Energy substrate utilization by isolated working hearts from newborn rabbits

Lopaschuk, Gary D.; Spafford, Marguerite A.

doi:10.1152/ajpheart.1990.258.5.h1274

Cited by 64 publications

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“…Changes in ACC activity have been demonstrated to contribute to the maturation of fatty acid oxidation in hearts obtained from both newborn rabbits (1 and 7 d of age) (9,17,28), as well as hearts obtained from newborn pigs (14 d of age) (9,17,28). As we did not observe any age-dependent alteration in the phosphorylation of ACC (indicative of ACC inhibition), the data in this study suggests that in the newborn human heart the synthesis of malonyl CoA and maturation of fatty acid oxidation is not regulated by ACC activity, but is rather regulated by the extent of ACC expression.…”

Section: Discussionmentioning

confidence: 99%

“…Although plasma fatty acid levels rapidly rise to levels seen in the adult immediately after birth (6), newborn rabbit studies have shown that the heart undergoes a transition from oxidizing glucose to oxidizing fatty acids during the 7 d immediately after birth (9,10). The time frame responsible for the maturation of fatty acid oxidation in the human newborn heart is not yet known.…”

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Myocardial Hypertrophy and the Maturation of Fatty Acid Oxidation in the Newborn Human Heart

et al. 2008

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After birth dramatic decreases in cardiac malonylCoA levels result in the rapid maturation of fatty acid oxidation. We have previously demonstrated that the decrease in malonyl CoA is due to increased activity of malonyl CoA decarboxylase (MCD), and decreased activity of acetyl CoA carboxylase (ACC), enzymes which degrade and synthesize malonyl CoA, respectively. Decreased ACC activity corresponds to an increase in the activity of 5Ј-AMP activated protein kinase (AMPK), which phosphorylates and inhibits ACC. These alterations are delayed by myocardial hypertrophy. As rates of fatty acid oxidation can influence the ability of the heart to withstand an ischemic insult, we examined the expression of MCD, ACC, and AMPK in the newborn human heart. Ventricular biopsies were obtained from infants undergoing cardiac surgery. Immunoblot analysis showed a positive correlation between MCD expression and age. In contrast, a negative correlation in both ACC and AMPK expression and age was observed. All ventricular samples displayed some degree of hypertrophy, however, no differences in enzyme expression were found between moderate and severe hypertrophy. This indicates that increased expression of MCD, and the decreased expression of ACC and AMPK are important regulators of the maturation of fatty acid oxidation in the newborn human heart. T he adult heart has an extremely high energy demand which is met by the oxidation of fatty acids, accounting for 60 -80% of cardiac ATP (ATP) production (1-5). Glycolysis, glucose oxidation, and lactate oxidation are responsible for the remainder of ATP production (2). Interestingly, cardiac energy substrate preference differs between the fetal and neonatal heart. In the fetal heart blood levels of fatty acids are low (6) and the heart has a low circulatory workload and meets its energy demands from glycolysis and lactate oxidation (6 -8). At birth, major cardiovascular changes occur, including a reduction in pulmonary vascular resistance and closure of the ductus arteriosus and foramen ovale. These changes are coupled to an increase in peripheral vascular resistance, and an increased workload on the newborn heart. With circulating substrate and hormonal changes there is a switch in the energy substrate preference of the heart, from glucose and lactate metabolism to fatty acid oxidation (6 -8).Although plasma fatty acid levels rapidly rise to levels seen in the adult immediately after birth (6), newborn rabbit studies have shown that the heart undergoes a transition from oxidizing glucose to oxidizing fatty acids during the 7 d immediately after birth (9,10). The time frame responsible for the maturation of fatty acid oxidation in the human newborn heart is not yet known.The increase in fatty acid oxidation after birth in the newborn rabbit heart is related to dramatic decreases in cardiac malonyl CoA levels (10,11). Malonyl CoA is a potent inhibitor of carnitine palmitoyl transferase-1 (CPT-1), the rate limiting enzyme of mitochondrial fatty acid uptake (12). Acetyl CoA Carboxy...

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Section: Discussionmentioning

confidence: 99%

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Myocardial Hypertrophy and the Maturation of Fatty Acid Oxidation in the Newborn Human Heart

et al. 2008

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“…Pioneering work by multiple groups has defined dynamic shifts in fuel utilization capacity and preferences during development and in disease states. The fetal and immediate postnatal heart relies primarily on glucose (glycolysis) and lactate as energy sources (3)(4)(5). However, very soon after birth the heart shifts to fatty acids as the major fuel substrate, coincident with the mitochondrial biogenic response (Figure 1 and refs.…”

Section: Brief Overview Of Cardiac Fuel and Energy Metabolismmentioning

confidence: 99%

Cardiac nuclear receptors: architects of mitochondrial structure and function

Vega¹,

Kelly²

2017

Journal of Clinical Investigation

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The adult mammalian heart has immense energy demands in order to support its role as a constantly active pump. Indeed, the human heart generates and utilizes kilogram quantities of ATP each day. The vast majority of ATP produced in the cardiac myocyte is generated via oxidative phosphorylation (OXPHOS) within a very-high-capacity mitochondrial system. The heart must continually adapt to changing physiologic conditions that influence workload, as well as alterations in oxygen and energy substrate availability. Notably, given that the heart has a limited capacity for fuel storage, it must utilize several energy substrates in an efficient and dynamic manner. As will be described, members of the nuclear receptor transcription factor superfamily serve to dynamically control preference and capacity for cardiac mitochondrial fuel metabolism during development and in response to myriad physiologic conditions. In addition, alterations in nuclear receptor signaling occur with pathologic cardiac growth and remodeling en route to heart failure.The adult cardiac myocyte has a higher density of mitochondria than any other cell type (1). The biogenesis of this highcapacity mitochondrial system occurs largely during the perinatal stage of development. This process involves a major burst of mitochondrial biogenesis at birth, followed by a period of mitochondrial maturation and remodeling during the postnatal period (2). Recent evidence indicates that postnatal mitochondrial maturation involves highly coordinated events including mitophagy, biogenesis, and dynamics (fusion and fission), resulting in a mitochondria network that is densely packed between sarcomeres to directly supply ATP to support cardiac contraction (2). The adult cardiac mitochondria are equipped with enzymatic machinery capable of oxidizing multiple substrates including fatty acids (the chief fuel) as well as glucose (pyruvate) and ketone bodies. This mitochondrial developmental maturation process occurs in parallel with well-characterized changes in the expression of contractile apparatus isoforms, ion channels, and calcium handling proteins. The collective perinatal programming in energy metabolic and structural genes results in an efficient and enduring pump for the adult life of the organism.The postnatal heart has an amazing capacity to oxidize multiple fuels and, therefore, is "omnivorous." Pioneering work by multiple groups has defined dynamic shifts in fuel utilization capacity and preferences during development and in disease states. The fetal and immediate postnatal heart relies primarily on glucose (glycolysis) and lactate as energy sources (3-5). However, very soon after birth the heart shifts to fatty acids as the major fuel substrate, coincident with the mitochondrial biogenic response (Figure 1 and refs. 5-8). The level of glucose oxidation also increases (8). The postnatal heart is also capable of oxidizing ketones, albeit at a low level, concomitant with the postnatal rise in circulating ketones (5). The shifts in fuel preference after birth ar...

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“…2). Circulating fatty acid levels are elevated during ischemia (74,85,97), and it has been shown that high plasma fatty acid levels are detrimental to both the ischemic and the reperfused ischemic heart (53,86,88,103). During myocardial ischemia, AMPK is activated, which leads to the phosphorylation and inhibition of ACC (72,73), increased GLUT4 levels in the sarcolemmal membrane (142), and the activation of PFK-2 (73, 106, 108, 109).…”

Section: Regulation Of Myocardial Energy Utilizationmentioning

confidence: 99%

Role of AMP-activated protein kinase in healthy and diseased hearts

Dolinsky¹,

Dyck²

2006

American Journal of Physiology-Heart and Circulatory Physiology

118

105

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Dolinsky, Vernon W., and Jason R. B. Dyck. Role of AMP-activated protein kinase in healthy and diseased hearts. Am J Physiol Heart Circ Physiol 291: H2557-H2569, 2006. First published July 14, 2006 doi:10.1152/ajpheart.00329.2006.-The heart is capable of utilizing a variety of substrates to produce the necessary ATP for cardiac function. AMP-activated protein kinase (AMPK) has emerged as a key regulator of cellular energy homeostasis and coordinates multiple catabolic and anabolic pathways in the heart. During times of acute metabolic stresses, cardiac AMPK activation seems to be primarily involved in increasing energy-generating pathways to maintain or restore intracellular ATP levels. In acute situations such as mild ischemia or short durations of severe ischemia, activation of cardiac AMPK appears to be necessary for cardiac myocyte function and survival by stimulating ATP generation via increased glycolysis and accelerated fatty acid oxidation. Whereas AMPK activation may be essential for adaptation of cardiac energy metabolism to acute and/or minor metabolic stresses, it is unknown whether AMPK activation becomes maladaptive in certain chronic disease states and/or extreme energetic stresses. However, alterations in cardiac AMPK activity are associated with a number of cardiovascular-related diseases such as pathological cardiac hypertrophy, myocardial ischemia, glycogen storage cardiomyopathy, and Wolff-Parkinson-White syndrome, suggesting the possibility of a maladaptive role. Although the precise role AMPK plays in the diseased heart is still in question, it is clear that AMPK is a major regulator of cardiac energy metabolism. The consequences of alterations in AMPK activity and subsequent cardiac energy metabolism in the healthy and the diseased heart will be discussed. ischemia; cardiac hypertrophy; cardiac energy metabolism; glycogen THE HEART is capable of utilizing a variety of substrates to meet its immense demand for energy. Under normal physiological circumstances, cardiac function is dependent on the production of intracellular ATP derived primarily by the utilization of fatty acids, glucose, and lactate (123). A variety of transport proteins and regulatory enzymes control the uptake and subsequent metabolism of these energy substrates. Whereas many of these enzymes are regulated through substrate supply and/or energy demand, covalent modification of a number of these enzymes is also important. These regulatory mechanisms mediate substrate utilization and are essential for proper cardiac function.Fatty acids provide a concentrated supply of energy accounting for ϳ50 -75% of the myocardial acetyl CoA-derived ATP (84). Upon entering the cardiac myocyte, fatty acids are transported into the mitochondria and undergo ␤-oxidation to produce acetyl CoA that is eventually used to produce ATP. Glucose is transported into the cell via glucose transporters (GLUT) and can undergo glycolytic metabolism to generate pyruvate and ATP. This can occur in the absence of oxygen while still producing ATP. However, i...

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Energy substrate utilization by isolated working hearts from newborn rabbits

Cited by 64 publications

References 0 publications

Myocardial Hypertrophy and the Maturation of Fatty Acid Oxidation in the Newborn Human Heart

Myocardial Hypertrophy and the Maturation of Fatty Acid Oxidation in the Newborn Human Heart

Cardiac nuclear receptors: architects of mitochondrial structure and function

Role of AMP-activated protein kinase in healthy and diseased hearts

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