Biomedical subjects

H Hoppeler

Publications and source records attributed to H Hoppeler.

At least 73 records · Page 4Linked to original sources

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. 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

Fatigue and the design of the respiratory system.

One source of muscle fatigue may be the failure to provide the required oxygen by any step in the oxygen transport cascade or a lack of the necessary machinery to utilize that oxygen. We favor abandoning the concept of a single rate-limiting step for the concept of tuned resistors, each contributing to the overall resistance to oxygen flow. However, because some of these steps have considerably less phenotypic plasticity than others, these are the component parts of the respiratory system that must be built with adequate "reserve" to accommodate adaptive increases in the other steps (Lindstedt et al., 1988; Weibel et al., 1992; Lindstedt et al., 1994). These structures will usually appear to be over built except in those rare individual animals at the species-specific limit of VO2 in which these less malleable structures may be limiting.

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

Ultrastructural modification of human skeletal muscle tissue with 6-month moderate-intensity exercise training.

The study was aimed at investigating if endurance training of moderate intensity and longer duration, intended to promote health rather than performance, evokes ultrastructural changes in skeletal muscle tissue comparable to those observed after high-intensity protocols. Twenty healthy, middle-aged men enrolled in a 6-month, home-based jogging program of 120 min/wk at 75% VO2max. Only 12 men showed a sufficient exercise adherence over the 6 months (> or = 60 min/wk on average) and were included into statistical analysis. Their average training activity was 105 +/- 31 min/wk. The results revealed significant increases in VO2max (+8.4%, p < 0.01) and submaximal power output (+18.1%, p < 0.01). Total mitochondrial volume density in M. vastus lateralis increased by 20% (p < 0.05) with a larger increase in subsarcolemmal volume compared to central volume (50% vs 15%). No changes in volume of intracellular lipid droplets, capillary density, capillary per fiber ratio, fiber mean cross-sectional area and muscle fiber type could be observed. Body composition analysis showed a decrease in trunk fat mass (-7.3%, p < 0.05) and an increase in trunk lean mass (+1.7%, p < 0.05), while changes in the legs were not significant. It can be concluded that a moderate-intensity, health oriented endurance training beneficially affected cardiovascular and muscle oxidation capacity as well as body composition in the trunk area. No adaptations in capillaries or lipid metabolism could be demonstrated. The results support the hypothesis of thresholds for induction of adaptation processes in muscle skeletal tissue depending on the intensity of the exercise stimulus.

Adipose Tissue↗

PubMed1995

Loss of muscle oxidative capacity after an extreme endurance run: the Paris-Dakar foot-race.

We measured changes in maximal oxygen uptake capacity (VO2max), ventilation, heart rate, plasma lactate and speed at the end of an incremental exercise test as a consequence of a relay foot race from Paris to Dakar in 6 subjects. Additionally, anthropometric measurements were taken and muscle biopsies from M. vastus lateralis were obtained before and after the race. The latter were analyzed with morphometric methods for fiber size, capillarity and muscle ultrastructural composition. Weight specific VO2max was significantly reduced from 62.4 to 60.5 ml/min.kg after the race while absolute VO2max and the other endurance related functional variables remained unchanged. Body fat, thigh cross-sectional area and thigh volume showed tendential reduction immediately after the race but regained pre-race values within a few days. Fiber size and capillarity were not affected by the race. Volume density of total mitochondria was significantly reduced from 6.98 to 4.89% of fiber volume. Both subsarcolemmal and interfibrillar mitochondria were significantly reduced by 59 and 21%, respectively. The volume density of satellite cell was increased about three-fold whereas the content of lipofuscin remained constant. It is concluded that extreme endurance events such as a multi-stage relay race may induce a considerable loss of oxidative capacity of skeletal muscle tissue.

Adipose Tissue↗

PubMed1995

mRNAs of enzymes involved in energy metabolism and mtDNA are increased in endurance-trained athletes.

Improvements in endurance capacity by training are associated with structural and biochemical adaptations of working muscles that affect the mitochondrial compartment. We investigated whether the 1.8-fold higher mitochondrial volume density in a group of endurance-trained athletes compared with untrained subjects was reflected by higher steady-state levels of mRNAs coding for components of the oxidative phosphorylation pathway using a quantitative polymerase chain reaction approach. We found that mitochondrially encoded RNAs (cytochrome-c oxidase subunit I, NADH reductase subunit 6, 16S rRNA), as well as nuclear-encoded RNAs (cytochrome-c oxidase subunit IV, succinate dehydrogenase, fumarase) are all increased coordinately in the athletes (1.54- to 1.94-fold). In addition, mitochondrial (mt) DNA concentration was also 1.55-fold higher in the trained athletes, whereas genomic DNA was not changed. Our findings thus show similar RNA expression of mitochondrially encoded genes in sedentary and endurance-trained subjects, whereas pretranslational control mechanisms account for higher levels of nuclear-encoded RNAs in the athletes.

Adult↗

PubMed1995

Maximal exercise performance in chronic hypoxia and acute normoxia in high-altitude natives.

Maximal O2 uptake (VO2max) was determined on a bicycle ergometer in chronic hypoxia (CH) and during acute exposure to normoxia (AN) in 50 healthy young men who were born and had lived at 3,600 m altitude (La Paz, Bolivia). VO2max was significantly improved (approximately 8%) by AN. However, the difference in VO2max measured in CH and AN (delta VO2max) was lower than that reported in sea-level natives (SN) who exercised in chronic normoxia and acute hypoxia. It is shown that high-altitude natives (HN) and SN have a similar VO2max in normoxia, but highlanders can attain a greater VO2max when O2 availability is reduced by altitude exposure. In addition, in HN, the higher the subject's VO2max in hypoxia, the smaller his delta VO2max. These results contrast with the data obtained in 14 lowlanders acclimatized to high altitude who showed that their delta VO2max was positively related to their VO2max in hypoxia, as previously reported in SN who exercised in acute hypoxia (A. J. Young, A. Cymerman, and R. L. Burse. Eur. J. Appl. Physiol. Occup. Physiol. 54: 12-15, 1985). Furthermore, arterial O2 saturation of HN behaved differently from acclimatized lowland natives, inasmuch as it fell less during exercise both in CH and AN. HN with high aerobic capacity display a lower exercise ventilation and a reduced arterial saturation, which could explain their inability to improve VO2max with normoxia.(ABSTRACT TRUNCATED AT 250 WORDS)

Acclimatization↗

PubMed1995

Training in hypoxia vs. training in normoxia in high-altitude natives.

To determine the interactions between endurance training and hypoxia on maximal exercise performance, we performed a study on sedentary high-altitude natives who were trained in normoxia at the same relative (n = 10) or at the same absolute (n = 10) intensity of work as hypoxia-trained subjects (n = 10). The training-induced improvement of maximal oxygen uptake (VO2max) in hypoxia-trained subjects was similar to that obtained in normoxia-trained sea-level natives submitted to the same training protocol (H. Hoppeler, H. Howald, K. Conley, S. L. Lindstedt, H. Claassen, P. Vock, and E. W. Weibel. J. Appl. Physiol. 59: 320-327, 1985). Training at the same absolute work intensity in the presence of increased oxygen delivery failed to provide a further increase in VO2max. VO2max was not improved to a greater extent by simultaneously increasing absolute work intensity and O2 delivery during the training sessions. In addition, training in normoxia is accompanied by an increased blood lactate accumulation during maximal exercise, leading to greater drops in arterial pH, bicarbonate concentration, and base excess. We conclude that, in high-altitude natives, 1) training at altitude does not provide any advantage over training at sea level for maximal aerobic capacity, whether assessed in chronic hypoxia or in acute normoxia; 2) VO2max improvement with training cannot be further enhanced by increasing O2 availability alone or in combination with an increased work intensity during the exercising sessions; and 3) training in normoxia in these subjects results in a reduced buffer capacity.

Adult↗

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↗

PubMed1994

An efficient polymerase chain reaction approach for the quantitation of multiple RNAs in human tissue samples.

We describe a PCR quantitation approach that we have set up to study gene expression in human skeletal muscle biopsies. It is characterized by the independent standardization of the individual steps and ignores attempts to control for the efficiency of the PCR. Different RNA extraction/reverse transcription efficiencies are normalized by the addition of an unrelated cRNA. Quantitation is achieved by parallel amplifications of reference samples containing known amounts of PCR products. Precision was achieved by multiple measurements of several samples. Our approach allows for the detection of less than twofold differences (27-88%, depending on the RNA species studied) among samples. A comparison of biopsies from highly trained endurance runners with biopsies from untrained subjects showed that the increased mitochondrial density in the runners' samples is accompanied by a proportional increase in the concentration of the mRNA of cytochrome c oxidase subunit IV.

Adult↗

PubMed1994

Cardiopulmonary adaptations to pneumonectomy in dogs. III. Ventilatory power requirements and muscle structure.

Static and dynamic mechanical characteristics of the respiratory system were measured in five adult foxhounds 6-15 mo after right pneumonectomy (R-PNX) and in five matched foxhounds that underwent right thoracotomy without pneumonectomy (Sham). In R-PNX dogs, elastic recoil was lower than that in the left lung of Sham dogs. On exercise, absolute ventilatory power requirements of the lung and its components were measured, i.e., power requirements to overcome elastic and viscous resistances of the lung as well as power requirements during inspiration and expiration. All components were higher for a given minute ventilation in R-PNX dogs than in both lungs of Sham dogs. Ventilatory power requirements after R-PNX were also higher than in three adult foxhounds after left PNX studied previously by the same techniques. After R-PNX, the mass of the right costal diaphragm and total mass of inspiratory muscles were greater than in Sham dogs. There were no significant differences in ultrastructural features of the costal diaphragm. The unilateral increase in muscle mass is likely the result of chronic elevation and stretch of the right costal diaphragm after R-PNX.

Air Pressure↗

PubMed1994

Relationship between the coenzyme A and the carnitine pools in human skeletal muscle at rest and after exhaustive exercise under normoxic and acutely hypoxic conditions.

Skeletal muscle CoA and carnitine metabolism were investigated in six human volunteers at rest and after exhaustive exercise under normoxic and hypoxic conditions. In comparison to the values at rest, exhaustive exercise was associated with a three- to fourfold increase in the skeletal muscle lactate, and with a twofold increase in the acetyl-CoA content, both under normoxic and hypoxic conditions. Since exercise did not significantly affect the skeletal muscle CoA radical (CoASH), total acid-soluble, or total CoA contents, the increase in the acetyl-CoA content was at the expense of short-chain acyl-CoAs different from acetyl-CoA. With exhaustive exercise, the skeletal muscle acetylcarnitine and short-chain acylcarnitine contents increased by a factor of three to four both under normoxic and hypoxic conditions. In contrast to the CoA pool, these increases were associated with a decrease in the free carnitine content, whereas the total acid-soluble and total carnitine contents were not affected by exercise. After exhaustive exercise, the skeletal muscle acetyl-CoA/CoASH ratio showed a linear correlation with the corresponding acetylcarnitine/free carnitine ratio. The plasma short-chain acylcarnitine concentration increased by a factor of two to three during exercise, and was not significantly different from the values at rest 40 min after completion of exercise. Thus, the current studies illustrate the close interaction between the CoA and carnitine pools in the exercising human skeletal muscle, and they underscore the important role of carnitine in maintaining the muscular CoASH content during exhaustive exercise.

Acetyl Coenzyme A↗

PubMed1994

Capillary blood transit time in muscles in relation to body size and aerobic capacity.

The mean minimal transit time for blood in muscle capillaries (tc) was estimated in six species, spanning two orders of magnitude in body mass and aerobic capacity: horse, steer, dog, goat, fox and agouti. Arterial (CaO2) and mixed venous (CvO2) blood O2 concentrations, blood hemoglobin concentrations ([Hb]) and oxygen uptake rates were measured while the animals ran on a treadmill at a speed that elicited the maximal oxygen consumption rate (VO2max) from each animal. Blood flow to the muscles (Qm) was assumed to be 85% of cardiac output, which was calculated using the Fick relationship. Total muscle capillary blood volume (Vc) and total muscle mitochondrial volume were estimated by morphometry, using a whole-body muscle sampling scheme. The tc was computed as Vc/Qm. The tc was 0.3-0.5 s in the 4 kg foxes and agoutis, 0.7-0.8 s in the 25 kg dogs and goats, and 0.8-1.0 s in the 400 kg horses and steers. The tc was positively correlated with body mass and negatively correlated with transcapillary O2 release rate per unit capillary length. Mitochondrial content was positively correlated with VO2max and with the product of Qm and [Hb]. These data suggested that Qm, Vc, maximal hemoglobin flux, and consequently tc, are co-adjusted to result in muscle O2 supply conditions that are matched to the O2 demands of the muscles at VO2max.

Aerobiosis↗