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Biomedical subjects

E R Weibel

Publications and source records attributed to E R Weibel.

At least 19 recordsLinked to original sources
PubMed1998

Limits for oxygen and substrate transport in mammals.

Environmental oxygen is transported by the respiratory cascade to the site of oxidation in active tissues. Under conditions of heavy exercise, it is ultimately the working skeletal muscle cells that set the aerobic demand because over 90 % of energy is spent in muscle cells. The pathways for oxygen and substrates converge in muscle mitochondria. In mammals, a structural limitation of carbohydrate and lipid transfer from the microvascular system to the muscle cells is reached at a moderate work intensity (i.e. at 40-50 % of VO2max). At higher work rates, intracellular substrate stores must be used for oxidation. Because of the importance of these intracellular stores for aerobic work, we find larger intramyocellular substrate stores in 'athletic' species as well as in endurance-trained human athletes. The transfer limitations for carbohydrates and lipids at the level of the sarcolemma imply that the design of the respiratory cascade from lungs to muscle mitochondria reflects primarily oxygen demand. Comparative studies indicate that the oxidative capacity of skeletal muscle tissue, and hence maximal oxygen demand, is adjusted by varying mitochondrial content. At the level of microcirculatory oxygen supply, it is found that muscle tissue capillarity is adjusted to muscle oxygen demand but that the capillary erythrocyte volume also plays a role. Oxygen delivery by the heart has long been recognized to be a key link in the oxygen transport chain. In allometric variation it is heart rate and in adaptive variation it is essentially stroke volume, and hence heart size, that determines maximal cardiac output. Again, haematocrit is an important variable that allows the heart of athletic species to generate higher flux rates for oxygen. The pulmonary gas exchanger offers only a negligible resistance to oxygen flux to the periphery. However, in contrast to all other steps in the respiratory cascade, the lungs have only a minimal phenotypical plasticity and appear, therefore, to be built with considerable structural redundancy in all but the most athletic species. Because of the lack of malleability, the lungs may ultimately become limiting for VO2max when adaptive processes have maximized O2 flux through the malleable downstream elements of the respiratory system: the heart, microcirculation and muscle mitochondria.

Animals↗
PubMed1997

Working underground: respiratory adaptations in the blind mole rat.

Mole rats (Spalax ehrenbergi superspecies) perform the heavy work of digging their subterranean burrows in Israel under highly hypoxic/hypercapnic conditions. Unlike most other mammals, they can achieve high levels of metabolic rate under these conditions, while their metabolic rate at low work rates is depressed. We explored, by comparing mole rats with white rats, whether and how this is related to adaptations in the design of the respiratory system, which determines the transfer of O2 from the lung to muscle mitochondria. At the same body mass, mole rats were found to have a significantly smaller total skeletal muscle mass than ordinary white rats (-22%). In contrast, the fractional volume of muscle mitochondria was larger by 46%. As a consequence, both species had the same total amount of mitochondria and achieved, under normoxia, the same V(O2max). Whereas the O2 transport capacity of the blood was not different, we found a larger capillary density (+31%) in the mole rat muscle, resulting in a reduced diffusion distance to mitochondria. The structural pulmonary diffusing capacity for O2 was greater in the mole rat (+44%), thus facilitating O2 uptake in hypoxia. We conclude that structural adaptations in lung and muscle tissue improve O2 diffusion conditions and serve to maintain high metabolic rates in hypoxia but have no consequences for achieving V(O2max) under normoxic conditions.

Adaptation, Physiological↗
PubMed1997

Effects of long-term hypergravity on muscle, heart and lung structure of mice.

Quantitative changes in lung, heart and muscle structure were assessed in mice exposed for 14 weeks to a gravitational field of 3 G since the age of 4 weeks; matched controls were kept at normal gravity (1 G). The body mass of 3-G-exposed mice was significantly reduced by 9%, while total skeletal muscle mass remained the same fraction of body mass. The mass of the soleus muscle was found to be significantly larger in 3-G-exposed mice both in absolute (+27%) and body mass specific terms (+42%). Capillary density was significantly reduced by 22% because of a relatively larger increase of fiber cross-sectional area (+47%) than of capillary to fiber ratio (+16%). Other morphometric variables remained unchanged with hypergravity. Heart mass and mitochondrial volume were both larger in 3-G-exposed mice (+15% and +27%, respectively). This difference reached statistical significance when normalized to body mass. The only significant difference in lung structure detectable by morphometric methods were a smaller volume (-9%), that paralleled lower body mass, and thinner alveolar septa (-12%). From these results it is concluded that the lung's support structures in mice are sufficiently strong to withstand the stress of long-term hypergravity; however, 3-G exposure leads to a selective hypertrophy of soleus muscle fibers while absolute capillary length in this muscle remains unaltered.

Adaptation, Physiological↗
PubMed1996

Development of the human fetal airway tree: analysis of the numerical density of airway endtips.

BACKGROUND: It has been long agreed that the lung contained, at the end of the pseudoglandular stage, mostly the future conductive airway tree and that the intra-acinar structures developed during the subsequent canalicular stage. Recent immunocytochemical investigations have disclosed that the epithelial cells lining the distal airways in the pseudoglandular stage have the characteristics of alveolar epithelial cells. The purpose of this study was to quantitatively evaluate the progress of fetal airway branching. METHODS: The numerical density of endtips of the airway tree was estimated in three human fetal right lungs after 3D reconstruction of airways from serial histologic sections. The CRLs of the three fetuses were 103 mm, 132 mm, and 145 mm. The former two corresponded to the late pseudoglandular stage and the last to the early canalicular stage. Three-dimensional reconstructions were performed on two portions of the upper and lower lobes in each lung. The numbers of endtips of the airway tree contained in the reconstructed portions were counted an the numerical densities calculated. RESULTS: The numerical densities in the parenchyma of the three right lungs were 1.2 x 10(3)/mm3, 1.7 x 10(3)/mm3, and 2.4 x 10(3)/mm3, respectively. The estimated total numbers of endtips in the whole right lung were 0.85 x 10(6), 2.25 x 10(6), and 5.17 x 10(6), which were equal to 2(19.8), 2(21.2), and 2(22.3), respectively. CONCLUSIONS: Since this suggests that 20 generations of branching were completed, we concluded that the airway branching has already reached the level of the future alveolar ducts in the late pseudoglandular stage.

Fetus↗
PubMed1996

Design of the oxygen and substrate pathways. I. Model and strategy to test symmorphosis in a network structure.

This first paper in a series develops a model of structure-function relationships for the oxygen and substrate pathways of oxidative metabolism in working muscle. This will be used in the subsequent experimental papers in asking how biological structures are designed if they serve more than one function and whether one function can be served by more than one structural pathway. We have used the concept of symmorphosis to address this question; in its original form, it postulates that no more structure is built and maintained at each step in a pathway than is required to meet functional demands. The concept of symmorphosis was developed to deal with the problem of modelling the pathway for oxygen from the environment to mitochondria, essentially a single series of interconnected transfer steps. In the present context, the application of this concept is more complex. Both oxygen and substrates are transported directly from the blood to the mitochondria in what appear to be shared steps. The flows along this direct pathway are adjusted during muscular work. However, substrates have an additional option. They can be stored intracellularly as lipid droplets or glycogen, and thus their supply to mitochondria can occur in two steps separated in time: from capillaries to stores during rest, and from stores to mitochondria during work. The integrated pathways have a network structure and the functional flows are partitioned to different branches of the network, and we must ask whether the partitioning of fluxes is related to design constraints. The principle of symmorphosis predicts that the best use is made of the available options and that the design of each step is matched to the specific functional demand in view of a balance to be achieved over the entire network. This will be tested in subsequent papers by determining maximal flows for oxygen, carbohydrates and lipids through each of the transport steps and their respective structural capacities, comparing dogs and goats, animals of the same size whose maximal oxidative capacities differ by more than twofold. Finally, we will ask whether the principle of symmorphosis can be extended to apply to network systems.

Animals↗
PubMed1996

Design of the oxygen and substrate pathways. II. Defining the upper limits of carbohydrate and fat oxidation.

This paper quantifies maximal flows of carbohydrates and lipids through the pathways supplying the mitochondria. Maximal flow rates are the main functional parameter used in testing the principle of symmorphosis, which states that structural capacities are quantitatively matched to functional demand. Only under rate-limiting conditions will all of the structural capacity be used. Dogs and goats were compared to obtain large differences in absolute rates. We exercised the animals for long enough to reach steady-state O2 and CO2 exchange rates at intensities eliciting 40%, 60% and 85% of the maximal rate of oxygen consumption (MO2max). We then calculated rates of fat and carbohydrate oxidation from the ratio of CO2 produced to O2 consumed (the respiratory exchange ratio). The dog's Mo2max was more than twice that of the goat (6517 versus 3026 mumol O2 kg-1 min-1). We found the same pattern of fuel selection as a function of exercise intensity in both species, and it appears to be general to mammals. Maximal rates of fat oxidation were reached at 40% exercise intensity, where 77% of the energy was supplied by fat. As exercise intensity increased, all additional energy was supplied by carbohydrates. We conclude that the partitioning of fuel supply to the fat and carbohydrate pathways follows the same pattern in both dogs and goats.

Aerobiosis↗
PubMed1996

Design of the oxygen and substrate pathways. III. Partitioning energy provision from carbohydrates.

This paper quantifies maximal fluxes through the pathway supplying carbohydrates to the mitochondria of muscle cells. Continuous infusions of D-[3-(3)H]glucose together with indirect calorimetry were used to investigate the partitioning of the supply of carbohydrates through the two branches of the pathway: from circulating glucose and from glycogen stores within the muscle cells to the mitochondria. The relative contribution of circulating glucose to total carbohydrate oxidation was small, accounting for only 13% and 23% of the carbohydrate oxidized at exercise intensities approaching MO2max in dogs and goats, respectively. Unexpectedly, maximal rates of circulating glucose oxidation were nearly the same in the two species (when expressed in absolute terms; dog:goat ratio = 1.2), despite the 2.2-fold difference in aerobic capacity. We conclude that the glycogen stores in the muscle cells are the major source of substrates at maximal rates of oxidation, supplying 60-70% of the total energy. Furthermore, it is this branch of the carbohydrate pathway that is adapted to the large difference in aerobic capacity between dogs and goats.

Animals↗
PubMed1996

Design of the oxygen and substrate pathways. IV. Partitioning energy provision from fatty acids.

This paper quantifies the fluxes of fatty acids through the pathways supplying muscle mitochondria with oxidative fuel in exercising dogs and goats. We used continuous infusions of 1-[14C]palmitate and indirect calorimetry to measure fatty acid supply from two sources: the circulation and the triglyceride stores within the muscle cells. Our goal was to determine maximal flux through these two branches of the lipid pathway as key functional parameters for testing the principle of symmorphosis, i.e. that structural capacity is quantitatively matched to functional demand in the oxidative substrate pathways. It is under these rate-limiting conditions that we predict that all of the structural capacity will be used. Maximal rates of fatty acid oxidation were reached at low exercise intensities of 40% Mo2max. Fatty acids from the circulation supplied only a small fraction (15-25%) of the total fat oxidized under these conditions. Although dogs were able to oxidize circulatory fatty acids faster than goats, maximal rates were not in proportion to the 2.2-fold difference in aerobic capacity between the two species. Dogs compensated for their relatively lower use of circulatory fatty acids by oxidizing more triglycerides from lipid droplets in their muscle cells. We conclude that fatty acids from intramuscular triglyceride stores are a major source of fuel during maximal rates of lipid oxidation. Furthermore, it is this branch of the fatty acid pathway that is adapted to the large difference in aerobic capacity between dogs and goats.

Animals↗
PubMed1996

Design of the oxygen and substrate pathways. V. Structural basis of vascular substrate supply to muscle cells.

This paper quantifies the structural capacity of the transport steps for oxygen, glucose and fatty acids from the blood in capillaries to the cytosol of muscle cells and compares it with maximal rates of oxygen and substrate transport measured in the same animals and reported in the preceding papers of this series. Dogs have relatively more muscle per unit body mass than goats (37 versus 26%), but the maximal rate of oxidation per gram of muscle is still larger in the dog by a factor of 1.55. The maximal rates of substrate supply from the circulation are similar in both species. We predict that these differences in physiological parameters should be matched by proportional differences in structural capacity. We find that capillary volume and surface area are matched to maximal oxygen demand. The rate of vascular substrate supply is proportional neither to the capillary surface area nor to the length of intercellular junctions. The sarcolemmal surface area per gram of muscle is the same in both species. Using the physiological data presented in the companion papers of this series, we have calculated the maximal flux densities of circulatory glucose and fatty acids across the capillary wall and the sarcolemma. We find, for both substrates, that the flux densities across the sarcolemma reach a maximum at nearly the same level and at low exercise intensities in both species. In contrast, the flux densities across the capillary surface and the endothelial junctions are higher in goats than in dogs. We conclude that the capillaries are designed for O2 supply up to maximal rates of oxidation but not for the supply of the substrates (glucose and fatty acids) at the rates required at high exercise intensities. These are limited by the transport capacities of the sarcolemma.

Animals↗
PubMed1996

Design of the oxygen and substrate pathways. VI. structural basis of intracellular substrate supply to mitochondria in muscle cells.

This paper quantifies the structures involved in the transport and oxidation of carbohydrates and fatty acids within the muscle cell. The structural capacity is measured on whole-body random samples of the musculature of dogs and pygmy goats and compared with maximal rates of oxygen consumption and substrate oxidation. Comparing dogs and goats of the same body size provided a 1.55-fold difference in the maximal rate of oxidation when related to muscle mass. As in previous studies, we found that the volume of mitochondria was approximately proportional to aerobic capacity. The maximal glucose flux from intracellular stores to mitochondria is 1.6 times greater in the dog than in the goat; we find that the amount of glycogen stored in the muscle cells is 4.2 times as great in the dog, but part of the intracellular glycogen pool is used for anaerobic rather than for oxidative metabolism. The maximal fatty acid flux from intracellular stores to mitochondria is 1.5 times larger in the dog, and the amount of lipid stored is 2.3 times as great in the dog. Every lipid droplet is in direct contact with the outer membrane of a mitochondrion and the contact surface area is 3.6 times greater in the dog than in the goat. Additional measurements are needed to investigate the role of structural limitation at this step. The amount of substrates stored intracellularly in the muscle cells of the dog is about twice as much as would match the differences in the maximal rates of utilization. This allows the endurance-specialized dogs to run for longer periods at higher rates of oxidation.

Animals↗
PubMed1996

Design of the oxygen and substrate pathways. VII. Different structural limits for oxygen and substrate supply to muscle mitochondria.

This paper integrates the results of a series of studies on the supply of O2 and substrates for oxidative muscle metabolism and draws conclusions on the role of structural design in partitioning and limiting substrate supply. The studies compared dogs and goats exercising at different intensities and combined physiological, biochemical and morphometric investigations. In both species, the rate of fatty acid oxidation reached an upper limit at low exercise intensities, and only glucose consumption was increased at higher exercise intensities. The supply of both glucose and fatty acids from the capillaries reached maximal rates at low exercise intensities; this limitation is related to the design of the sarcolemma as calculations suggest that the endothelium introduces only a small resistance to substrate flux. From these findings, it appears that the capillaries are designed to satisfy O2 supply up to maximal O2 demand. The increase in substrate supply to the mitochondria at higher exercise intensities is achieved by drawing on intracellular stores of glycogen and lipids. The size of these stores is larger in dogs than in goats, providing the athletic species with twice the fuel reserves. These findings are interpreted on the basis of a network model with fluxes partitioned between direct and indirect pathways and with some structures shared by more than one function. Whereas O2 is supplied through a direct pathway, the supply of both substrates is split temporally to allow, during exercise, immediate fuel supply to the mitochondria from intracellular stores; these are replaced from the vasculature, during periods of rest, to a size commensurate with high rates of combustion. Considering this complexity, we conclude that the results are compatible with the principle of symmorphosis applied to a network structure and that the adjustment of design to functional demand involves different structures for O2 and for substrates.

Animals↗
PubMed1995

Cold acclimation and endurance training in guinea pigs: changes in daily and maximal metabolism.

The physiological effects of training or cold acclimation on maximal oxygen uptake (VO2,max) and average daily metabolic rate (VO2,dav) of a small mammal, the guinea pig, are described. Young male guinea pigs were assigned to three experimental groups; control, endurance trained (70% VO2,max) or cold acclimated (5-7 degrees C) for six weeks. Measurements of VO2,max and VO2,dav were made before and after the treatments. VO2,max increased significantly in cold acclimated (+29%) and endurance trained (+23%) animals and was achieved at a higher maximal running speed compared to post-treatment controls. Maximal blood lactate concentration was significantly higher in cold acclimated compared to endurance trained animals. Endurance trained animals had a reduced VO2,dav compared to control animals, whereas cold acclimation raised VO2,dav in the cold as expected, but also at room temperature. All three groups showed a daily pattern in metabolic rate (night > day). In conclusion, both endurance training and cold acclimation lead to enhanced VO2,max and changes in resting oxygen consumption throughout the day.

Acclimatization↗
PubMed1995

Cold acclimation and endurance training in guinea pigs: changes in lung, muscle and brown fat tissue.

The effects of an intermittent high intensity stimulus (running) or a chronic low intensity stimulus (cold acclimation) of oxidative metabolism on maximal oxygen uptake (VO2,max), lung O2 diffusing capacity (DLO2) and skeletal muscle as well as fat tissue mitochondrial content in growing guinea pigs are described. Young male guinea pigs were assigned to three experimental groups (n = 5): control (C), endurance trained (T; at 70% VO2max) or cold acclimated (CA; 5-7 degrees C) for six weeks. Animals were sacrificed at the end of the experimental period and tissue for morphometric analysis of the lung, muscle and interscapular fat was sampled. T and CA animals significantly increased weight specific VO2max by 23% and 29%, respectively. Despite a significant increase in absolute lung volume in T (+10%) and in weight specific lung volume in CA (+20%) neither absolute nor weight specific DLO2 was significantly affected by the experimental treatments. In trained animals the total volume of mitochondria remained unchanged in samples representative for the entire musculature but was significantly increased in M. vastus intermedius (+72%). Intramyocellular lipids increased significantly both in M. vastus intermedius (+244%) as well as in the whole body musculature (+164%). Cold acclimation increased the mitochondrial content of the interscapular fat pad by approximately 20-fold but had no effect on total mitochondrial volume in muscle. We conclude that the increase in oxygen demand resulting from exercise training or from cold acclimation could be accomodated by the existing lung diffusing capacity and did not induce a global change of oxidative capacity in skeletal muscle tissue in growing guinea pigs. Exercise training caused oxidative capacity to increase only in a locomotor muscle activated during running whereas cold acclimation greatly increased interscapular fat tissue oxidative capacity.

Acclimatization↗
PubMed1995

Heart mitochondrial properties and aerobic capacity are similarly related in a mammal and a reptile.

The heart mitochondrial properties and the aerobic capacity (VO2max) of the rat (Sprague-Dawley breed) and the Cuban iguana (Cyclura nubila) were used to evaluate the relationship between the oxidative capacity of the heart and the maximum oxygen delivery rate. Both species are active at body temperatures of 37-39 degrees C, have similar heart mitochondrial volumes [Vmt; 0.43 +/- 0.02 ml (S.E.M.) in the rat and 0.48 +/- 0.02 ml in the iguana] and differ less than twofold in VO2max (29.2 +/- 1.6 and 16.9 +/- 0.6 ml min-1, respectively). We found that Vmt was closely correlated with VO2max in the rat (r2 = 0.77, P < 0.005) and the iguana (r2 = 0.82; P < 0.001). Furthermore, the inner mitochondrial membrane (cristae) area (Sim) per unit VO2max did not differ between the rat and the iguana (0.60 +/- 0.02 and 0.71 +/- 0.02 m2 min ml-1 O2, respectively). This correspondence of Sim/VO2max indicates that the rat and the iguana have the same cardiac oxidative capacity at the maximum oxygen delivery rate. These results suggest that, despite the differences between the cardiovascular systems of these species, the cardiac cost of delivering oxygen at the aerobic capacity is similar in this mammal and this reptile.

Aerobiosis↗