Metabolic Control Mechanisms Research Articles

Metabolic setpoint control mechanisms in different physiological systems at rest and during exercise

Using a number of different homeostatic control mechanisms in the brain and peripheral physiological systems, metabolic activity is continuously regulated at rest and during exercise to prevent catastrophic system failure. Essential for the function of these regulatory processes are baseline “setpoint” levels of metabolic function, which can be used to calculate the level of response required for the maintenance of system homeostasis after system perturbation, and to which the perturbed metabolic activity levels are returned to at the end of the regulatory process. How these setpoint levels of all the different metabolic variables in the different peripheral physiological systems are created and maintained, and why they are similar in different individuals, has not been well explained. In this article, putative system regulators of metabolic setpoint levels are described. These include that: (i) innate setpoint values are stored in a certain region of the central nervous system, such as the hypothalamus; (ii) setpoint values are created and maintained as a response to continuous external perturbations, such as gravity or “zeitgebers”, (iii) setpoint values are created and maintained by complex system dynamical activity in the different peripheral systems, where setpoint levels are regulated by the ongoing feedback control activity between different peripheral variables; (iv) human anatomical and biomechanical constraints contribute to the creation and maintenance of metabolic setpoints values; or (v) a combination of all these four different mechanisms occurs. Exercise training and disease processes can affect these metabolic setpoint values, but the setpoint values are returned to pre-training or pre-disease levels if the training stimulus is removed or if the disease process is cured. Further work is required to determine what the ultimate system regulator of metabolic setpoint values is, why some setpoint values are more stringently protected by homeostatic regulatory mechanisms than others, and the role of conscious decision making processes in determining the regulation of metabolic setpoint values.

METABOLISM: INTERFACE BETWEEN INTEGRATIVE PHYSIOLOGY AND FUNCTIONAL GENOMICS

Edited by Kenneth B. Storey Wiley Press (2004) pp. 616. ISBN 0-471-41090-X (hbk) £ 76.50/ 108.40 (hbk) ![Figure][1] Metabolism is the principal and indispensable manifestation of life that supports the life-long homeostasis of organisms. It comprises a number of

Regulatory analysis of amino acid synthesis pathway in Escherichia coli: aspartate family

Proteins have various compositions of twenty specific naturally occurring amino acids. In spite of their importance in cellular metabolism, biosynthesis mechanisms, changing control conditions, and affection of effectors are not clearly understood yet. So we have made an effort to elucidate the details of metabolic control mechanisms in amino acid synthesis pathways through examining an extensive database search. In this study, we have newly constructed six amino acid biosynthesis pathways including aspartate, asparagine, methionine, threonine, isoleucine, and lysine, which we call the aspartate family. They contain the major reaction mechanisms, which inhibitory control loops and activating compounds. Moreover, we have tried to collect all of the effectors which might affect the aspartate family biosynthetic networks.

Microvasculature in acute myocardial ischemia: part I: evolving concepts in pathophysiology, diagnosis, and treatment.

Microvasculature in acute myocardial ischemia: part I: evolving concepts in pathophysiology, diagnosis, and treatment.

Control of metabolic energy by space systems. Part 1: Theoretical reports of space flow structure and function

In past papers, a notion emerged that space had elements common to the energy of atomic shells to which it could flow by paths to control metabolic energy of animate systems. This paper examines several authors on the structure and function of space energy wave bundle flows seeking mechanisms for metabolic control. The application of time to these waves provides two compartments, time symmetric and time asymmetric, respectively imaginary and real, in a sensitively balanced state as part of a specific system from space to orbits. Disturbance to the balance, where minimal, results in a reflection outside the system to the heat bath consistent with physiology. Arbitrarily more than minimal, results in pathology. A black-hole-like monitor maintains the balance in alliance with a multi-system space stream, the meridian of traditional Chinese medicine. This macroscopic state is now consistent with manipulation using conventional electronics, by way of remedy.

METABOLISMO RESPIRATÓRIO EM RELAÇÃO À TEMPERATURA E FOTOPERÍODO EM Oxidus gracilis (Diplopoda, Polydesmida, Strongylosomidae)

O metabolismo respiratório do diplópodo Oxidus gracilis foi pesquisado tendo como referência os parâmetros temperatura e fotoperíodo, buscando, no primeiro
 caso, detectar eventuais ajustes metabólicos compensatórios para variações da temperatura e, no segundo, as alterações decorrentes do ritmo de atividade no ciclo de 24 horas. Nos dois casos foi empregado o microrespirômetro de Warburg, usando-se frascos de 20 ml de capacidade volumétrica, aos quais foram adicionados 0,3 ml de solução de KOH a 14% para a absorção do CO2 expirado. Os testes com temperatura foram feitos a 5°, 10°, 15°, 20°, 25° 30°, 35° e 40°C e os de ritmos metabólicos foram feitos somente a
 25°C, durante 24 horas; com medidas respirométricas a cada 3 horas. Os dados foram apresentados como taxas respiratórias traduzidas em m l O2.g(vivo)-1.hora-1. Os
 resultados indicaram a ocorrência de uma estabilização metabólica a na curva R-T (Respiração-Temperatura), tendo sido detectados "platôs" entre as temperaturas de 20 e 25°, 25 e 30°, 30 e 35°, bem como entre 20 e 30°, 20 e 35°, 25 e 35° e entre 15 e 35°C. Abaixo de 15°C, ou seja, a 10° e 5°C os diplópodos ficaram imobilizados pelo frio em situação de narcose reversível. No extremo superior, entre 35° e 40°C, foi detectado o menor índice de variação metabólica (Q10=0,52). A 40°C os diplópodos apresentaram
 sinais de torpor pelo calor. Nos experimentos de ritmos de 24 horas as taxas respiratórias de Oxidus gracilis foram mais altas à noite que durante o dia, confirmando as
 observações largamente encontradas na literatura sobre os hábitos comportamentais noturnos dos diplópodos em geral . Tais hábitos sugerem uma maior economia energética
 e, consequentemente, maior controle da água perdida pela desidratação.

Happily at Work

Happily at Work

Diurnal variations in human urinary excretion of nicotinamide catabolites: effects of stress on the metabolism of nicotinamide

More than 500 enzymes need niacin coenzymes. Therefore, elucidation of the control mechanisms of coenzyme metabolism is fundamentally important. NAD(+) is involved in ATP production. Because energy expenditure is generally higher during the day than at night, we investigated whether the metabolism of nicotinamide changes at various times of day and whether stress affects nicotinamide metabolism. Twelve women were housed in the same facility and followed the same schedule for activities of daily living for 12 d. Urinary outputs were collected during 5 specific periods to investigate diurnal variations in nicotinamide metabolism. The effects of cold exposure (physical stress), having to perform arithmetic calculations (mental stress), and dark exposure (emotional stress) on nicotinamide metabolism were investigated. A diurnal variation in the nicotinamide metabolites N(1)-methylnicotinamide, N(1)-methyl-2-pyridone-5-carboxamide, and N(1)-methyl-4-pyridone-3-carboxamide was observed. Of the stresses studied, cold exposure significantly increased the urinary excretory outputs of the nicotinamide metabolites. Diurnal variations in nicotinamide metabolism were found in these women. The biosynthesis of nicotinamide from tryptophan seemed to be increased by cold exposure.

Distributed Client-Server System Architecture for High Performance Simulations on Genomic Object Net

As studies of genome analysis proceed, information processing of biopathway in vivo becomes one of the most important topics in bioinformatics. By processing biopathway information, medical development and/or appropriate treatments would be possible in the future; that is, it could be a great help for us. We have developed Genomic Object Net (GON), with which we simulated biopathway models such as metabolic pathways, signal transduction, and gene control mechanisms, based on hybrid fucntional Petri net with extension (HFPNe) [2, 3]. In GON, places and transitions, are converted to biological/medical terms. It also provides colorful viewpoints to simulations by GON with “Visualizer [1]”, the presentation tool for XML documents into visible state. However, GON is not good for simulation with super computers at remote locations despite growing needs of high-speed work to process complex pathways. Besides, users have to download the latest version, each time they want to use it. Thus, the purpose of the paper is to set a goal to build a client-server system that utilizes distributed objects, and that make it possible to control simulations at the central server and to share information.

Mechanism of metabolic control. Target of rapamycin signaling links nitrogen quality to the activity of the Rtg1 and Rtg3 transcription factors.

De novo biosynthesis of amino acids uses intermediates provided by the TCA cycle that must be replenished by anaplerotic reactions to maintain the respiratory competency of the cell. Genome-wide expression analyses in Saccharomyces cerevisiae reveal that many of the genes involved in these reactions are repressed in the presence of the preferred nitrogen sources glutamine or glutamate. Expression of these genes in media containing urea or ammonia as a sole nitrogen source requires the heterodimeric bZip transcription factors Rtg1 and Rtg3 and correlates with a redistribution of the Rtg1p/Rtg3 complex from a predominantly cytoplasmic to a predominantly nuclear location. Nuclear import of the complex requires the cytoplasmic protein Rtg2, a previously identified upstream regulator of Rtg1 and Rtg3, whereas export requires the importin-beta-family member Msn5. Remarkably, nuclear accumulation of Rtg1/Rtg3, as well as expression of their target genes, is induced by addition of rapamycin, a specific inhibitor of the target of rapamycin (TOR) kinases. We demonstrate further that Rtg3 is a phosphoprotein and that its phosphorylation state changes after rapamycin treatment. Taken together, these results demonstrate that target of rapamycin signaling regulates specific anaplerotic reactions by coupling nitrogen quality to the activity and subcellular localization of distinct transcription factors.

An intervention resembling caloric restriction prolongs life span and retards aging in yeast.

The yeast Saccharomyces cerevisiae has a finite life span that is measured by the number of daughter cells an individual produces. The 20 genes known to determine yeast life span appear to function in more than one pathway, implicating a variety of physiological processes in yeast longevity. Less attention has been focused on environmental effects on yeast aging. We have examined the role that nutritional status plays in determining yeast life span. Reduction of the glucose concentration in the medium led to an increase in life span and to a delay in appearance of an aging phenotype. The increase in life span was the more extensive the lower the glucose levels. Life extension was also elicited by decreasing the amino acids content of the medium. This suggests that it is the decline in calories and not a particular nutrient that is responsible, in striking similarity to the effect on aging of caloric restriction in mammals. The caloric restriction effect did not require the induction of the retrograde response pathway, which signals the functional status of the mitochondrion and determines longevity. Furthermore, deletion of RTG3, a downstream mediator in this pathway, and caloric restriction had an additive effect, resulting in the largest increase (123%) in longevity described thus far in yeast. Thus, retrograde response and caloric restriction operate along distinct pathways in determining yeast longevity. These pathways may be exclusive, at least in part. This provides evidence for multiple mechanisms of metabolic control in yeast aging. Inasmuch as caloric restriction lowers blood glucose levels, this study raises the possibility that reduced glucose alters aging at the cellular level in mammals.

Adenosine is not responsible for local metabolic control of coronary blood flow in dogs during exercise.

The purpose of this investigation was to quantitatively evaluate the role of adenosine in coronary exercise hyperemia. Dogs (n = 10) were chronically instrumented with catheters in the aorta and coronary sinus, and a flow probe on the circumflex coronary artery. Cardiac interstitial adenosine concentration was estimated from arterial and coronary venous plasma concentrations using a previously tested mathematical model. Coronary blood flow, myocardial oxygen consumption, heart rate, and aortic pressure were measured at rest and during graded treadmill exercise with and without adenosine receptor blockade with either 8-phenyltheophylline (8-PT) or 8-p-sulfophenyltheophylline (8-PST). In control vehicle dogs, exercise increased myocardial oxygen consumption 4.2-fold, coronary blood flow 3.8-fold, and heart rate 2.5-fold, whereas mean aortic pressure was unchanged. Coronary venous plasma adenosine concentration was little changed with exercise, and the estimated interstitial adenosine concentration remained well below the threshold for coronary vasodilation. Adenosine receptor blockade did not significantly alter myocardial oxygen consumption or coronary blood flow at rest or during exercise. Coronary venous and estimated interstitial adenosine concentration did not increase to overcome the receptor blockade with either 8-PT or 8-PST as would be predicted if adenosine were part of a high-gain, negative-feedback, local metabolic control mechanism. These results demonstrate that adenosine is not responsible for local metabolic control of coronary blood flow in dogs during exercise.

Lactate metabolism during exercise: analysis by an integrative systems model.

To provide a framework for quantitative analysis of metabolic and transport processes associated with ATP production during exercise, we adapted a recently developed model that links cellular metabolism and its control to whole body responses at rest. The enhanced model is based on dynamic mass balances for glycogen, glucose, pyruvate (PY), lactate (LA), O(2), and CO(2) and is solved numerically to simulate responses to acute (<20 min), moderate exercise (i.e., below the LA threshold, less than approximately 60% maximal rate of O(2) uptake). Simulations of responses to a step change in muscle ATP turnover predict substrate changes in muscle, splanchnic, and other tissues compartments, as well as changes in other metabolites (e.g., NADH, ADP) whose reactions are coupled to the main reactions. Even a significant (64%) decrease in muscle O(2) concentration (C(m, O(2))) did not affect muscle O(2) consumption. Model simulations of moderate exercise show that 1) muscle oxygenation is sufficient (C(m, O(2)) >2 mM) even during the transient state; 2) transient increases in concentration of muscle LA and arterial concentration of LA are associated with increases in glycolysis from increases in ADP/ATP and in LA production associated with a rise in NADH/NAD; 3) muscle ADP/ATP reaches a higher steady state that stimulates glycolysis, glycogenolysis, and oxidative phosphorylation to match the ATP demand; and 4) muscle NADH/NAD reaches a lower steady state that stimulates LA oxidation. It is suggested that the continuous stimulation of ATP synthesis processes during moderate exercise is mainly due to a higher ADP/ATP, not to a higher NADH/NAD. Critical measurements needed to quantify metabolic control mechanisms are identified.

Effect of sevoflurane and desflurane on the myogenic constriction and flow-induced dilation in rat coronary arterioles.

Determinants of myocardial blood flow distribution include metabolic, myogenic, endothelial, and neurohumoral control mechanisms. The authors studied the effect of sevoflurane and desflurane on the myogenic and endothelial mechanisms. Wistar rat subepicardial microvessels, approximately 100 microm in diameter, were monitored for diameter changes in vitro using a video detection system. Myogenic vasomotion was studied by varying the intraluminal pressure from 10 mmHg to 120 mmHg. Flow-induced, endothelium-dependent dilation was evaluated in U46619-preconstricted vessels by varying the pressure gradient across the isolated vessel from 10 mmHg to 80 mmHg, while maintaining the midpoint luminal pressure constant at 40 mmHg to avoid myogenic effects. Myogenic and flow-induced vasomotion both were studied in the presence of sevoflurane, 1 or 2 minimum alveolar concentration (MAC) (MAC is a unit of inhalational anesthetic potency), desflurane, 1 or 2 MAC, or no anesthetic (control). Myogenic constriction was shown above intraluminal pressures of 70 mmHg. Myogenic constriction was unchanged by sevoflurane, 1 MAC (P = 0.24), but was mildly enhanced by sevoflurane, 2 MAC (P < 0.05), or desflurane, 1 (P < 0.05) or 2 MAC (P < 0.01). Flow-induced dilation was shown over the pressure gradient range of 10-80 mmHg. Flow-induced dilation was not altered significantly by sevoflurane, 1 or 2 MAC (P > 0.3 each), but was significantly attenuated by desflurane, 1 or 2 MAC (P < 0.001 each). Sevoflurane maintains myogenic and endothelial determinants of myocardial blood flow distribution. Conversely, desflurane attenuates endothelium-dependent flow-induced dilation while mildly enhancing myogenic constriction.

Classification and Sensitivity Analysis of a Proposed Primary Metabolic Reaction Network forStreptomyces Lividans

Constructing a metabolic flux analysis model is in principle fairly straightforward. However, there are a number of mathematical pitfalls. First, dependent reactions are a recurring problem and, second, the choice of reactions to measure may not be straightforward. A method for systematic identification of dependent reactions and a thorough reactions classification procedure is presented. A well-defined stoichiometric presentation can provide significant insight into metabolic control mechanisms. Two methods for analyzing the impact of perturbations in the measured fluxes on the remaining metabolism and the impact of changes in biomass composition on the calculated metabolic reactions is developed. A metabolic reaction network proposed forStreptomyces lividansis used as an example to demonstrate the outlined analysis. It is concluded that oxygen utilization has the highest influence on the pathway fluxes and that realistic perturbations in the biomass composition do not significantly alter the flux patterns.

Exercise biochemistry as an approach to the study of intermediary metabolism

The study of metabolism during exercise addresses all major aspects of metabolic pathways, their distribution between tissues as well as their metabolic control mechanisms. An experiment in teaching metabolism from this point of view, using student-presented seminars, is described. This approach turned out to be a popular and successful alternative to lecture-based teaching.

Is Calcium a Coronary Vasoconstrictor In Vivo?

Calcium produces constriction in isolated coronary vessels and in the coronary circulation of isolated hearts, but the importance of this mechanism in vivo remains controversial. The left anterior descending coronary arteries of 20 anesthetized dogs whose chests had been opened were perfused at 80 mmHg. Myocardial segmental shortening was measured with ultrasonic crystals and coronary blood flow with a Doppler flow transducer. The coronary arteriovenous oxygen difference was determined and used to calculate myocardial oxygen consumption and the myocardial oxygen extraction ratio. The myocardial oxygen extraction ratio served as an index of effectiveness of metabolic vasodilation. Data were obtained during intracoronary infusions of CaCl2 (5, 10, and 15 mg/min) and compared with those during intracoronary infusions of dobutamine (2.5, 5.0, and 10.0 microg/min). CaCl2 caused dose-dependent increases in segmental shortening, accompanied by proportional increases in myocardial oxygen consumption. Although CaCl2 also increased coronary blood flow, these increases were less than proportional to those in myocardial oxygen consumption, and therefore the myocardial oxygen extraction ratio increased. Dobutamine caused dose-dependent increases in segmental shortening and myocardial oxygen consumption that were similar in magnitude to those caused by CaCl2. In contrast to CaCl2, however, the accompanying increases in coronary blood flow were proportional to the increases in myocardial oxygen consumption, with the result that the myocardial oxygen extraction ratio remained constant. Calcium has a coronary vasoconstricting effect and a positive inotropic effect in vivo. This vasoconstricting effect impairs coupling of coronary blood flow to the augmented myocardial oxygen demand by metabolic vascular control mechanisms. Dobutamine is an inotropic agent with no apparent direct action on coronary resistance vessels in vivo.

Modifications of Intracellular Calcium Release Channels and Calcium Mobilization Following 70% Hepatectomy

The aim of this study was to investigate the properties of ryanodine and IP3receptors in regenerating liver following 70% hepatectomy, and to evaluate the hepatic Ca2+distribution and mobilization during this process. Specific [3H]ryanodine and [3H]IP3binding to hepatic smooth endoplasmic reticulum membranes, as well as subcellular Ca2+determination by atomic absorption flame photometry and Ca2+mobilization by INDO-1 AM spectrofluorescence in hepatocytes, was performed in regenerating livers after surgical 70% hepatectomy. Incorporation of14C amino acids into proteins and of32P into phospholipids was done in subcellular fractions. Ryanodine receptorKdpresented a dramatic increase after 12 h of surgery and remained high up to 2 days of treatment. IP3receptorBmaxshowed a significant augmentation starting at 6 h after hepatectomy and returning to normal values after 1 week. Cytosolic total calcium content decreased from 12 h until 4 days after hepatectomy whereas the microsomal and mitochondrial total calcium increased at 1 and 2–4 days of liver regeneration, which coincided with the differential turnover of proteins and phospholipids in these fractions. ATP-induced Ca2+transients in hepatocytes of 24-h-hepatectomized rats confirmed the altered sensitivity of the ryanodine receptor toward its ligand, since 10 times more ryanodine was necessary to alter the ATP-induced Ca2+transient. The data support the notion that the calcium release channels are targets of mechanisms of metabolic control during the proliferative response following 70% hepatectomy and might be part of the modified intracellular Ca2+dynamics during liver regeneration.

Carbohydrate supplements to the callus culture medium modify the growth of potato tuber moth larvae feeding on Lycopersicon chmielewskii callus

Lycopersicon esculentum and L. chmielewskii are respectively susceptible and resistant to the potato tuber moth (Phthorimaea operculella Zeller) in the field. Feeding bioassays were conducted with the herbivore caterpillars reared on callus derived from both tomato species and grown in vitro, and the influence of carbohydrate supplements to the callus culture medium, on the insect's feeding behavior was investigated. Newly‐hatched larvae fed with L. esculentum or L. chmielewskii callus raised on a medium with 88 mM sucrose, reached a weight of 12–15 mg and 1.5–3.0 mg, respectively, within 9 days. Restriction of larval weight increase in insects reared on L. chmielewskii callus, disappeared when the host tissue was transferred 24 h prior to the callus‐insect assay to a medium supplemented with 264 mM of either sucrose, glucose, fructose or mannose. The capability of L. chmielewskii callus to restrict growth of larvae was restored in host tissue retransferred from a medium with 264 mM sucrose to a 24‐h incubation on one supplemented with 264 mM of either mannitol, sorbitol, glycerol or myo‐inositol, before the callus‐insect bioassay. The larval growth response remained unaltered by callus incubated on a medium with 264 mM xylose. The ameliorating effect on insect growth of high sucrose in the callus medium was not due to sucrose as an ingredient of the insect's diet. The diverse response of L. chmielewskii callus, and its dependence on the type of carbohydrate in the medium, rule out effects of these substances as nonspecific medium osmotica. The swift callus responses to carbohydrates (within hours of a change in medium composition), as reflected in the insect's growth, were not accompanied by visible morphological variations in the host tissue. We suggest that suppression by high levels of exogenously applied saccharides and derepression by exogenous polyols and myo‐inositol of the impedement to growth of the potato tuber moth larva, reflect the existence in L. chmielewskii of a carbon metabolic control mechanism of gene expression whose products affect insect growth.

Nitric Oxide Modulation of Erythropoiesis in Rats

To the Editor: We have read with interest Ponka's article[1][1] reviewing distinct control mechanisms of iron metabolism and heme synthesis in erythroid cells. Erythroid cell growth and differentiation may be regulated by many autocrine and paracrine factors secreted by progenitor cells and other