Metabolomics of aerobic metabolism in mice selected for increased maximal metabolic rate

Maximal aerobic metabolic rate (MMR) is an important physiological and ecological variable that sets an upper limit to sustained, vigorous activity. How the oxygen cascade from the external environment to the mitochondria may affect MMR has been the subject of much interest, but little is known about the metabolic profiles that underpin variation in MMR. We tested how seven generations of artificial selection for high mass-independent MMR affected metabolite profiles of two skeletal muscles (gastrocnemius and plantaris) and the liver. MMR was 12.3% higher in mass selected for high MMR than in controls. Basal metabolic rate was 3.5% higher in selected mice than in controls. Artificial selection did not lead to detectable changes in the metabolic profiles from plantaris muscle, but in the liver amino acids and tricarboxylic acid cycle (TCA cycle) metabolites were lower in high-MMR mice than in controls. In gastrocnemius, amino acids and TCA cycle metabolites were higher in high-MMR mice than in controls, indicating elevated amino acid and energy metabolism. Moreover, in gastrocnemius free fatty acids and triacylglycerol fatty acids were lower in high-MMR mice than in controls. Because selection for high MMR was associated with changes in the resting metabolic profile of both liver and gastrocnemius, the result suggests a possible mechanistic link between resting metabolism and MMR. In addition, it is well established that diet and exercise affect the composition of fatty acids in muscle. The differences that we found between control lines and lines selected for high MMR demonstrate that the composition of fatty acids in muscle is also affected by genetic factors.     

Practical limits on the maximal speed of solution exchange for patch clamp experiments.

Studying ligand-gated ion channels often requires the ability to change solutions quickly. Using finite element models, I have examined the practical limitations of how fast solutions can be exchanged on an outside-out patch using a dual stream switcher. The primary factors controlling the speed of response are the flow velocity, proximity of the patch to the exit ports, the width of the partition between the two streams, the velocity with which the streams can be moved across the patch, and the viscosity of the solutions. The practical limit seems to be a rise time of approximately 20 microseconds. The rate-limiting step is the velocity of the (usually piezo) motor that translates the streams across the patch. Increasing the perfusate viscosity improves speed by slowing dissipation of the concentration gradients. A flow switcher can also be used for bipolar temperature jumps with a rise time of approximately 100 microseconds.     

Respiratory gas exchange ratio and prediction of aerobic power.

The Issekutz procedure for the prediction of maximum oxygen intake from the respiratory exchange ratio (R) has been evaluated on a diverse group of 308 subjects, including "whites" and Eskimos, men and women ranging in age from 16 to 65 yr. When applied to young white men performing 12 min of progressive step or treadmill exercise, the prediction procedure has a coefficient of variation of less than 10%, without systematic error. Unfortunately, the standard equation lacks generality, and erroneous predictions can arise from a change of test protocol, the use of a different exercise modality, or application to older subjects. If a brief exercise format is used, low R values may be reported during an early phase of relative hypoventilation. At a given metabolic loading, bicycle ergometry yields a higher respiratory minute volume than other modes of exercise. A heavy loading of one muscle group seems responsible, and the results is a high R value in submaximum effort. Aging is associated with a lowering of maximum blood lactate levels and thus maximum figures for R.     

The variability of respiratory pattern and gas exchange

It is known, that spectral analysis of heart rate and respiratory variability allows to find out the very low frequency (VLF) rhythm. However it is not known, it is necessary to carry this rhythm to what type of wave processes. The purpose of the present researches was to study the respiratory variability and the variability of gas exchange parameters. 10 healthy subjects have been surveyed. The pneumogramms within 30 minutes spent record, and then a method "breath-by-breath" within 30 minutes registered gas exchange parameters (Ve--lung ventilation, V(O2) -O2 consumption and other parameters). Fast Fourier transform method has found out two groups of the basic peaks. The first--in a range 0.2-0.3 Hz (a time cycle--3-5 s), that corresponds respiratory frequency which size at subjects varied from 12 to 20 per minute. The second--in a range 0.002-0.0075 Hz, that corresponds VLF diapason (a time cycle--1-3.5 minutes). At the analysis pneumogramms rhythms in the same ranges have been established. The carried out researches allow to draw a conclusion on steady character of wave process in a VLF-range. It can be carried to quasi-periodic oscillations type. First oscillator or respiratory frequency it is formed by means of mechanisms of chemoreception. Considering, that V(O2) and V(CO2) are function energy exchange, it is possible to believe, what exactly energy demand define the second oscillator.     

The variability of pulmonary gas exchange and respiratory pattern

Very-low-frequency (VLF) fluctuations, whose nature is probably determined by rhythms of energy processes, are known to determine the variability of respiratory and heart rates. It is still unclear to which type of wave processes (chaotic or regular) these rhythm patterns belong. The goal of this study was to investigate the rhythms of pulmonary gas exchange and the variability of the respiratory pattern, as well as to find their possible relation. To analyze the variability of ventilation indices in the VLF band, pneumograms were recorded for 30 min and then the pulmonary gas exchange indices (Ve, pulmonary ventilation; V_O2 V_{O_2 }, oxygen consumption; V_CO2 V_{CO_2 }, carbon dioxide release) were recorded for 30 min using the breath-by-breath method in ten healthy subjects. Spectral analysis carried out using the fast Fourier transform revealed two groups of major peaks: the first one was in the range from 0.2 to 0.3 Hz (the time interval of 3–5 s), which was in good agreement with the respiratory rate varied from 12 to 20 per min in tested subjects; the second was from 0.002 to 0.0075 Hz, which corresponded to the VLF band. The data make it possible to draw a conclusion about the stability of the wave processes found. Apparently, the slow-wave pattern of the pulmonary gas exchange indices belongs to the quasi-periodic oscillation type, reflecting synchronization of oscillators with incommensurable frequencies when the two-frequency pattern dominates. The first oscillator is the chemoreceptor mechanism of the regulation of ventilation, the nature of the second one is still unclear. Taking into consideration that V_O2 V_{O_2 } and V_CO2 V_{CO_2 } depend on energy demand, one can suppose that energy processes form (an)other oscillator(s) of periodic processes.     

Discontinuous gas exchange in dung beetles: patterns and ecological implications

This study correlates a distinctive pattern of external gas exchange, referred to as the discontinuous gas exchange cycle (DGC), observed in the laboratory, with habitat associations of five species of telecoprid dung beetles. The beetles were chosen from a variety of habitats that would be expected to present different amounts of water stress. All five species exhibited DGC. Sisyphus fasciculatus has been recorded only in woodland areas, and does not have strict spiracular control during its DGC. Anachalcos convexus and Scarabaeus rusticus are associated with open mesic habitats. Both species exhibit a distinct DGC, previously found in some other insect species, but intermediate within this study group. Sc. flavicornis and Circellium bacchus are typically found in arid regions, and have the most unusual form of DGC, with spiracular fluttering during the burst phase. These results support the hypothesis that spiracular fluttering reduces respiratory water loss. From this study we conclude that the DGC is an ancestral adaptation, most probably as a result of anoxic environments in underground burrows, but that spiracular control is enhanced to reduce respiratory water loss in beetle species that live in arid habitats. Received 4 August 1999 / Accepted: 7 October 1999     

Cytokines, macrophage lipid metabolism and foam cells: implications for cardiovascular disease therapy

Cardiovascular disease is the biggest killer globally and the principal contributing factor to the pathology is atherosclerosis; a chronic, inflammatory disorder characterized by lipid and cholesterol accumulation and the development of fibrotic plaques within the walls of large and medium arteries. Macrophages are fundamental to the immune response directed to the site of inflammation and their normal, protective function is harnessed, detrimentally, in atherosclerosis. Macrophages contribute to plaque development by internalizing native and modified lipoproteins to convert them into cholesterol-rich foam cells. Foam cells not only help to bridge the innate and adaptive immune response to atherosclerosis but also accumulate to create fatty streaks, which help shape the architecture of advanced plaques. Foam cell formation involves the disruption of normal macrophage cholesterol metabolism, which is governed by a homeostatic mechanism that controls the uptake, intracellular metabolism, and efflux of cholesterol. It has emerged over the last 20 years that an array of cytokines, including interferon-γ, transforming growth factor-β1, interleukin-1β, and interleukin-10, are able to manipulate these processes. Foam cell targeting, anti-inflammatory therapies, such as agonists of nuclear receptors and statins, are known to regulate the actions of pro- and anti-atherogenic cytokines indirectly of their primary pharmacological function. A clear understanding of macrophage foam cell biology will hopefully enable novel foam cell targeting therapies to be developed for use in the clinical intervention of atherosclerosis.     

Effect of acetazolamide on gas exchange and acid-base control after maximal exercise.

To investigate the interactions between the systems that contribute to acid-base homeostasis after severe exercise, we studied the effects of carbonic anhydrase inhibition on exchange of strong ions and CO2 in six subjects after 30 s of maximal isokinetic cycling exercise. Each subject exercised on two randomly assigned occasions, a control (CON) condition and 30 min after intravenous injection of 1,000 mg acetazolamide (ACZ) to inhibit blood carbonic anhydrase activity. Leg muscle power output was similar in the two conditions; peak O2 uptake (VO2) after exercise was lower in ACZ (2,119 +/- 274 ml/min) than in CON (2,687 +/- 113, P less than 0.05); peak CO2 production (VCO2) was also lower (2,197 +/- 241 in ACZ vs. 3,237 +/- 87 in CON, P less than 0.05) and was accompanied by an increase in the recovery half-time from 1.7 min in CON to 2.3 min in ACZ. Whereas end-tidal PCO2 was lower in ACZ than in CON, arterial PCO2 (PaCO2) was higher, and a large negative end-tidal-to-arterial difference (less than or equal to 20 Torr) was present in ACZ on recovery. In ACZ, postexercise increases in arterial plasma [Na+] and [K+] were greater but [La-] was lower. Arteriovenous differences across the forearm showed a greater uptake of La- and Cl- in CON than in ACZ. Carbonic anhydrase inhibition with ACZ, in addition to impairing equilibration of the CO2 system to the acid-base challenge of exercise, was accompanied by changes in equilibration of strong inorganic ions. A lowered plasma [La-] was not accompanied by greater uptake of La- by inactive muscle.     

A meta-analysis of leaf gas exchange and nitrogen in trees grown under elevated carbon dioxide

The response of trees to rising atmospheric CO₂ concentration ([CO₂]) is of concern to forest ecologists and global carbon modellers and is the focus of an increasing body of research work. I review studies published up to May 1994, and several unpublished works, which reported at least one of the following: net CO₂ assimilation (A), stomatal conductance (g_s), leaf dark respiration (R_d) leaf nitrogen or specific leaf area (SLA) in woody plants grown at <400 μmol mol^?1 CO₂ or at 600–800 μmol mol^?1 CO₂. The resulting data from 41 species were categorized according to growth conditions (unstressed versus stressed), length of CO₂ exposure, pot size and exposure facility [growth chamber (GC), greenhouse (GH), or open-top chamber (OTC)] and interpreted using meta-analytic methods. Overall, A showed a large and significant increase at elevated [CO₂] but length of CO₂ exposure and the exposure facility were important modifiers of this response. Plants exposed for < 50 d had a significantly greater response, and those from GCs had a significantly lower response than plants from longer exposures or from OTC studies. Negative acclimation of A was significant and general among stressed plants, but in unstressed plants was influenced by length of CO₂ exposure, the exposure facility and/or pot size. Growth at elevated [CO₂] resulted in moderate reductions in gs in unstressed plants, but there was no significant effect of CO₂ on gs in stressed plants. Leaf dark respiration (mass or area basis) was reduced strongly by growth at high [CO₂] > while leaf N was reduced only when expressed on a mass basis. This review is the first meta-analysis of elevated CO₂ studies and provides statistical confirmation of several general responses of trees to elevated [CO₂]. It also highlights important areas of continued uncertainty in our understanding of these responses.     

Effects of human pregnancy and aerobic conditioning on alveolar gas exchange during exercise

This study examined the effects of aerobic conditioning during the second and third trimesters of human pregnancy on ventilatory responses to graded cycling. Previously sedentary pregnant women were assigned randomly to an exercise group (n = 14) or a nonexercising control group (n = 14). Data were collected at 15-17 weeks, 25-27 weeks and 34-36 weeks of pregnancy. Testing involved 20 W.min-1 increases in work rate to a heart rate of 170 beats.min-1 and (or) volitional fatigue. Breath-by-breath ventilatory and alveolar gas exchange measurements were compared at rest, a standard submaximal .VO2 and peak exercise. Within both groups, resting .V(E), .V(A), and V(T)/T(I) increased significantly with advancing gestation. Peak work rate, O2 pulse (.VO2/HR), .V(E), .V(A) respiratory rate, V(T)/T(I), .VO2, .VCO2, and the ventilatory threshold (T(vent)) were increased after physical conditioning. Chronic maternal exercise has no significant effect on pregnancy-induced changes in ventilation and (or) alveolar gas exchange at rest or during standard submaximal exercise. Training-induced increases in T(vent) and peak oxygen pulse support the efficacy of prenatal fitness programs to improve maternal work capacity.     

High-frequency partial liquid ventilation in respiratory distress syndrome: hemodynamics and gas exchange

Sukumar, Minakshi, Mahesh Bommaraju, John E. Fisher,Frederick C. Morin III, Michele C. Papo, Bradley P. Fuhrman, Lynn J. Hernan, and Corinne Lowe Leach. High-frequency partial liquidventilation in respiratory distress syndrome: hemodynamics and gasexchange. J. Appl. Physiol. 84(1):327-334, 1998.Partial liquid ventilation using conventionalventilatory schemes improves lung function in animal models ofrespiratory failure. We examined the feasibility of high-frequencypartial liquid ventilation in the preterm lamb with respiratorydistress syndrome and evaluated its effect on pulmonary and systemichemodynamics. Seventeen lambs were studied in three groups:high-frequency gas ventilation (Gas group), high-frequency partialliquid ventilation (Liquid group), and high-frequency partial liquidventilation with hypoxia-hypercarbia (Liquid-Hypoxiagroup). High-frequency partial liquid ventilation increased oxygenation compared with high-frequency gas ventilation over5 h (arterial oxygen tension 253 ± 21.3 vs. 17 ± 1.8 Torr; P < 0.001).Pulmonary vascular resistance decreased 78%(P < 0.001), pulmonary blood flowincreased fivefold (P < 0.001), andaortic pressure was maintained (P < 0.01) in the Liquid group, in contrast to progressive hypoxemia,hypercarbia, and shock in the Gas group. Central venouspressure did not change. The Liquid-Hypoxia group was similar tothe Gas group. We conclude that high-frequency partial liquidventilation improves gas exchange and stabilizes pulmonary and systemichemodynamics compared with high-frequency gas ventilation. Thestabilization appears to be due in large part to improvement in gasexchange.