study heart field migration and myocardial progenitor addition and differentiation. Combining transgenic reporters with rapid genome engineering via CRISPR-Cas9 allows for functional testing of candidate genes associated with congenital heart defects and the discovery of molecular causes leading to observed phenotypes. Here, we summarize key insights gained through zebrafish studies into the early patterning of uncommitted lateral plate mesoderm into cardiac progenitors and their regulation. We review the central genetic mechanisms, available tools, and approaches for modeling congenital heart anomalies in the zebrafish as a representative vertebrate model.

scholarly journals p38γ and p38δ regulate postnatal cardiac metabolism through glycogen synthase 1

PLoS Biology ◽  
2021 ◽  
Vol 19 (11) ◽  
pp. e3001447
Author(s):  
Ayelén M. Santamans ◽  
Valle Montalvo-Romeral ◽  
Alfonso Mora ◽  
Juan Antonio Lopez ◽  
Francisco González-Romero ◽  
...  
Keyword(s):  
Heart Development ◽  
Glycogen Synthase ◽  
Maternal Diet ◽  
Cardiac Metabolism ◽  
Whole Body ◽  
Acid Oxidation ◽  
Metabolic Shift ◽  
Heart Metabolism ◽  
Metabolic Switch ◽  
Newborn Mice

During the first weeks of postnatal heart development, cardiomyocytes undergo a major adaptive metabolic shift from glycolytic energy production to fatty acid oxidation. This metabolic change is contemporaneous to the up-regulation and activation of the p38γ and p38δ stress-activated protein kinases in the heart. We demonstrate that p38γ/δ contribute to the early postnatal cardiac metabolic switch through inhibitory phosphorylation of glycogen synthase 1 (GYS1) and glycogen metabolism inactivation. Premature induction of p38γ/δ activation in cardiomyocytes of newborn mice results in an early GYS1 phosphorylation and inhibition of cardiac glycogen production, triggering an early metabolic shift that induces a deficit in cardiomyocyte fuel supply, leading to whole-body metabolic deregulation and maladaptive cardiac pathogenesis. Notably, the adverse effects of forced premature cardiac p38γ/δ activation in neonate mice are prevented by maternal diet supplementation of fatty acids during pregnancy and lactation. These results suggest that diet interventions have a potential for treating human cardiac genetic diseases that affect heart metabolism.

scholarly journals Amino Acid Metabolism in Lupus

2021 ◽  
Vol 12 ◽  
Author(s):  
Michihito Kono ◽  
Nobuya Yoshida ◽  
George C. Tsokos
Keyword(s):  
T Cells ◽  
Amino Acid ◽  
T Cell ◽  
T Cell Activation ◽  
Amino Acid Metabolism ◽  
Acid Metabolism ◽  
Cell Metabolism ◽  
Cell Subset ◽  
Metabolic Reprogramming ◽  
Acid Oxidation

T cell metabolism is central to cell proliferation, survival, differentiation, and aberrations have been linked to the pathophysiology of systemic autoimmune diseases. Besides glycolysis and fatty acid oxidation/synthesis, amino acid metabolism is also crucial in T cell metabolism. It appears that each T cell subset favors a unique metabolic process and that metabolic reprogramming changes cell fate. Here, we review the mechanisms whereby amino acid transport and metabolism affects T cell activation, differentiation and function in T cells in the prototype systemic autoimmune disease systemic lupus erythematosus. New insights in amino acid handling by T cells should guide approaches to correct T cell abnormalities and disease pathology.

scholarly journals PPARdelta signaling activation improves metabolic and contractile maturation of human pluripotent stem cell-derived cardiomyocytes.

2021 ◽  
Author(s):  
Nadeera M Wickramasinghe ◽  
David Sachs ◽  
Bhavana Shewale ◽  
David M Gonzalez ◽  
Priyanka Dhanan-Krishnan ◽  
...  
Keyword(s):  
Stem Cell ◽  
Heart Development ◽  
Regulatory Networks ◽  
Pluripotent Stem Cell ◽  
Disease Modeling ◽  
Acid Oxidation ◽  
Metabolic Switch ◽  
Ppar Signaling ◽  
Signaling Activation ◽  
Cardiac Maturation

Pluripotent stem cell-derived cardiomyocytes (PSC-CMs) provide an unprecedented opportunity to study human heart development and disease. A major caveat however is that they remain functionally and structurally immature in culture, limiting their potential for disease modeling and regenerative approaches. Here, we address the question of how different metabolic pathways can be modulated in order to induce efficient hPSC-CM maturation. We show that PPAR signaling acts in an isoform-specific manner to balance glycolysis and fatty acid oxidation (FAO). PPARD activation or inhibition results in efficient respective up- or down-regulation of the gene regulatory networks underlying FAO in hPSC-CMs. PPARD induction further increases mitochondrial and peroxisome content, enhances mitochondrial cristae formation and augments FAO flux. Lastly PPARD activation results in enhanced myofibril organization and improved contractility. Transient lactate exposure, commonly used in hPSC-CM purification protocols, induces an independent program of cardiac maturation, but when combined with PPARD activation equally results in a metabolic switch to FAO. In summary, we identify multiple axes of metabolic modifications of hPSC-CMs and a role for PPARD signaling in inducing the metabolic switch to FAO in hPSC-CMs. Our findings provide new and easily implemented opportunities to generate mature hPSC-CMs for disease modeling and regenerative therapy.

Abstract 357: Branched-Chain Amino Acid Metabolic Reprogramming in Heart Failure

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Haipeng Sun ◽  
Kristine Olson ◽  
Meiyi Zhou ◽  
Domenick Prosdocimo ◽  
Chen Gao ◽  
...  
Keyword(s):  
Heart Failure ◽  
Amino Acid ◽  
Building Blocks ◽  
Metabolic Reprogramming ◽  
Genetic Ablation ◽  
Failing Heart ◽  
Catabolic Genes ◽  
Metabolic Remodeling ◽  
Heart Failure Progression ◽  
Branched Chain

Metabolic remodeling is an integral part of heart failure. Current studies are largely focusing on glucose and fatty acid metabolism, while little is known about the changes in amino acid homeostasis during heart failing process. Branched chain amino acids (BCAAs), including leucine, isoleucine, and valine, serve as not only essential building blocks for protein synthesis, but also important energy source and signaling molecules that have significant effects on cell growth and function. In this study, we demonstrated that the BCAA catabolic intermediate branched-chain keto acid (BCKA) accumulated in both mouse and human failing heart. BCAA catabolic genes were selectively and significantly down-regulated at both mRNA and protein levels in failing heart in mice, mimicking a similar expression pattern observed in neonatal heart. Using both in vitro and in vivo models, we established that BCAA catabolic genes were regulated by Krüppel-like factor 15 (KLF15), a key transcriptional regulator for glucose, fat, and amino acid nutrient homeostasis, suggesting that the KLF15-mediated BCAA catabolic regulation is part of the metabolic remodeling during heart failure. Genetic ablation of PP2Cm, a key regulator of BCAA catabolism, led to a significant impairment of BCAA catabolic activities and accumulation of BCKA in cardiac tissue. Importantly, PP2Cm deficiency accelerated heart failure under pressure overload. PP2Cm deficiency or elevated BCKA induced oxidative stress in cardiomyocytes and impairment of oxygen consumption and ATP production of mitochondria. Antioxidant treatment ameliorated the heart failure progression in PP2Cm deficient animals. Taken together, our data established for the first time that BCAA catabolic reprogramming is an integral component of metabolic remodeling during heart failure, and this remodeling can significantly contribute to heart failure progression.

scholarly journals The Apelin receptor enhances Nodal/TGFβ signaling to ensure proper cardiac development

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Ashish R Deshwar ◽  
Serene C Chng ◽  
Lena Ho ◽  
Bruno Reversade ◽  
Ian C Scott
Keyword(s):  
Heart Development ◽  
Cardiac Development ◽  
Cardiac Differentiation ◽  
Tgfβ Signaling ◽  
Cardiac Progenitors ◽  
Early Migration ◽  
Apelin Receptor ◽  
And Migration ◽  
Peptide Agonist ◽  
Fine Tune

The Apelin receptor (Aplnr) is essential for heart development, controlling the early migration of cardiac progenitors. Here we demonstrate that in zebrafish Aplnr modulates Nodal/TGFβ signaling, a key pathway essential for mesendoderm induction and migration. Loss of Aplnr function leads to a reduction in Nodal target gene expression whereas activation of Aplnr by a non-peptide agonist increases the expression of these same targets. Furthermore, loss of Aplnr results in a delay in the expression of the cardiogenic transcription factors mespaa/ab. Elevating Nodal levels in aplnra/b morphant and double mutant embryos is sufficient to rescue cardiac differentiation defects. We demonstrate that loss of Aplnr attenuates the activity of a point source of Nodal ligands Squint and Cyclops in a non-cell autonomous manner. Our results favour a model in which Aplnr is required to fine-tune Nodal output, acting as a specific rheostat for the Nodal/TGFβ pathway during the earliest stages of cardiogenesis.

Sign in / Sign up

Export Citation Format

Share Document