Enzymatic flux capacities in hummingbird flight muscles: a “one size fits all” hypothesis

2011 ◽  
Vol 89 (10) ◽  
pp. 985-991 ◽  
Author(s):  
M.J. Fernández ◽  
F. Bozinovic ◽  
R.K. Suarez
Keyword(s):  
Energy Metabolism ◽  
Metabolic Regulation ◽  
Metabolic Flux ◽  
Interspecific Variation ◽  
Enzyme Concentration ◽  
Acid Oxidation ◽  
Hovering Flight ◽  
Allosteric Regulator ◽  
Flight Muscles ◽  
Proximate Explanation

Hummingbirds (family Trochilidae) are among the smallest endothermic vertebrates representing an extreme, among birds, in their physiological design. They are unique in their ability to sustain hovering flight, one of the most energetically demanding forms of locomotion. Given that hovering metabolic rate (HMR) in hummingbirds scales allometrically as M0.78(M is mass), we tested the hypothesis that variation in HMR may be correlated with variation in maximal enzyme activities (Vmaxvalues) of key enzymes in glucose and fatty acid oxidation pathways in the flight muscles of four species of hummingbirds ranging in body mass from 4 to 20 g. We also estimated metabolic flux rates from respirometric data obtained during hovering flight. The data are striking in the lack of correlation between Vmaxvalues and flux rates at most steps in energy metabolism, particularly at the hexokinase and carnitine palmitoyltransferase reactions. In the context of hierarchical regulation analysis, this finding suggests that metabolic regulation (resulting from variation in substrate, product, or allosteric regulator concentrations) dominates as the proximate explanation for the interspecific variation in flux. On the other hand, we found no evidence of hierarchical regulation of flux, which results from variation in Vmaxand is based on variation in enzyme concentration [E]. The evolutionary conservation of pathways of energy metabolism suggests that “one size fits all” among hummingbirds.

The life and work of Dermot Hedley (‘Derek’) Williamson (1929–1998)

2001 ◽  
Vol 29 (2) ◽  
pp. 237-240
Author(s):  
R. D. Evans ◽  
M. Stubbs ◽  
G. F. Gibbons ◽  
E. A. Newsholme
Keyword(s):  
Metabolic Pathways ◽  
Metabolic Regulation ◽  
Ketone Body ◽  
Scientific Discovery ◽  
Lipid Synthesis ◽  
Acid Oxidation ◽  
Citation Classic ◽  
Integrated Regulation ◽  
Ketone Body Metabolism

Derek Williamson's scientific career spanned the ‘Golden Age’ of research into metabolic regulation, to which he made an important and sustained contribution. Derek joined Hans Krebs' laboratory at Sheffield University in 1946 and moved to Krebs' MRC Unit in Oxford in 1960. He elaborated an enzymic method for the determination of acetoacetate and 3-hydroxybutyrate [Williamson, Mellanby and Krebs, Biochem. J. (1962) 82, 90–96], which opened up the field of ketone body metabolism and its regulation and became a Citation Classic. Another Citation Classic followed [Williamson, Lund and Krebs, Biochem. J. (1967) 103, 514–527]. He moved with Krebs to the Metabolic Research Laboratory at the Radcliffe Infirmary in 1967, where he blossomed, formulating his ideas about the integrated regulation of metabolic pathways, particularly with regard to fatty acid oxidation, lipid synthesis and ketone body metabolism. His success was illustrated by more than 200 publications. Derek implanted and nurtured a sense of the excitement of scientific discovery in his colleagues and students, and he worked hard to provide a friendly, supportive and encouraging environment. Many lives have been enriched by the privilege of working with him.

scholarly journals A Cybernetic Approach to Modeling Lipid Metabolism in Mammalian Cells

Processes ◽  
2018 ◽  
Vol 6 (8) ◽  
pp. 126 ◽  
Author(s):  
Lina Aboulmouna ◽  
Shakti Gupta ◽  
Mano Maurya ◽  
Frank DeVilbiss ◽  
Shankar Subramaniam ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Metabolic Regulation ◽  
Metabolic Flux ◽  
Optimal Parameter ◽  
Gene Knockout ◽  
Model Parameters ◽  
Mouse Bone Marrow ◽  
Optimization Approach ◽  
Substrate Uptake ◽  
Data Set

The goal-oriented control policies of cybernetic models have been used to predict metabolic phenomena such as the behavior of gene knockout strains, complex substrate uptake patterns, and dynamic metabolic flux distributions. Cybernetic theory builds on the principle that metabolic regulation is driven towards attaining goals that correspond to an organism’s survival or displaying a specific phenotype in response to a stimulus. Here, we have modeled the prostaglandin (PG) metabolism in mouse bone marrow derived macrophage (BMDM) cells stimulated by Kdo2-Lipid A (KLA) and adenosine triphosphate (ATP), using cybernetic control variables. Prostaglandins are a well characterized set of inflammatory lipids derived from arachidonic acid. The transcriptomic and lipidomic data for prostaglandin biosynthesis and conversion were obtained from the LIPID MAPS database. The model parameters were estimated using a two-step hybrid optimization approach. A genetic algorithm was used to determine the population of near optimal parameter values, and a generalized constrained non-linear optimization employing a gradient search method was used to further refine the parameters. We validated our model by predicting an independent data set, the prostaglandin response of KLA primed ATP stimulated BMDM cells. We show that the cybernetic model captures the complex regulation of PG metabolism and provides a reliable description of PG formation.

scholarly journals Acetylation and succinylation contribute to maturational alterations in energy metabolism in the newborn heart

2016 ◽  
Vol 311 (2) ◽  
pp. H347-H363 ◽  
Author(s):  
Arata Fukushima ◽  
Osama Abo Alrob ◽  
Liyan Zhang ◽  
Cory S. Wagg ◽  
Tariq Altamimi ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Energy Metabolism ◽  
Fatty Acid Oxidation ◽  
Glucose Oxidation ◽  
Acid Oxidation ◽  
Amino Acid Synthesis ◽  
Oxidation Rates ◽  
Cardiac Energy Metabolism ◽  
Cardiac Energy ◽  
The Impact

Dramatic maturational changes in cardiac energy metabolism occur in the newborn period, with a shift from glycolysis to fatty acid oxidation. Acetylation and succinylation of lysyl residues are novel posttranslational modifications involved in the control of cardiac energy metabolism. We investigated the impact of changes in protein acetylation/succinylation on the maturational changes in energy metabolism of 1-, 7-, and 21-day-old rabbit hearts. Cardiac fatty acid β-oxidation rates increased in 21-day vs. 1- and 7-day-old hearts, whereas glycolysis and glucose oxidation rates decreased in 21-day-old hearts. The fatty acid oxidation enzymes, long-chain acyl-CoA dehydrogenase (LCAD) and β-hydroxyacyl-CoA dehydrogenase (β-HAD), were hyperacetylated with maturation, positively correlated with their activities and fatty acid β-oxidation rates. This alteration was associated with increased expression of the mitochondrial acetyltransferase, general control of amino acid synthesis 5 like 1 (GCN5L1), since silencing GCN5L1 mRNA in H9c2 cells significantly reduced acetylation and activity of LCAD and β-HAD. An increase in mitochondrial ATP production rates with maturation was associated with the decreased acetylation of peroxisome proliferator-activated receptor-γ coactivator-1α, a transcriptional regulator for mitochondrial biogenesis. In addition, hypoxia-inducible factor-1α, hexokinase, and phosphoglycerate mutase expression declined postbirth, whereas acetylation of these glycolytic enzymes increased. Phosphorylation rather than acetylation of pyruvate dehydrogenase (PDH) increased in 21-day-old hearts, accounting for the low glucose oxidation postbirth. A maturational increase was also observed in succinylation of PDH and LCAD. Collectively, our data are the first suggesting that acetylation and succinylation of the key metabolic enzymes in newborn hearts play a crucial role in cardiac energy metabolism with maturation. Listen to this article’s corresponding podcast at http://ajpheart.podbean.com/e/acetylation-control-of-energy-metabolism-in-newborn-hearts/ .

scholarly journals Substrate oxidation in primary human skeletal muscle cells is influenced by donor age

2020 ◽  
Vol 382 (3) ◽  
pp. 599-608
Author(s):  
Vigdis Aas ◽  
G. Hege Thoresen ◽  
Arild C. Rustan ◽  
Jenny Lund
Keyword(s):  
Skeletal Muscle ◽  
Oleic Acid ◽  
Energy Metabolism ◽  
Substrate Oxidation ◽  
Pyruvate Dehydrogenase Kinase ◽  
Acid Oxidation ◽  
Acid Uptake ◽  
Donor Age ◽  
Human Myotubes ◽  
Human Skeletal Muscle Cells

AbstractPrimary human myotubes represent an alternative system to intact skeletal muscle for the study of human diseases related to changes in muscle energy metabolism. This work aimed to study if fatty acid and glucose metabolism in human myotubes in vitro were related to muscle of origin, donor gender, age, or body mass index (BMI). Myotubes from a total of 82 donors were established from three different skeletal muscles, i.e., musculus vastus lateralis, musculus obliquus internus abdominis, and musculi interspinales, and cellular energy metabolism was evaluated. Multiple linear regression analyses showed that donor age had a significant effect on glucose and oleic acid oxidation after correcting for gender, BMI, and muscle of origin. Donor BMI was the only significant contributor to cellular oleic acid uptake, whereas cellular glucose uptake did not rely on any of the variables examined. Despite the effect of age on substrate oxidation, cellular mRNA expression of pyruvate dehydrogenase kinase 4 (PDK4) and peroxisome proliferator–activated receptor gamma coactivator 1 alpha (PPARGC1A) did not correlate with donor age. In conclusion, donor age significantly impacts substrate oxidation in cultured human myotubes, whereas donor BMI affects cellular oleic acid uptake.

scholarly journals Reduced Liver-Specific PGC1a Increases Susceptibility for Short-Term Diet-induced Weight Gain in Male Mice

2020 ◽  
Author(s):  
E. Matthew Morris ◽  
Roberto D. Noland ◽  
Michael E. Ponte ◽  
Michelle L. Montonye ◽  
Julie A. Christianson ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Weight Gain ◽  
Energy Metabolism ◽  
Energy Balance ◽  
Fatty Acid Oxidation ◽  
Positive Energy ◽  
Acid Oxidation ◽  
Male Mice ◽  
Short Term

AbstractCentral integration of peripheral neural signals is one mechanism by which systemic energy homeostasis is regulated. Previous work described increased acute food intake following chemical reduction of hepatic fatty acid oxidation and ATP levels, which was prevented by common hepatic branch vagotomy (HBV). However, possible offsite actions of the chemical compounds confound the precise role of liver energy metabolism. Herein, we used a liver-specific PGC1a heterozygous (LPGC1a) mouse model, with associated reductions in mitochondrial fatty acid oxidation and respiratory capacity, to assess the role of liver energy metabolism in systemic energy homeostasis. LPGC1a male mice have 70% greater high-fat/high-sucrose (HFHS) diet-induced weight gain and 35% greater positive energy balance compared to wildtype (WT) (p<0.05). The greater energy balance was associated with altered feeding behavior and lower activity energy expenditure during HFHS in LPGC1a males. Importantly, no differences in HFHS-induced weight gain or energy metabolism was observed between female WT and LPGC1a mice. WT and LPGC1a mice underwent sham or HBV to assess whether vagal signaling was involved in HFHS-induced weight gain of male LPGC1a mice. HBV increased HFHS-induced weight gain (85%, p<0.05) in male WT, but not LPGC1a mice. As above, sham LPGC1a males gain 70% more weight during short-term HFHS feeding than sham WT (p<0.05). These data demonstrate a sexspecific role of reduced liver energy metabolism in acute diet-induced weight gain, and the need of more nuanced assessment of the role of vagal signaling in short-term diet-induced weight gain.Key Points SummaryReduced liver PGC1a expression results in reduced mitochondrial fatty acid oxidation and respiratory capacity in male mice.Male mice with reduced liver PGC1a expression (LPGC1a) demonstrate greater short-term high-fat/high-sucrose diet-induced weight gain compared to wildtype.Greater positive energy balance during HFHS feeding in male LPGC1a mice is associated with altered food intake patterns and reduced activity energy expenditure.Female LPGC1a mice do not have differences in short-term HFHS-induced body weight gain or energy metabolism compared to wildtype.Disruption of vagal signaling through common hepatic branch vagotomy increases short-term HFHS-induced weight gain in male wildtype mice, but does not alter male LPGC1a weight gain.

Energy substrates for flight in the blister beetle Decapotoma lunata (Meloidae)

1995 ◽  
Vol 198 (6) ◽  
pp. 1423-1431 ◽  
Author(s):  
L Auerswald ◽  
G Gäde
Keyword(s):  
Locusta Migratoria ◽  
Rest Period ◽  
Fresh Mass ◽  
Simultaneous Increase ◽  
Acid Oxidation ◽  
Flight Period ◽  
Migratory Locust ◽  
Flight Muscles ◽  
Carbohydrate Levels ◽  
Blister Beetle

We investigated the substrates for flight in the blister beetle Decapotoma lunata by (a) establishing the patterns of maximum activities of enzymes of various metabolic pathways in the flight muscles, (b) measuring the respiratory rates of flight muscle mitochondria with various substrates and (c) determining metabolite concentrations in flight muscles and haemolymph during a flight period of up to 17 min and over a rest period of up to 2 h following 10 min of flight. Activities of enzymes involved in proline metabolism (glutamate dehydrogenase, alanine aminotransferase, malic enzyme) were much higher in the blister beetle than in the migratory locust Locusta migratoria, whereas the activity of an enzyme responsible for fatty acid oxidation (ss-hydroxyacyl-CoA dehydrogenase) was much lower. Mitochondria from flight muscles of D. lunata have a much higher capacity to oxidise proline than those from L. migratoria. The glycerophosphate shuttle, however, was equally active in both insects. Whereas lipid levels in the haemolymph did not change significantly during flight, there was a continuous decrease in proline levels from 34.8 to 6.6 micromol ml-1 and a simultaneous increase in alanine concentration; carbohydrate levels dropped from 20.1 to 12.2 mg ml-1. In the thorax (flight muscles), glycogen levels were diminished between 2 and 17 min of flight from 25.9 to 6.7 micromol glucose equivalents g-1 fresh mass. Proline concentration dropped continuously from an initial 49.5 to 10.1 micromol g-1 fresh mass, whereas alanine levels rose concomitantly from 2.9 to 17.3 micromol g-1 fresh mass. After termination of a 10 min flight, pre-flight levels of proline in the haemolymph and flight muscles were only re-established after 2 h. In contrast, glycogen levels in the thorax were restored after 1 h. Using the rates of utilisation of substrates during the first 10 min of flight to calculate rates of oxygen consumption during flight, it was shown that overall haemolymph substrates contribute 75 % and those of the flight muscles only 25 %. Although proline is an important substrate for flight in D. lunata, its role is secondary to that of carbohydrates. This type of substrate usage is different from that of the Colorado potato beetle Leptinotarsa decemlineata or the African fruit beetle Pachnoda sinuata, in which carbohydrates are of negligible or only slight importance, respectively.

Abstract 15649: Pharmacological Inhibition of Aldose Reductase by AT001 Prevents Abnormal Cardiac Energy Metabolism and Improves Heart Function in an Animal Model of Diabetic Cardiomyopathy

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Keshav Gopal ◽  
Qutuba Karwi ◽  
Seyed Amirhossein Tabatabaei Dakhili ◽  
Riccardo Perfetti ◽  
Ravichandran Ramasamy ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Energy Metabolism ◽  
Fatty Acid Oxidation ◽  
Diabetic Cardiomyopathy ◽  
Acid Oxidation ◽  
Cardiac Energetics ◽  
Cardiac Efficiency ◽  
Oxidation Rates ◽  
Cardiac Energy Metabolism ◽  
Cardiac Energy

Introduction: Diabetic Cardiomyopathy (DCM) is a major cause of death in people with type 2 diabetes (T2D). Alterations in cardiac energy metabolism including increased fatty acid oxidation rates and reduced glucose oxidation rates are key contributing factors to the development of DCM. Studies have shown that Aldose Reductase (AR), an enzyme activated under hyperglycemic conditions, can modulate myocardial glucose and fatty acid oxidation, and promotes cardiac dysfunction. Hypothesis: Pharmacological inhibition of AR using a next-generation inhibitor AT-001, can mitigate DCM in mice by modulating cardiac energy metabolism and improving cardiac efficiency. Methods: Male human AR overexpressing (hAR-Tg) and C57BL/6J (Control) mice were subjected to experimental T2D (high-fat diet [60% kcal from lard] for 10-wk with a single intraperitoneal streptozotocin injection of 75 mg/kg) and treated for the last 3-wk with AT-001 (40mg/kg/day) or vehicle via oral gavage. Cardiac energy metabolism and in vivo cardiac function were assessed via isolated working heart perfusions and ultrasound echocardiography, respectively. Results: AT-001 treatment significantly improved cardiac energetics in a murine model of DCM (hAR-Tg mice with T2D). Particularly, AT-001-treated mice exhibited decreased cardiac fatty acid oxidation rates compared to the vehicle-treated mice (342 ± 53 vs 964 ± 130 nmol/min/g dry wt.). Concurrently, there was a significant decrease in cardiac oxygen consumption in the AT-001-treated compared to the vehicle-treated mice (41 ± 12 vs 60 ± 11 μmol/min/g dry wt.), suggesting increased cardiac efficiency. Furthermore, treatment with AT-001 prevented cardiac structural and functional abnormalities present in DCM, including diastolic dysfunction as reflected by an increase in the tissue Doppler E’/A’ ratio and decrease in E/E’ ratio. Moreover, AT-001 treatment prevented cardiac hypertrophy as reflected by a decrease in LV mass in AT-001-treated mice. Conclusions: AR inhibition with AT-001 prevents cardiac structural and functional abnormalities in a mouse model of DCM, and normalizes cardiac energetics by shifting cardiac metabolism towards a non-diabetic metabolic state.

Barth Syndrome-Related Cardiomyopathy is Associated with a Reduction in Myocardial Glucose Oxidation

2021 ◽  
Author(s):  
Amanda A. Greenwell ◽  
Keshav Gopal ◽  
Tariq Altamimi ◽  
Christina T. Saed ◽  
Faqi Wang ◽  
...  
Keyword(s):  
Heart Failure ◽  
Energy Metabolism ◽  
Glucose Oxidation ◽  
Genetic Disorder ◽  
Left Ventricular ◽  
Barth Syndrome ◽  
Acid Oxidation ◽  
Functional Impairments ◽  
Myocardial Energy Metabolism ◽  
Oxidation Rates

Heart failure presents as the leading cause of infant mortality in individuals with Barth syndrome (BTHS), a rare genetic disorder due to mutations in the tafazzin (TAZ) gene affecting mitochondrial structure and function. Investigations into the perturbed bioenergetics in the BTHS heart remain limited. Hence, our objective was to identify the potential alterations in myocardial energy metabolism and molecular underpinnings that may contribute to the early cardiomyopathy and heart failure development in BTHS. Cardiac function and myocardial energy metabolism were assessed via ultrasound echocardiography and isolated working heart perfusions, respectively, in a mouse model of BTHS (doxycycline-inducible Taz knockdown (TazKD) mice). In addition, we also performed mRNA/protein expression profiling for key regulators of energy metabolism in hearts from TazKD mice and their wild-type (WT) littermates. TazKD mice developed hypertrophic cardiomyopathy as evidenced by increased left ventricular anterior and posterior wall thickness, as well as increased cardiac myocyte cross sectional area, though no functional impairments were observed. Glucose oxidation rates were markedly reduced in isolated working hearts from TazKD mice compared to their WT littermates in the presence of insulin, which was associated with decreased pyruvate dehydrogenase activity. Conversely, myocardial fatty acid oxidation rates were elevated in TazKD mice, whereas no differences in glycolytic flux or ketone body oxidation rates were observed. Our findings demonstrate that myocardial glucose oxidation is impaired prior to the development of overt cardiac dysfunction in TazKD mice, and may thus represent a pharmacological target for mitigating the development of cardiomyopathy in BTHS.

Abstract 13921: Targeting Receptor-Interacting Protein 140 to Modulate Energy Metabolism in the Failing Heart

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Tsunehisa Yamamoto ◽  
Elizabeth Pruzinsky ◽  
Kirill Batmanov ◽  
Daniel P Kelly
Keyword(s):  
Skeletal Muscle ◽  
Energy Metabolism ◽  
Systolic Function ◽  
Systolic Dysfunction ◽  
Acid Oxidation ◽  
Peroxisome Proliferator ◽  
Interacting Protein ◽  
Failing Heart ◽  
Metabolic Genes ◽  
Cardiac Energy

The nuclear receptors, peroxisome proliferator-activated receptors (PPARs), estrogen-related receptors (ERRs), and their co-regulator PPARγ coactivator-1α (PGC-1α), control postnatal cardiac mitochondrial biogenesis and energy metabolism. During the development of heart failure (HF), the activity of PGC-1/PPAR/ERR is reduced resulting in diminished capacity for fatty acid oxidation (FAO) and ATP production potentially contributing to an “energy-starved” state that contributes to progression of HF. Receptor-Interacting protein 140 (RIP140) serves as a co-repressor of PGC-1/PPAR/ERR in skeletal muscle and adipose tissue. We hypothesized that RIP140 represses cardiac energy metabolism in the normal and failing heart. Accordingly, we targeted Nrip1 (encoding RIP140) using a muscle creatinine kinase (MCK)-driven Cre recombinase to generate striated muscle-specific RIP140 knockout (msRIP140 KO) mice. msRIP140 KO mice appeared normal at baseline with no difference in survival or cardiac systolic function compared to littermate controls. RNA-sequence analysis demonstrated that the expression of genes involved in a wide array of mitochondrial energy metabolic pathways including FAO, tricarboxylic acid (TCA) cycle, oxidative phosphorylation (OXPHOS), and branched-chain amino acid (BCAA) degradation pathways were upregulated in msRIP140 KO ventricles, and in msRIP140 KO skeletal muscle. msRIP140 KO mice exhibited significantly less cardiac hypertrophy and diastolic dysfunction in response to chronic pressure overload. Next, cardiac-specific (cs) RIP140 KO mice were generated and subjected to transverse aortic constriction/apical myocardial infarction surgery (TAC/MI), an established HF model. csRIP140 KO mice exhibited less cardiac remodeling and systolic dysfunction compared to littermate controls, along with less downregulation of metabolic genes and induction of cardiac stress ( Nppa and Nppb ) and fibrosis response markers ( Tgfb2 and Col3a1 ). We conclude that RIP140 serves as a global co-repressor of cardiac energy metabolic genes in the adult heart and that modulation of RIP140 activity could prove to be a novel therapeutic approach for HF.

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