Postnatal anatomical and functional development of the heart: A species comparison

Hew, Kok Wah; Keller, Kit A.

doi:10.1002/bdrb.10034

Cited by 121 publications

(63 citation statements)

References 134 publications

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“…[22][23][24] Immunohistochemical studies revealed a diffuse lamin A/C protein staining in connective tissue and myoblasts at E11.0. 4,5 Lamin A/C protein levels increase until day E14.0 and lamin A/C protein was only detected in a few more tissues during embryonic development from this age onwards.…”

Section: Discussionmentioning

confidence: 99%

Post-natal myogenic and adipogenic developmental

Kubben¹,

Voncken²,

Konings³

et al. 2011

Nucleus

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A-type lamins are a major component of the nuclear lamina. Mutations in the LMNA gene, which encodes the A-type lamins A and C, cause a set of phenotypically diverse diseases collectively called laminopathies. While adult LMNA null mice show various symptoms typically associated with laminopathies, the effect of loss of lamin A/C on early postnatal development is poorly understood. Here we developed a novel LMNA null mouse (LMNA GT-/-) based on genetrap technology and analyzed its early post-natal development. We detect LMNA transcripts in heart, the outflow tract, dorsal aorta, liver and somites during early embryonic development. Loss of A-type lamins results in severe growth retardation and developmental defects of the heart, including impaired myocyte hypertrophy, skeletal muscle hypotrophy, decreased amounts of subcutaneous adipose tissue and impaired ex vivo adipogenic differentiation. These defects cause death at 2 to 3 weeks post partum associated with muscle weakness and metabolic complications, but without the occurrence of dilated cardiomyopathy or an obvious progeroid phenotype. Our results indicate that defective early postnatal development critically contributes to the disease phenotypes in adult laminopathies. Post-natal myogenic and adipogenic developmentalDefects and metabolic impairment upon loss of A-type lamins myocytes, skeletal muscle hypotrophy, decreased subcutaneous adipose tissue deposits, decreased adipogenic differentiation of MEFs and metabolic derangements. Ultimately these tissue differentiation and maturation defects are lethal before mice are weaned. These results demonstrate that lamin A/C is crucial in the early post-natal period and they provide novel insights into the physiological function of A-type lamins in the context of the developing animal.

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Section: Discussionmentioning

confidence: 99%

Post-natal myogenic and adipogenic developmental

Kubben¹,

Voncken²,

Konings³

et al. 2011

Nucleus

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“…Infants born preterm may eventually catch up to their counterparts born at term, although to what extent presumably depends on whether key events occur at the proper time and in the correct sequence, e.g. changes in baroreflex control (which normally strengthens), cardiovagal inhibition (which weakens), metabolism (which slowly decreases), vascular resistance (which increases), and within the heart itself (27,42,43). Because the HR of the preterm infant is often elevated at 6 mo, central and peripheral mechanisms involved in cardiac (and perhaps circulatory) control may be quite slow to reset or normalize (if at all) (44).…”

Section: Discussionmentioning

confidence: 99%

Abnormal Circulatory Stress Responses of Preterm Graduates

2007

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Preterm birth and chronic lung disease may increase the risk of hypertension and cardiovascular disease in infancy and adolescence. Here we looked for evidence of early circulatory dysfunction associated with these perinatal complications. We compared infants born at term (n ϭ 12) with those born preterm with an uncomplicated neonatal course (n ϭ 12) or diagnosed with bronchopulmonary dysplasia (BPD) (n ϭ 10). We measured blood pressure (BP) (Finometer), and heart rate (HR) responses to 4 min of breathing 4% CO 2 during quiet sleep. Hypercapnia accelerated HR and increased BP of term infants. Preterm infants either (i) had an exaggerated pressor but little or no HR response to CO 2 (healthy or mild-moderate BPD) or (ii) had a diminished pressor response and accompanying decrease in HR (severe BPD). Short-term reflex cardiovascular control was consequently altered by premature birth, with potentially more serious aberrations associated with severe BPD. Most anomalies had not resolved by the time infants born preterm reached term age; some may be early signs of emerging long-term cardiovascular dysfunction. W ith the impressive increase in survival of very preterm and low birth weight infants come new challenges. Evidence already indicates that this "new generation" of children and adolescents may have accelerated disease onset later in life (1). One factor contributing to their higher risk of cardiovascular disease may be abnormal vascular and circulatory development (2-4). Cardiovascular activity is normally carefully regulated, but if some or all of the central and peripheral regulatory mechanisms involved fail to develop normally, perfusion, growth, and function may be compromised. In exceptional circumstances during infancy, persistent serious dysfunction could result in a sudden catastrophic decrease in BP and HR or prevent autoresuscitative recovery, culminating in sudden infant death syndrome (SIDS) (5,6). In other cases, dysfunction may be relatively benign, although there may still be side effects with adverse consequences of their own.We know relatively little about how BP and HR control develops, and the potentially adverse effects of fetal and perinatal stress. A better understanding of these issues could lead to new therapies or strategies to prevent neonatal complications and improve long-term outcome. In the study described here, we looked for evidence that development of neonatal circulatory control is altered by common perinatal complications (7). We studied three different groups of newborn infants: those born normally at term, those born preterm but otherwise healthy, and infants born very preterm suffering from chronic lung disease (BPD). Infants with BPD are at particularly high risk of long-term cardiovascular complications and SIDS (8 -10). We compared BP and HR responses of these infants to a routine physiologic stress (breathing a low concentration of CO 2 for several minutes) commonly used to unmask autonomic anomalies (11). Normally, acute exposure to CO 2 increases BP and HR ...

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“…Humans are born at a more mature point in development, and as indicated above, at the time of birth, body fat percentage is higher in humans than in rats and mice (37,48,(53)(54)(55). In these neonatal rodents, ketogenesis is driven by suckling, rather than fasting (37,38).…”

Section: Oxct1mentioning

confidence: 96%

Obligate Role for Ketone Body Oxidation in Neonatal Metabolic Homeostasis

Cotter¹,

d’Avignon

Wentz³

et al. 2011

Journal of Biological Chemistry

107

102

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To compensate for the energetic deficit elicited by reduced carbohydrate intake, mammals convert energy stored in ketone bodies to high energy phosphates. Ketone bodies provide fuel particularly to brain, heart, and skeletal muscle in states that include starvation, adherence to low carbohydrate diets, and the neonatal period. Here, we use novel Oxct1 ؊/؊ mice, which lack the ketolytic enzyme succinyl- Transition from the intrauterine to the extrauterine environment incurs a marked shift in nutrient delivery and energy metabolism. A continuous pipeline replete with glucose and lactate, but calorically reduced in lipid, is replaced by a reduced carbohydrate, high fat milk diet that is cyclically interrupted by periods of nutrient deprivation (1-3). High energy-requiring organs like heart and skeletal muscle are poised to meet the energetic demands of this new nutrient environment because they are endowed with enzymatic machinery that avidly generates high energy phosphates from oxidative metabolism of fatty acids and lactate (4). Unlike cardiomyocytes and skeletal myocytes, most neurons oxidize fatty acids poorly and therefore remain dependent on hepatic gluconeogenesis to support energetic needs (5-8). However, because newborn brain comprises 10% of body weight and requires up to 60% of total body energy expenditure, maintenance of energetic homeostasis in the nervous system requires allocation of multiple fuels for metabolic homeostasis in the neonatal period. The rate of ketone body extraction by human neonatal brain is up to 40-fold higher than adult brain. Furthermore, ketones contribute uniquely to maturation within the nervous system (1-3, 9 -16).Most ketogenesis occurs in the liver and is driven primarily by rates of fatty acid oxidation. Mitochondrial fatty acid oxidation-derived acetoacetyl-CoA (AcAc-CoA) and acetyl-CoA together serve as the primary ketogenic substrates. Ketogenic reactions are sequentially catalyzed by HMG-CoA synthase 2 and HMG-CoA lyase, generating acetoacetate (AcAc), 3 which is converted to D-␤-hydroxybutyrate (␤OHB) in an NAD ϩ / NADH-coupled redox reaction catalyzed by ␤OHB dehydrogenase. AcAc and ␤OHB diffuse into the bloodstream and are delivered to ketolytic organs, in which they are exceptionally energy-efficient substrates (12,(17)(18)(19)(20)(21)(22). Within mitochondria of ketolytic organs, ␤OHB is oxidized back to AcAc in a reaction catalyzed by ␤OHB dehydrogenase. AcAc receives a CoA moiety from succinyl-CoA, generating AcAc-CoA in a reaction catalyzed by succinyl-CoA:3-oxo-acid CoA-transferase (SCOT, EC 2.8.3.5), encoded by nuclear Oxct1. This enzyme is not expressed in liver (12,23). Mitochondrial AcAc-CoA thiolase catalyzes conversion of AcAc-CoA to acetyl-CoA, which is terminally oxidized within the tricarboxylic acid cycle.Reports of ϳ20 individuals who harbor homozygous or compound heterozygous OXCT1 loss-of-function mutations (Online Mendelian Inheritance in Man 245050) indicate that a functional allele is required for ketone body oxidation, and as such patients t...

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Postnatal anatomical and functional development of the heart: A species comparison

Cited by 121 publications

References 134 publications

Post-natal myogenic and adipogenic developmental

Post-natal myogenic and adipogenic developmental

Abnormal Circulatory Stress Responses of Preterm Graduates

Obligate Role for Ketone Body Oxidation in Neonatal Metabolic Homeostasis

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