p38γ and p38δ regulate postnatal cardiac metabolism through glycogen synthase 1

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.

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

10.1101/579433 ◽

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.

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

Circulation ◽

10.1161/circ.142.suppl_3.16335 ◽

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.

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Energy sensing by the AMP-activated protein kinase and its effects on muscle metabolism

Proceedings of The Nutrition Society ◽

10.1017/s0029665110003915 ◽

2010 ◽

Vol 70 (1) ◽

pp. 92-99 ◽

Cited By ~ 81

Author(s):

D. Grahame Hardie

Keyword(s):

Protein Kinase ◽

Endurance Exercise ◽

Glycogen Synthase ◽

Glycogen Synthesis ◽

Whole Body ◽

Acid Oxidation ◽

Ampk Activation ◽

Energy Status ◽

Cellular Energy ◽

Amp Activated Protein Kinase

The AMP-activated protein kinase (AMPK) is a sensor of cellular energy status, and a regulator of energy balance at both the cellular and whole body levels. Although ubiquitously expressed, its function is best understood in skeletal muscle. AMPK contains sites that reversibly bind AMP or ATP, with an increase in cellular AMP:ATP ratio (signalling a fall in cellular energy status) switching on the kinase. In muscle, AMPK activation is therefore triggered by sustained contraction, and appears to be particularly important in the metabolic changes that occur in the transition from resistance to endurance exercise. Once activated, AMPK switches on catabolic processes that generate ATP, while switching off energy-requiring processes not essential in the short term. Thus, it acutely activates glucose uptake (by promoting translocation of the transporter GLUT4 to the membrane) and fatty acid oxidation, while switching off glycogen synthesis and protein synthesis (the later via inactivation of the mammalian target-of-rapamycin pathway). Prolonged AMPK activation also causes some of the chronic adaptations to endurance exercise, such as increased GLUT4 expression and mitochondrial biogenesis. AMPK contains a glycogen-binding domain that causes a sub-fraction to bind to the surface of the glycogen particle, and it can inhibit glycogen synthesis by phosphorylating glycogen synthase. We have shown that AMPK is inhibited by exposed non-reducing ends in glycogen. We are working on the hypothesis that this ensures that glycogen synthesis is rapidly activated when glycogen becomes depleted after exercise, but is switched off again as soon as glycogen stores are replenished.

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

10.1101/2021.07.12.451352 ◽

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.

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Reversal of cardiomyopathy resulting from prenatal exposure to ethanol

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100113469 ◽

1984 ◽

Vol 42 ◽

pp. 716-717

Author(s):

C. Uphoff ◽

C. Nyquist-Battie

Keyword(s):

Prenatal Exposure ◽

Heart Development ◽

Membrane Integrity ◽

Ethanol Exposure ◽

Prenatal Ethanol Exposure ◽

Pathological Changes ◽

Prenatally Exposed ◽

Inner Mitochondrial Membrane ◽

Fetal Alcohol ◽

Newborn Mice

Fetal Alcohol Syndrone (FAS) is a syndrome with characteristic abnormalities resulting from prenatal exposure to ethanol. In many children with FAS syndrome gross pathological changes in the heart are seen with septal defects the most prevalent abnormality recorded. Few studies in animal models have been performed on the effects of ethanol on heart development. In our laboratory, it has been observed that prenatal ethanol exposure of Swiss albino mice results in abnormal cardiac muscle ultrastructure when mice were examined at birth and compared to pairfed and normal controls. Fig. 1 is an example of the changes that are seen in the ethanol-exposed animals. These changes include enlarged mitochondria with loss of inner mitochondrial membrane integrity and loss of myofibrils. Morphometric analysis substantiated the presence of these alterations from normal cardiac ultrastructure. The present work was undertaken to determine if the pathological changes seen in the newborn mice prenatally exposed to ethanol could be reversed with age and abstinence.

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Adipocyte PHLPP2 inhibition prevents obesity-induced fatty liver

Nature Communications ◽

10.1038/s41467-021-22106-2 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

KyeongJin Kim ◽

Jin Ku Kang ◽

Young Hoon Jung ◽

Sang Bae Lee ◽

Raffaela Rametta ◽

...

Keyword(s):

Fatty Liver ◽

Whole Body ◽

Acid Oxidation ◽

Chow Diet ◽

Peroxisome Proliferator ◽

Obese Mice ◽

Ph Domain ◽

Peroxisome Proliferator Activated Receptor

AbstractIncreased adiposity confers risk for systemic insulin resistance and type 2 diabetes (T2D), but mechanisms underlying this pathogenic inter-organ crosstalk are incompletely understood. We find PHLPP2 (PH domain and leucine rich repeat protein phosphatase 2), recently identified as the Akt Ser473 phosphatase, to be increased in adipocytes from obese mice. To identify the functional consequence of increased adipocyte PHLPP2 in obese mice, we generated adipocyte-specific PHLPP2 knockout (A-PHLPP2) mice. A-PHLPP2 mice show normal adiposity and glucose metabolism when fed a normal chow diet, but reduced adiposity and improved whole-body glucose tolerance as compared to Cre- controls with high-fat diet (HFD) feeding. Notably, HFD-fed A-PHLPP2 mice show increased HSL phosphorylation, leading to increased lipolysis in vitro and in vivo. Mobilized adipocyte fatty acids are oxidized, leading to increased peroxisome proliferator-activated receptor alpha (PPARα)-dependent adiponectin secretion, which in turn increases hepatic fatty acid oxidation to ameliorate obesity-induced fatty liver. Consistently, adipose PHLPP2 expression is negatively correlated with serum adiponectin levels in obese humans. Overall, these data implicate an adipocyte PHLPP2-HSL-PPARα signaling axis to regulate systemic glucose and lipid homeostasis, and suggest that excess adipocyte PHLPP2 explains decreased adiponectin secretion and downstream metabolic consequence in obesity.

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CDK9 Inhibition Induces a Metabolic Switch that Renders Prostate Cancer Cells Dependent on Fatty Acid Oxidation

Neoplasia ◽

10.1016/j.neo.2019.05.001 ◽

2019 ◽

Vol 21 (7) ◽

pp. 713-720 ◽

Cited By ~ 6

Author(s):

Harri M. Itkonen ◽

Ninu Poulose ◽

Suzanne Walker ◽

Ian G. Mills

Keyword(s):

Prostate Cancer ◽

Fatty Acid ◽

Cancer Cells ◽

Fatty Acid Oxidation ◽

Acid Oxidation ◽

Prostate Cancer Cells ◽

Metabolic Switch

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Glucocorticoids produce whole body insulin resistance with changes in cardiac metabolism

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00453.2006 ◽

2007 ◽

Vol 292 (3) ◽

pp. E654-E667 ◽

Cited By ~ 70

Author(s):

Dake Qi ◽

Brian Rodrigues

Keyword(s):

Insulin Resistance ◽

Fatty Acid ◽

Glucose Utilization ◽

Experimental Studies ◽

Cardiac Metabolism ◽

Multiple Organ ◽

Whole Body ◽

Metabolic Abnormalities ◽

Organ Systems ◽

Per Se

Insulin resistance is viewed as an insufficiency in insulin action, with glucocorticoids being recognized to play a key role in its pathogenesis. With insulin resistance, metabolism in multiple organ systems such as skeletal muscle, liver, and adipose tissue is altered. These metabolic alterations are widely believed to be important factors in the morbidity and mortality of cardiovascular disease. More importantly, clinical and experimental studies have established that metabolic abnormalities in the heart per se also play a crucial role in the development of heart failure. Following glucocorticoids, glucose utilization is compromised in the heart. This attenuated glucose metabolism is associated with altered fatty acid supply, composition, and utilization. In the heart, elevated fatty acid use has been implicated in a number of metabolic, morphological, and mechanical changes and, more recently, in “lipotoxicity”. In the present article, we review the action of glucocorticoids, their role in insulin resistance, and their influence in modulating peripheral and cardiac metabolism and heart disease.

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Abnormal Cardiac Development in the Absence of Heart Glycogen

Molecular and Cellular Biology ◽

10.1128/mcb.24.16.7179-7187.2004 ◽

2004 ◽

Vol 24 (16) ◽

pp. 7179-7187 ◽

Cited By ~ 68

Author(s):

Bartholomew A. Pederson ◽

Hanying Chen ◽

Jill M. Schroeder ◽

Weinian Shou ◽

Anna A. DePaoli-Roach ◽

...

Keyword(s):

Cardiac Function ◽

Cardiac Muscle ◽

Heart Development ◽

Congenital Heart ◽

Cardiac Development ◽

Glycogen Synthase ◽

Heart Defects ◽

Mendelian Inheritance ◽

And Function ◽

Impaired Cardiac Function

ABSTRACT Glycogen serves as a repository of glucose in many mammalian tissues. Mice lacking this glucose reserve in muscle, heart, and several other tissues were generated by disruption of the GYS1 gene, which encodes an isoform of glycogen synthase. Crossing mice heterozygous for the GYS1 disruption resulted in a significant underrepresentation of GYS1-null mice in the offspring. Timed matings established that Mendelian inheritance was followed for up to 18.5 days postcoitum (dpc) and that ∼90% of GYS1-null animals died soon after birth due to impaired cardiac function. Defects in cardiac development began between 11.5 and 14.5 dpc. At 18.5 dpc, the hearts were significantly smaller, with reduced ventricular chamber size and enlarged atria. Consistent with impaired cardiac function, edema, pooling of blood, and hemorrhagic liver were seen. Glycogen synthase and glycogen were undetectable in cardiac muscle and skeletal muscle from the surviving null mice, and the hearts showed normal morphology and function. Congenital heart disease is one of the most common birth defects in humans, at up to 1 in 50 live births. The results provide the first direct evidence that the ability to synthesize glycogen in cardiac muscle is critical for normal heart development and hence that its impairment could be a significant contributor to congenital heart defects.

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The activity of the pyruvate dehydrogenase complex in heart and liver from mice during the development of obesity and insulin resistance

Biochemical Journal ◽

10.1042/bj2430549 ◽

1987 ◽

Vol 243 (2) ◽

pp. 549-553 ◽

Cited By ~ 7

Author(s):

I D Caterson ◽

L D Astbury ◽

P F Williams ◽

M A Vanner ◽

G J Cooney ◽

...

Keyword(s):

Insulin Resistance ◽

Pyruvate Dehydrogenase ◽

Serum Insulin ◽

Pyruvate Dehydrogenase Complex ◽

Active Form ◽

Whole Body ◽

Acid Oxidation ◽

Mitochondrial Fatty Acid Oxidation ◽

Gold Thioglucose ◽

Mitochondrial Fatty Acid

The amount of pyruvate dehydrogenase in the active form (PDHa) was increased 1.7-fold compared with controls in heart muscle of mice 1 week after induction of obesity with a single injection of gold-thioglucose. At 4 weeks post injection, the amount of PDHa was decreased to 32% of control, a value which was observed in later stages of the obesity syndrome. In contrast, liver PDHa was increased and remained at an increased activity during the development of obesity. Despite normal post-prandial serum insulin contents, liver membrane insulin-receptor numbers were decreased 1 week after gold-thioglucose injection, and there was no change in receptor affinity. The decrease in heart PDHa in the obese animals was reversed by a single dose of 2-tetradecylglycidic acid, but this inhibitor of mitochondrial fatty acid oxidation did not affect liver PDHa in these animals. These early and diverse changes in PDHa argue for a multifactorial aetiology in the development of the whole-body insulin resistance seen in older gold-thioglucose-treated obese animals.

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