Arnold tongue entrainment reveals dynamical principles of the embryonic segmentation clock.

Living systems exhibit an unmatched complexity, due to countless, entangled interactions across scales. Here, we aim to understand a complex system, that is, segmentation timing in mouse embryos, without a reference to these detailed interactions. To this end, we develop a coarse-grained approach, in which theory guides the experimental identification of the segmentation clock entrainment responses. We demonstrate period- and phase-locking of the segmentation clock across a wide range of entrainment parameters, including higher-order coupling. These quantifications allow to derive the phase response curve (PRC) and Arnold tongues of the segmentation clock, revealing its essential dynamical properties. Our results indicate that the somite segmentation clock has characteristics reminiscent of a highly non-linear oscillator close to an infinite period bifurcation and suggests the presence of long-term feedbacks. Combined, this coarse-grained theoretical-experimental approach reveals how we can derive simple, essential features of a highly complex dynamical system, providing precise experimental control over the pace and rhythm of the somite segmentation clock.

Development of mRNA manufacturing for vaccines and therapeutics: mRNA platform requirements and development of a scalable production process to support early phase clinical trials.

The remarkable success of SARS CoV-2 mRNA-based vaccines and the ensuing interest in mRNA vaccines and therapeutics have highlighted the need for a scalable clinical-enabling manufacturing process to produce such products, and robust analytical methods to demonstrate safety, potency, and purity. To date, production processes have either not been disclosed or are bench-scale in nature and cannot be readily adapted to clinical and commercial scale production. To address these needs, we have advanced an aqueous-based scalable process that is readily adaptable to GMP-compliant manufacturing, and developed the required analytical methods for product characterization, quality control release, and stability testing. We also have demonstrated the products produced at manufacturing scale under such approaches display good potency and protection in relevant animal models with mRNA products encoding both vaccine immunogens and antibodies. Finally, we discuss continued challenges in raw material identification, sourcing and supply, and the cold chain requirements for mRNA therapeutic and vaccine products. While ultimate solutions have yet to be elucidated, we discuss approaches that can be taken that are aligned with regulatory guidance.

Remodeling of skeletal muscle microvasculature in sickle cell trait and alpha-thalassemia.

The influence of sickle cell trait and/or alpha-thalassemia on skeletal muscle microvascular network characteristics was assessed and compared with control subjects [hemoglobin (Hb) AA] in 30 Cameroonian residents [10 HbAA, 5 HbAA alpha-thalassemia (alpha-t), 6 HbAS, and 9 HbASalpha-t] matched for maximal work capacity and daily energy expenditure. Subjects performed an incremental exercise to exhaustion and underwent a muscle biopsy. Muscle fiber type and surface area were not different among groups. However, sickle cell trait (SCT) was associated with lower capillary density (P < 0.05), lower capillary tortuosity (P < 0.001), and enlarged microvessels (P < 0.01). SCT carriers had reduced counts of microvessels <5-microm diameter, but a higher percentage of broader microvessels, i.e., diameter >10 microm (P < 0.05). alpha-Thalassemia seemed to be characterized by a higher capillary tortuosity and unchanged capillary density and diameter. Thus, while SCT is a priori clinically benign, we demonstrate for the first time that significant remodeling of the microvasculature occurs in SCT carriers. These modifications may possibly reflect protective adaptations against hemorheological and microcirculatory dysfunction induced by the presence of HbS. The remodeling of the microvascular network occurs to a lesser extent in alpha-thalassemia. In alpha-thalassemic subjects, increased capillary tortuosity would promote oxygen supply to muscle tissues and might compensate for the lower Hb content often reported in those subjects.

Effect of graded leg cycling on postischaemic forearm blood flow in healthy subjects.

This study assessed in healthy subjects, the effect of leg cycling on the forearm vascular responses to ischaemia to confirm previous results showing that exercise-induced sympathetic activation during leg cycling reduced postischaemic forearm hyperaemia. Seven young healthy subjects performed two bouts of cycling exercises at 50% and 80% of their maximal aerobic capacity (Ex(50), Ex(80) respectively) during which forearm arterial blood flow was successively occluded for 40, 90 and 180 s. Control forearm blood flow (FBF) and postischaemic forearm blood flow (pi-FBF) measured at the release of arterial occlusions were assessed using plethysmography. Digital arterial pressure was continuously monitored allowing calculation of control and postischaemic forearm conductance (FC and pi-FC respectively). At rest, pi-FBF increased with the duration of ischaemia (5 +/- 1, 19 +/- 3, 29 +/- 3, 31 +/- 4 ml min(-1) 100 ml(-1) after 0, 40, 90 and 180 s of ischaemia respectively). During Ex(50), FBF and pi-FBF did not change significantly although pi-FC was significantly reduced (Deltapi-FC = -39%, -33%, -27% for 40, 90, 180 s of ischaemia respectively). During Ex(80), there was a further dramatic decrease in pi-FC (-53%, -66%, -62% from rest) and pi-FBF were largely blunted (13 +/- 4 versus 19 +/- 3, 14 +/- 4 versus 29 +/- 3, 17 +/- 5 versus 31 +/- 4 ml min(-1) 100 ml(-1)). These results demonstrated that forearm responses to ischaemia depended on leg activities. It was suggested that exercise-induced sympathetic activation may have interfered on local vasodilatation because of ischaemia.

Importance of pH regulation and lactate/H+ transport capacity for work production during supramaximal exercise in humans.

We examine the influence of the cytosolic and membrane-bound contents of carbonic anhydrase (CA; CAII, CAIII, CAIV, and CAXIV) and the muscle content of proteins involved in lactate and proton transport [monocarboxylate transporter (MCT) 1, MCT4, and Na(+)/H(+) exchanger 1 (NHE1)] on work capacity during supramaximal exercise. Eight healthy, sedentary subjects performed exercises at 120% of the work rate corresponding to maximal oxygen uptake (W(max)) until exhaustion in placebo (Con) and metabolic alkalosis (Alk) conditions. The total (W(tot)) and supramaximal work performed (W(sup)) was measured. Muscle biopsies were obtained before and immediately after standardized exercises (se) at 120% W(max) in both conditions to determine the content of the targeted proteins, the decrease in muscle pH (DeltapH(m)), and the muscle lactate accumulation ([Lac](m)) per joule of W(sup) (DeltapH(m)/W(sup-se) and Delta[Lac](m)/W(sup-se), respectively) and the dynamic buffer capacity. In Con, W(sup) was positively [corrected] correlated with [corrected] MCT1, and tended to be positively correlated with MCT4 and NHE1. CAII + CAIII were correlated positively with DeltapH(m)/W(sup-se) and negatively with Delta[Lac](m)/W(sup-se), while CAIV was positively related to W(tot). The changes in W(sup) with Alk were correlated positively with those in dynamic buffer capacity and negatively with W(sup) in Con. Performance improvement with Alk was greater in subjects having a low content of proteins involved in pH regulation and lactate/proton transport. These results show the importance of pH regulating mechanisms and lactate/proton transport on work capacity and the role of the CA to delay decrease in pH(m) and accumulation in [Lac](m) during supramaximal exercise in humans.

Muscle MCT4 Content Is Correlated with the Lactate Removal Ability during Recovery Following All-Out Supramaximal Exercise in Highly-Trained Rowers.

The purpose of this study was to test if the lactate exchange (γ1) and removal (γ2) abilities during recovery following short all-out supramaximal exercise correlate with the muscle content of MCT1 and MCT4, the two isoforms of the monocarboxylate transporters family involved in lactate and H(+) co-transport in skeletal muscle. Eighteen lightweight rowers completed a 3-min all-out exercise on rowing ergometer. Blood lactate samples were collected during the subsequent passive recovery to assess an individual blood lactate curve (IBLC). IBLC were fitted to the bi-exponential time function: La(t) = [La](0) + A1(1 - [Formula: see text]) + A2(1 - [Formula: see text]) where [La](0) is the blood lactate concentration at exercise completion and the velocity constants γ1 and γ2 denote the lactate exchange and removal abilities, respectively. An application of the bi-compartmental model of lactate distribution space allowed estimation of the lactate removal rate at exercise completion [LRR(0)]. Biopsy of the right vastus lateralis was taken at rest to measure muscle MCT1 and MCT4 content. Fiber type distribution, activity of key enzymes and capillary density (CD) were also assessed. γ1 was correlated with [La](0) (r = -0.54, P < 0.05) but not with MCT1, MCT4 or CD. γ2 and LRR(0) were correlated with MCT4 (r = 0.63, P < 0.01 and r = 0.73, P < 0.001, respectively) but not with MCT1 or cytochrome c oxidase activity. These findings suggest that the lactate exchange ability is highly dependent on the milieu so that the importance of the muscle MCT1 and MCT4 content in γ1 was hidden in the present study. Our results also suggest that during recovery following all-out supramaximal exercise in well-trained rowers, MCT4 might play a significant role in the distribution and delivery of lactate for its subsequent removal.

Effect of endurance training on the VO2-work rate relationship in normoxia and hypoxia.

PURPOSE: We postulated that the relationship between VO2 and work rate (VO2-WR relationship) during incremental exercise is dependent on O2 availability, and that training-induced adaptations alter this relationship. We therefore studied the effect of endurance training on VO2 response during incremental exercise in normoxia and hypoxia (FIO2=0.134). METHODS: Before and after training (6 d.wk, 4 wk), eight subjects performed incremental exercises under normoxia and hypoxia and one constant-work rate exercise in normoxia at 80% of pretraining VO2max. The slopes of the VO2-WR relationship during incremental exercise were calculated using all the points (whole slope) or only points before the lactate threshold (pre-LT slope). The difference between VO2max measured and VO2max expected from the pre-LT slope (DeltaVO2) was determined, as was the difference between VO2 at minute 10 and VO2 at minute 4 during the constant-work rate exercise (DeltaVO2(10'-4')). RESULTS: In normoxia, training induced a significant decrease in the whole slope (11.0+/-1.0 vs 9.9+/-0.4 mL.min.W, P<0.05). In hypoxia, training induced a significant increase in the pre-LT slope (8.7+/-1.2 vs 9.8+/-0.7 mL.min.W; P<0.05) and the whole slope (8.5+/-1.2 vs 9.4+/-0.5 mL.min.W; P<0.05). A significant correlation between the decrease of DeltaVO2 and the decrease of DeltaVO2(10'-4') with training was found in normoxia (P<0.01, r=0.79). CONCLUSIONS: Taken together, these results indicate that adaptations induced by endurance training are associated with more efficient incremental and constant-workload exercise performed in normoxia. Moreover, training contributes to improved O2 delivery during moderate exercise performed in hypoxia, and to enhanced near-maximal exercise tolerance.

A methodology to assess the accuracy of a portable metabolic system (VmaxST).

PURPOSE: Validity of a portable metabolic system (VmaxST) was investigated during gas exchanges simulations by a mechanical system (GESS) and during human exercise. METHODS: Three tests were conducted while gas exchanges were measured continuously by VmaxST. Test 1 was composed of six simulations of gas exchanges during steady-state exercise (20 min at V̇E = 80 L.min-1). Test 2 was composed of seven simulations of gas exchanges during incremental exercise (V̇O(2) from 300 to 5600 mL.min-1). In the human trial, 11 subjects performed an incremental running exercise on a treadmill while gas exchanges were measured at the end of each stage with the Douglas bag method (DBM). RESULTS: Test 1 showed that the VmaxST measurements were stable, despite inaccurate measurements of gas concentrations at the start of the test. During test 2, the mean error (difference between measured and predicted value) and the upper and lower limits of agreement were -8.0%, -12.6%, and -3.4% for V̇O(2); -4.6%, -12.0%, and +2.8% for V̇CO(2); and -0.7%, -4.7%, and +3.3% for V̇E. During the human trial, no significant difference was shown between V̇O(2) measured by VmaxST and by DBM at any stage of exercise. The mean difference and the upper and lower limits of agreement between the VmaxST and the DBM measurements were -0.5%, -14.3%, and +13.3% for V̇O(2); -6.3%, -20.9%, and +8.3% for V̇CO(2); and -9.9%, -25.5%, and +5.7% for V̇E. CONCLUSIONS: The use of GESS showed that measurements of V̇O(2) by VmaxST could be biased in a standardized condition. In more realistic condition of use, this bias was lower but the accuracy of measurements was impaired.

Assessment of arterial gas pressures and cardiac output using a breathing lung model.

PURPOSE: The aim of this investigation was to evaluate a breathing lung model to estimate arterial gas partial pressures and cardiac output at rest and during exercise. METHODS: A mathematical model was used to describe variations in gas fractions, alveolar volume, and gas exchange in the pulmonary capillaries during the breathing cycle. Experimental data were obtained from 17 healthy subjects at rest and during exercise at 40, 50, 65, and 75% VO(2max) on a cycle ergometer. VO(2), VCO(2), and P(ET,CO2) were monitored continuously with a MedGraphics CPX/D gas exchange system. Arterial gases were measured in brachial artery blood samples drawn simultaneously with gas exchange. Cardiac output was measured using the CO(2) rebreathing method corrected by the arterial blood sample data. The model parameters including cardiac output, end-expiratory alveolar volume, and mixed-venous gas contents were estimated by fitting modelVCO(2) to experimental values over 50 breaths. RESULTS: The fit of model parameters gave arterial gas partial pressures not significantly different from measured data. Measured P(a,C02) and P(a,O2) were significantly correlated with model outputs (R(2) = 0.991 for P(a,CO2) and R(2) = 0.999 for P(a, CO2); P < 0.0001). The cardiac output values estimated using the breathing lung model were significantly correlated with the values obtained with the corrected CO rebreathing method (R(2) = 0.71; P < 0.0001). There was, however, a significant 2.3 L x min(-1) difference between these two methods. CONCLUSION: Results obtained with the proposed method were in good agreement with measured arterial gas partial pressures. Despite a certain degree of bias, the promising results for cardiac output demonstrate the reliability of this method that should be now evaluated using a gold standard method.

Modeling of end-tidal and arterial PCO2 gradient: comparison with experimental data.

PURPOSE: The aim of this study was to test whether a tidally ventilated homogeneous lung model can correctly describe arterial and end-tidal gas partial pressures and thus the difference in end-tidal and arterial gas partial pressures at rest and during exercise. METHODS: The implemented mathematical modeling described variations during the breathing cycle in CO2 and O2 fractions, alveolar volume, and pulmonary capillary gas exchange. Experimental data were obtained from measurements performed by 17 healthy subjects at rest and during 40, 50, 65, and 75% exercise .VO(2max) on a cycle ergometer. VO2, VCO2, and PET,CO2 were continuously measured using the MedGraphics CPX/D gas exchange system. Arterial gases were measured in brachial artery blood samples drawn simultaneously with gas exchange. Cardiac output was measured using the CO2 rebreathing method corrected by the blood sample data. The model was driven using experimental data for ventilation, VO2, VCO2, and cardiac output. RESULTS: The mean difference and the upper and lower limits of agreement between measured and simulated data were -0.004, +0.84, and -0.84 Torr for Pa,CO2; -0.06, +0.64, and -0.76 Torr for Pa,O2; -1.96, +2.84, and -6.76 Torr for PET,CO2; and +7.20, +25.80, and -11.40 Torr for PET,O2. Actual PET,CO2-Pa,CO2 difference increased significantly with workload (P < 0.0001) from 0.3 +/- 3 Torr at rest to 4.7 +/- 2.5 Torr at 75% .VO(2max). Model-simulated PET,CO2-Pa,CO2 difference also increased significantly with exercise (P < 0.0001) from 0.7 +/- 1.7 Torr at rest to 9.1 +/- 3.4 Torr at 75% .VO(2max). CONCLUSION: The lung model described actual arterial CO2 partial pressures better than variations in end-tidal CO2 partial pressures and thus better than the gradient in end-tidal arterial CO2 partial pressures.

Physical fitness is independently related to blood leptin concentration and insulin sensitivity index in male subjects with central adiposity.

AIM: To compare the maximal power output (MPO) of subjects presenting a central adiposity to those of controls and to study the links between plasma leptin or indices of insulin sensitivity (QUICKI) and physical fitness (PF). METHODS: MPO was determined for 169 middle-aged men divided into two groups according to waist circumference (WC- < 94 cm, WC+ ≥ 94 cm) each subdivided in two subgroups with low and high PF (WC-L, WC-H, WC+L, WC+H) determined from the median MPO relative to fat free mass (3.06 W/kg(FFM)). RESULTS: MPO (W/kg(FFM)) was lower in WC+ than in WC-. Expressed relative to fat mass, leptin was lower and QUICKI higher in WC- than in WC+. In WC+H, leptin and QUICKI were significantly less disturbed than in WC+L and were independently correlated to MPO (r = -0.36 and r = 0.32 respectively; p < 0.001). In WC+, when visceral perimeter was added to the analysis, the relationships MPO/leptin remained significant but not MPO/QUICKI. CONCLUSION: The low PF in subjects with abdominal obesity is independently linked to plasma leptin and insulin sensitivity even if leptin and insulin may share common pathways in their peripheral effects. Visceral adiposity participates to the link between MPO and QUICKI, but not between MPO and leptin.

Effects of regular physical activity on skeletal muscle structural, energetic, and microvascular properties in carriers of sickle cell trait.

To assess the effects of regular physical activity on muscle functional characteristics of carriers of sickle cell trait (SCT), 39 untrained (U) and trained (T) hemoglobin (Hb)AA (CON) and SCT subjects (U-CON, n = 12; U-SCT, n = 8; T-CON, n = 10; and T-SCT, n = 9) performed a graded exercise and a time to exhaustion (T(ex)) test, and were subjected to a muscle biopsy. Maximal power, total work performed during T(ex), citrate synthase and cytochrome c oxidase (COX) activities, respiratory chain complexes I and IV content, and capillary density (CD), diameter (COD), and surface area (CSA) were upregulated by the same proportion in T-CON and T-SCT compared with their untrained counterparts. These proportionally similar differences imply that the observed discrepancies between U-SCT and U-CON remained in the trained subjects. Specifically, both CD and COX remained and tended to remain lower, and both COD and CSA remained and tended to remain higher in T-SCT than in T-CON. Besides, carriers of SCT displayed specific adaptations with regular physical activity: creatine kinase activity; complexes II, III, and V content; and type I fiber surface area and capillary tortuosity were lower or unchanged in T-SCT than in U-SCT. In summary, our results show that 1) carriers of SCT adapted almost similarly to CON to regular physical activity for most of the studied muscle characteristics, 2) oxidative potential remains altered in physically active carriers of SCT compared with HbAA counterparts, and 3) the specific remodeling of muscle microvascular network persists in the trained state.

Skeletal muscle structural and energetic characteristics in subjects with sickle cell trait, alpha-thalassemia, or dual hemoglobinopathy.

Previous studies have shown that subjects with sickle cell trait (SCT), alpha-thalassemia (alpha-t), and the dual hemoglobinopathy (SCT/alpha-t) manifest subtle, albeit significant, differences during exercise. To better understand such differences, we assessed skeletal muscle histomorphological and energetic characteristics in 10 control HbAA subjects (C), 5 subjects with alpha-t (alpha-t), 6 SCT carriers (SCT) and 9 SCT carriers with alpha-t (SCT/alpha-t). Subjects underwent a muscle biopsy and also performed an incremental maximal exercise and a time to exhaustion test. There were no observable differences in daily energy expenditure, maximal power output (Pmax), or time to exhaustion at 110% Pmax (Tex) among the groups. Blood lactate concentrations measured at the end of the Tex, muscle fiber type distribution, and mean phosphofructokinase (PFK), lactate dehydrogenase (LDH), beta-hydroxyacyl-CoA-dehydrogenase (HAD), and citrate synthase (CS) activities were all similar among the four groups. However, SCT was associated with a lower cytochrome-c oxidase (COx) activity in type IIa fibers (P<0.05), and similar trends were observed in fiber types I and IIx. Trends toward lower creatine kinase (CK) activity (P=0.0702) and higher surface area of type IIx fibers were observed in SCT (P=0.0925). In summary, these findings support most of the previous observations in SCT, such as 1) similar maximal power output and associated maximal oxygen consumption (VO2max) values and 2) lower exercise performances during prolonged submaximal exercise. Furthermore, performances during short supramaximal exercise were not different in SCT. Finally, the dual hemoglobinopathy condition does not seem to affect muscle characteristics.

Effects of combined lower body endurance and upper body resistance training on the satellite cell pool in elderly subjects.

To distinguish the respective potential of endurance and resistance training to increase the satellite cell pool, we investigated the effects of 14 weeks of concurrent lower body endurance and upper body resistance training (3 sessions/week) on vastus lateralis (VLat) and deltoid (Del) muscles of 10 active elderly men. NCAM+ satellite cells and myonuclear number were assessed in VLat and Del. After 14 weeks of training the NCAM+ satellite cell pool increased similarly (+38%) in both muscles, mainly in type II muscle fibers (P < 0.05). There was no significant change in myonuclear number or myonuclear domain in either muscle. Combining resistance training in the upper limbs with endurance training in the lower limbs is an efficient strategy to enhance the satellite cell pool in upper and lower body muscles in elderly subjects. Our results provide a practical reference for the determination of optimal exercise protocols to improve muscle function and regeneration in the elderly.

An elevated sarcolemmal lactate (and proton) transport capacity is an advantage during muscle activity in healthy humans.

The etiology of muscle fatigue remains incompletely solved especially in vivo (3). The causes of muscle fatigue vary according to the type, duration and intensity of exercise, and to the physical fitness and health status of the subjects. Nevertheless, an elevated sarcolemmal lactate (and proton) transport capacity constitutes an advantage during muscle activity. During moderate-intensity exercise, efficient lactate exchanges contribute to the cell-cell lactate shuttle i.e., the delivery of lactate for its utilization as fuel by neighboring or distant active and oxidative muscles fibers or as substrate by other tissues (e.g. for neoglucogenesis by the liver) (1). During high-intensity exercise, the lactate exchange ability was positively correlated with the capacity to prolong exercise (4). Whether this correlation between the lactate exchange ability and performance was (directly or indirectly) causal or coincidental, the question is still under debate. Nevertheless, it remains that an elevated lactate exchange ability seems to constitute a protective mechanism against muscle fatigue. Since the transport of lactate across the sarcolemma is mediated mainly by the lactate-H+ cotransport via the monocarboxylate transporters MCT1 and MCT4, an elevated lactate transport capacity delays both muscle lactate accumulation and intracellular pH decrease and seems to favor muscle activity. In accordance, previous experiments have shown that metabolic alkalosis enhances the net lactate release rate from the active muscles and work capacity (2, 5) contrary to acidosis that reduces lactate efflux from muscle and exercise tolerance (5). All this makes an elevated sarcolemmal lactate (and proton) transport capacity an advantage during muscle activity.

Combined lower body endurance and upper body resistance training improves performance and health parameters in healthy active elderly.

We investigated the effects of combined lower body (LB) endurance and upper body (UB) resistance training on endurance, strength, blood lipid profile and body composition in active older men. Ten healthy still active men (73+/-4 years, V(O2) peak: 36 (31-41) ml min-1 kg-1) were tested before and after 14 weeks of combined training (3 times week-1). Training consisted of 3x12 min of high intensity interval training on a bicycle for endurance interspersed by 3x12 min of UB resistance exercises. V(O2) peak during leg cycling and arm cranking, isokinetic torque of knee extensor and shoulder abductor and the cross-sectional area (CSA) of several muscles from UB and LB were measured. Sagittal abdominal diameter (SAD) and abdominal fat area were measured on MRI scans. Total body composition was assessed by hydrostatic weighing (HW) and dual-energy X-ray absorptiometry (DEXA). Blood lipid profile was assessed before and after training. By the end of the training period, V(O2) peak (l min-1) increased significantly by 9 and 16% in leg cycling and arm cranking tests, respectively. Maximal isokinetic torque increased both for the knee extensor and shoulder abductor muscle groups. CSA increased significantly in deltoid muscle. Percentage of body fat decreased by 1.3% (P<0.05) and abdominal fat and SAD decreased by 12 and 6%, respectively (P<0.01). There was also a significant decrease in total cholesterol and low-density lipoprotein. Thus, combined LB endurance and UB resistance training can improve endurance, strength, body composition and blood lipid profile even in healthy active elderly.

Are the effects of training on fat metabolism involved in the improvement of performance during high-intensity exercise?

The objective of the present study was to relate changes in certain muscle characteristics and indicators of metabolism in response to endurance training to the concomitant changes in time to exhaustion (T(lim)) at a work rate corresponding to maximal oxygen uptake VO(2speak). Eight healthy sedentary subjects pedalled on a cycle ergometer 2 h a day, 6 days a week, for 4 weeks. Training caused increases in VO(2peak) (by 8%), T(lim) (from 299 +/- 23 s before to 486 +/- 63 s after training), citrate synthase and 3-hydroxyl-acyl-CoA dehydrogenase (HAD) activities (by 54% and 16%, respectively) and capillary density (by 31%). Decreases in activity of lactate dehydrogenase (LDH) and muscle type of LDH (by 24% and 28%, respectively) and the phosphofructokinase/citrate synthase ratio (by 37%) were also observed. Respiratory exchange ratio (RER) tended to be lower (P < 0.1) at all relative work rates after training while the corresponding ventilation rates (VE) were unchanged. At the same absolute work rate, RER and (VE) were lower after training (P < 0.05). The improvement of T(lim) with training was related to the increases in HAD activity (r = 0.91, P = 0.0043), and to the decreases in RER calculated for Pa(peak) (r = 0.71, P = 0.0496). The present results suggest that the training-induced adaptations in fat metabolism might influence T(lim) at a work rate corresponding to VO(2peak) and stimulate the still debated and incompletely understood role of fat metabolism during short high-intensity exercise.

Study of the auditory tube by ventilation scintigraphy with technetium-99m.

The two essential regulating mechanisms of the middle ear pressure are the trans-mucosal gas exchange in the middle ear and the ventilation function of the eustachian tube (ET). The physiological mechanism of these both functions is not yet clear. The purpose of this study was to evaluate the role of the ET pressure equilibrium function by ventilation scintigraphy with technetium-99m. The rabbit animal model in vivo was used to study the presence and role of the ventilation of the tympanic cavity via auditory tube. The obtained results did not show any ventilation function of the ET despite active opening by muscle movement. In our experience, ventilation scintigraphy with technetium-99m is not a reliable method to study the auditory tube pressure equilibrium function in physiological conditions.

Effect of hyperoxia on maximal O2 uptake in exercise-induced arterial hypoxaemic subjects.

This study focuses on the effect of hyperoxia on maximal oxygen uptake VO2max and maximal power (Pmax) in subjects exhibiting exercise-induced arterial hypoxemia (EIH) at sea level. Sixteen competing male cyclists VO2max > 60 ml.min(-1).kg(-1)) performed exhaustive ramp exercise (cycle-ergometer) under normoxia and moderate hyperoxia (FIO2 = 30%). After the normoxic trial, the subjects were divided into those demonstrating EIH during exercise [arterial O2 desaturation (delta SaO2) >5%; n = 9] and those who did not (n = 7). Under hyperoxia, SaO2 raised and the increase was greater for the EIH than for the non-EIH group (P<0.001). VO2max improved for both groups and to a greater extent for EIH (12.8 +/- 5.7% vs. 4.2 +/- 4.6%, P<0.01; mean+/-SD) and the increase was correlated to the gain in SaO2 for all subjects (r = 0.71, P<0.01). Pmax improved by 3.3 +/- 3.3% (P<0.01) regardless of the group. These data suggest that pulmonary gas exchange contributes to a limitation in VO2max and power for especially EIH subjects.