Muscle O2 Uptake Research Articles

Combination of hyperoxia and a right-shifted HbO2 dissociation curve delays V̇o2 kinetics during maximal contractions in isolated muscle.

Acute enhancement of peripheral O2 diffusion may accelerate skeletal muscle O2 uptake (V̇o2) kinetics and lessen fatigue during transitions from rest to maximal contractions. Surgically isolated canine gastrocnemius muscles in situ (n = 6) were studied during transitions from rest to 4 min of electrically stimulated isometric tetanic contractions at V̇o2peak, in two conditions: normoxia (CTRL) and hyperoxia ([Formula: see text] = 1.00) + administration of a drug (RSR-13), which right shifts the Hb-O2 dissociation curve (Hyperoxia + RSR-13). Before and during contractions, muscles were pump-perfused with blood at constant elevated flow ([Formula: see text]) and infused with the vasodilator adenosine. Arterial ([Formula: see text]) and muscle venous ([Formula: see text]) O2 concentrations were determined at rest and at 5- to 7-s intervals during contractions; V̇o2 was calculated as [Formula: see text]·([Formula: see text] - [Formula: see text]). Po2 at 50% of Hb saturation (standard P50) and mean microvascular Po2 ([Formula: see text]) were calculated by the Hill equation and a numerical integration technique. P50 [42 ± 7 (means ± SD) mmHg vs. 33 ± 2 mmHg, P = 0.02] and [Formula: see text] (218 ± 73 mmHg vs. 49 ± 4 mmHg, P = 0.003) were higher in Hyperoxia + RSR-13. Muscle force and fatigue were not different in the two conditions. V̇o2 kinetics (monoexponential fitting) were unexpectedly slower in Hyperoxia + RSR-13, due to a longer time delay (TD) [9.9 ± 1.7 s vs. 4.4 ± 2.2 s (P = 0.001)], whereas the time constant (τ) was not different [13.7 ± 4.3 s vs. 12.3 ± 1.9 s (P = 0.37)]; the mean response time (TD + τ) was longer in Hyperoxia + RSR-13 [23.6 ± 3.5 s vs. 16.7 ± 3.2 s (P = 0.003)]. Increased O2 availability deriving, in Hyperoxia + RSR-13, from higher [Formula: see text] and from presumably greater intramuscular O2 stores did not accelerate the primary component of the V̇o2 kinetics, and delayed the metabolic activation of oxidative phosphorylation.NEW & NOTEWORTHY In isolated perfused skeletal muscle, during transitions from rest to V̇o2peak, hyperoxia and a right-shifted oxyhemoglobin dissociation curve increased O2 availability by increasing microvascular Po2 and by presumably increasing intramuscular O2 stores. The interventions did not accelerate the primary component of the V̇o2 kinetics (as calculated from blood O2 unloading) and delayed the metabolic activation of oxidative phosphorylation. V̇o2 kinetics appear to be mainly controlled by intramuscular factors related to the use of high-energy "buffers."

Insight into type 2 diabetes impaired exercising mitochondrial oxidative flux: is it blood flow, mitochondria, or neither?

Insight into type 2 diabetes impaired exercising mitochondrial oxidative flux: is it blood flow, mitochondria, or neither?

Exercise training in COPD: muscle O2 transport plasticity.

Both convective oxygen (O2) transport to, and diffusive transport within, skeletal muscle are markedly diminished in patients with COPD. However, it is unknown how these determinants of peak muscle O2 uptake (V'mO2peak) respond to exercise training in patients with COPD. Therefore, the purpose of this study was to assess the plasticity of skeletal muscle O2 transport determinants of V'mO2peak in patients with COPD.Adaptations to 8 weeks of single-leg knee-extensor exercise training were measured in eight patients with severe COPD (mean±sem forced expiratory volume in 1 s (FEV1) 0.9±0.1 L) and eight healthy, well-matched controls. Femoral arterial and venous blood samples, and thermodilution-assessed leg blood flow were used to determine muscle O2 transport and utilisation at maximal exercise pre- and post-training.Training increased V'mO2peak in both COPD (by ∼26% from 271±29 to 342±35 mL·min-1) and controls (by ∼32% from 418±37 to 553±41 mL·min-1), restoring V'mO2peak in COPD to only ∼80% of pre-training control V'mO2peak Muscle diffusive O2 transport increased similarly in both COPD (by ∼38% from 6.6±0.9 to 9.1±0.9 mL·min-1·mmHg-1) and controls (by ∼36% from 10.4±0.7 to 14.1±0.8 mL·min-1·mmHg-1), with the patients reaching ∼90% of pre-training control values. In contrast, muscle convective O2 transport increased significantly only in controls (by ∼26% from 688±57 to 865±69 mL·min-1), leaving patients with COPD (438±45 versus 491±51 mL·min-1) at ∼70% of pre-training control values.While muscle diffusive O2 transport in COPD was largely restored by exercise training, V'mO2peak remained constrained by limited plasticity in muscle convective O2 transport.

Measurement of muscle blood flow and O2 uptake via near-infrared spectroscopy using a novel occlusion protocol

We describe here a novel protocol that sequentially combines venous followed by arterial occlusions to determine muscle blood flow and O2 uptake from a single measurement point using near-infrared spectroscopy (NIRS) during handgrip exercise. NIRS data were obtained from the flexor digitorum superficialis (FDS) muscle on the dominant arm of 15 young, healthy adults (3 women; 26 ± 7 years; 78.6 ± 9.1 kg). Participants completed a series of 15-s static handgrip contractions at 20, 40 and 60% of maximal voluntary contraction (MVC) immediately followed by either a: (i) venous occlusion (VO); (ii); arterial occlusion (AO); or venous then arterial occlusion (COMBO). Each condition was repeated 3 times for each exercise-intensity. The concordance correlation coefficient (CCC) and robust linear mixed effects modeling were used to determine measurement agreement between vascular occlusion conditions. FDS muscle blood flow ({dot{text{Q}}}_{{{text{FDS}}}}) and conductance ({text{C}}_{{{text{FDS}}}}) demonstrated strong absolute agreement between VO and COMBO trials from rest up to 60%MVC, as evidenced by high values for CCC (> 0.82) and a linear relationship between conditions that closely approximated the line-of-identity (perfect agreement). Conversely, although FDS muscle O2 uptake ({{dot {text{V}}}}{{text{O}}_{2{text{FDS}}}}) displayed “substantial” to “near perfect” agreement between methods across exercise intensities (i.e., CCC > 0.80), there was a tendency for COMBO trials to underestimate {{dot {text{V}}}}{{text{O}}_{2{text{FDS}}}} by up to 7%. These findings indicate that the COMBO method provides valid estimates of {dot {text{Q}}}_{{text{FDS}}} and, to a slightly lesser extent, {{dot {text{V}}}}{{text{O}}_{2{text{FDS}}}} at rest and during static handgrip exercise up to 60%MVC. Practical implications and suggested improvements of the method are discussed.

Effect of Blood Flow on Hemoglobin and Myoglobin Oxygenation in Contracting Muscle Using Near-Infrared Spectroscopy.

Insufficient O2 delivery to, and uptake by skeletal muscle can produce mobility limitations for patients with chronic diseases. Near-infrared spectroscopy (NIRS) can be used to noninvasively quantify the balance between skeletal muscle O2 delivery and utilization during contraction. However, it is not clear how the oxygenated or deoxygenated NIRS signal should be used to assess muscle O2 changes. This issue is related to the fact that the contributions of hemoglobin (Hb) and myoglobin (Mb) cannot be distinguished. This conundrum can be resolved by quantitative analysis of experimental data by computer simulations with a mechanistic, mathematical model. Model simulations distinguish dynamic responses of the oxygenated (HbO2, MbO2) and deoxygenated (HHb, HMb) contributions to the NIRS signal components (HbMbO2, HHbMb). Simulations of muscle O2 uptake and NIRS kinetics correspond closely to published experimental data (Hernández et al.,J Appl Physiol 108: 1169-1176, 2010). Simulated muscle O2 uptake and oxygenation kinetics with different blood flows indicate (1) faster O2 delivery is responsible for slower muscle oxygenation kinetics; (2) Hb and Mb contributions to the HbMbO2 are similar (40-60%); and (3) Hb and Mb contributions to the HHbMb are significantly different, 80% and 20%, respectively. The effect of slow blood flow kinetics on oxygenated Hb and Mb contributions is minimal. However, the effect on the imbalance between O2 delivery and utilization rates causes significant overshoots and undershoots of deoxygenated Hb and Mb contributions. Model analysis in combination with NIRS measurements and information on hemodynamic and microvascular distribution can help to determine the use of NIRS signal in evaluating the factors limiting exercise tolerance in health and disease states.

Physiological Evidence That the Critical Torque Is a Phase Transition, Not a Threshold.

ABSTRACTIntroductionDistinct physiological responses to exercise occur in the heavy- and severe-intensity domains, which are separated by the critical power or critical torque (CT). However, how the transition between these intensity domains actually occurs is not known. We tested the hypothesis that CT is a sudden threshold, with no gradual transition from heavy- to severe-intensity behavior within the confidence limits associated with the CT.MethodsTwelve healthy participants performed four exhaustive severe-intensity trials for the determination of CT, and four 30-min trials in close proximity to CT (one or two SE above or below each participant’s CT estimate; CT − 2, CT − 1, CT + 1, CT + 2). Muscle O2 uptake, rectified electromyogram, and torque variability and complexity were monitored throughout each trial, and maximal voluntary contractions (MVC) with femoral nerve stimulation were performed before and after each trial to determine central and peripheral fatigue responses.ResultsThe rates of change in fatigue-related variables, muscle O2 uptake, electromyogram amplitude, and torque complexity were significantly faster in the severe trials compared with CT − 2. For example, the fall in MVC torque was −1.5 ± 0.8 N·m·min−1 in CT − 2 versus –7.9 ± 2.5 N·m·min−1 in the lowest severe-intensity trial (P < 0.05). Individual analyses showed a low frequency of severe responses even in the circa-CT trials ostensibly above the CT, but also the rare appearance of severe-intensity responses in all circa-CT trials.ConclusionsThese data demonstrate that the transition between heavy- and severe-intensity exercise occurs gradually rather than suddenly.

Edward F. Adolph Distinguished Lecture. Contemporary model of muscle microcirculation: gateway to function and dysfunction.

This review strikes at the very heart of how the microcirculation functions to facilitate blood-tissue oxygen, substrate, and metabolite fluxes in skeletal muscle. Contemporary evidence, marshalled from animals and humans using the latest techniques, challenges iconic perspectives that have changed little over the past century. Those perspectives include the following: the presence of contractile or collapsible capillaries in muscle, unitary control by precapillary sphincters, capillary recruitment at the onset of contractions, and the notion of capillary-to-mitochondrial diffusion distances as limiting O2 delivery. Today a wealth of physiological, morphological, and intravital microscopy evidence presents a completely different picture of microcirculatory control. Specifically, capillary red blood cell (RBC) and plasma flux is controlled primarily at the arteriolar level with most capillaries, in healthy muscle, supporting at least some flow at rest. In healthy skeletal muscle, this permits substrate access (whether carried in RBCs or plasma) to a prodigious total capillary surface area. Pathologies such as heart failure or diabetes decrease access to that exchange surface by reducing the proportion of flowing capillaries at rest and during exercise. Capillary morphology and function vary disparately among tissues. The contemporary model of capillary function explains how, following the onset of exercise, muscle O2 uptake kinetics can be extremely fast in health but slowed in heart failure and diabetes impairing contractile function and exercise tolerance. It is argued that adoption of this model is fundamental for understanding microvascular function and dysfunction and, as such, to the design and evaluation of effective therapeutic strategies to improve exercise tolerance and decrease morbidity and mortality in disease.

Exercise training improves blood flow to contracting skeletal muscle of older men via enhanced cGMP signaling

Physical activity has the potential to offset age-related impairments in the regulation of blood flow and O2 delivery to the exercising muscles; however, the mechanisms underlying this effect of physical activity remain poorly understood. The present study examined the role of cGMP in training-induced adaptations in the regulation of skeletal muscle blood flow and oxidative metabolism during exercise in aging humans. We measured leg hemodynamics and oxidative metabolism during exercise engaging the knee extensor muscles in young [ n = 15, 25 ± 1 (SE) yr] and older ( n = 15, 72 ± 1 yr) subjects before and after a period of aerobic high-intensity exercise training. To determine the role of cGMP signaling, pharmacological inhibition of phosphodiesterase 5 (PDE5) was performed. Before training, inhibition of PDE5 increased ( P < 0.05) skeletal muscle blood flow and O2 uptake during moderate-intensity exercise in the older group; however, these effects of PDE5 inhibition were not detected after training. These findings suggest a role for enhanced cGMP signaling in the training-induced improvement of regulation of blood flow in contracting skeletal muscle of older men. NEW & NOTEWORTHY The present study provides evidence for enhanced cyclic GMP signaling playing an essential role in the improved regulation of blood flow in contracting skeletal muscle of older men with aerobic exercise training.

Sex-Specific Impact of Ischemic Preconditioning on Tissue Oxygenation and Maximal Concentric Force.

Prior peripheral hypoxia induced via remote ischemic preconditioning (IPC) can improve physical performance in male athletes through improved O2 delivery and utilization. Since females may have an innate protective mechanism against ischemia-reperfusion injury, and since muscle metabolism during contraction differs between sexes, it is relevant to examine the impact of sex in response to IPC to determine whether it is also ergogenic in females. In a randomized, crossover, single-blind study, we investigated muscle performance, hemodynamic and O2 uptake in strength-trained males (n = 9) and females (n = 8) performing five sets of 5 maximum voluntary knee extensions on an isokinetic dynamometer, preceded by either IPC (3 × 5-min ischemia/5-min reperfusion cycles at 200 mmHg) or SHAM (20 mmHg). Changes in deoxy-hemoglobin (Δ[HHb], expressed in percentage of arterial occlusion and considered an index of O2 extraction), and total hemoglobin (Δ[THb]) concentrations of the vastus lateralis muscle were continuously monitored by near-infrared spectroscopy. The metabolic efficiency of the contractions was calculated as the average force/Δ[HHb]avg ratio. Cohen's effect sizes (ES) ± 90% confidence limits were used to estimate IPC-induced changes and sex differences. IPC increased total muscular force in males only (13.0%, ES 0.64, 0.37;0.90), and this change was greater than in females (10.4% difference, ES 0.40, 0.10;0.70). Percent force decrement was only attenuated in females (−19.8%, ES −0.38, −0.77;0.01), which was clearly different than males (sex difference: ES 0.45, −0.16;1.07). IPC also induced different changes between sexes for average muscle O2 uptake in set 2 (males: 6.4% vs. females: −16.7%, ES 0.21, −0.18;0.60), set 3 (males: 7.0% vs. females: −44.4%, ES 0.56, −0.17;1.29), set 4 (males: 9.1% vs. females: −40.2%, ES 0.51, −0.10;1.13), and set 5 (males: 10.2% vs. females: −40.4%, ES 0.52, −0.04;1.09). However, metabolic efficiency was not meaningfully different between conditions and sexes. IPC increased muscle blood volume (↑[THb]) at rest and during recovery between sets, to the same extent in both sexes. Despite a similar IPC-induced initial increase in O2 delivery in both sexes, males displayed greater peripheral O2 extraction and greater strength enhancement. This ergogenic effect appears to be mediated in part via an up regulated oxidative function in males. We conclude that strength-trained males might benefit more from IPC than their female counterparts during repeated, maximal efforts.

Enhanced muscular oxygen extraction in athletes exaggerates hypoxemia during exercise in hypoxia.

High rate of muscular oxygen utilization facilitates the development of hypoxemia during exercise at altitude. Because endurance training stimulates oxygen extraction capacity, we investigated whether endurance athletes are at higher risk to developing hypoxemia and thereby acute mountain sickness symptoms during exercise at simulated high altitude. Elite athletes (ATL; n = 8) and fit controls (CON; n = 7) cycled for 20 min at 100 W (EX100W), as well as performed an incremental maximal oxygen consumption test (EXMAX) in normobaric hypoxia (0.107 inspired O2 fraction) or normoxia (0.209 inspired O2 fraction). Cardiorespiratory responses, arterial Po2 (PaO2), and oxygenation status in m. vastus lateralis [tissue oxygenation index (TOIM)] and frontal cortex (TOIC) by near-infrared spectroscopy, were measured. Muscle O2 uptake rate was estimated from change in oxyhemoglobin concentration during a 10-min arterial occlusion in m. gastrocnemius. Maximal oxygen consumption in normoxia was 70 ± 2 ml·min(-1·)kg(-1) in ATL vs. 43 ± 2 ml·min(-1·)kg(-1) in CON, and in hypoxia decreased more in ATL (-41%) than in CON (-25%, P < 0.05). Both in normoxia at PaO2 of ∼95 Torr, and in hypoxia at PaO2 of ∼35 Torr, muscle O2 uptake was twofold higher in ATL than in CON (0.12 vs. 0.06 ml·min(-1)·100 g(-1); P < 0.05). During EX100W in hypoxia, PaO2 dropped to lower (P < 0.05) values in ATL (27.6 ± 0.7 Torr) than in CON (33.5 ± 1.0 Torr). During EXMAX, but not during EX100W, TOIM was ∼15% lower in ATL than in CON (P < 0.05). TOIC was similar between the groups at any time. This study shows that maintenance of high muscular oxygen extraction rate at very low circulating PaO2 stimulates the development of hypoxemia during submaximal exercise in hypoxia in endurance-trained individuals. This effect may predispose to premature development of acute mountain sickness symptoms during exercise at altitude.

Rebuttal from Carsten Lundby and David Montero.

Our opponent warrants the regulation of by diffusion of O2 from microvessels into active muscle fibres on the authority of two selected observations based on experiments conducted in isolated canine gastrocnemius preparations (Wagner, 2015). Of these observations only one is de facto, however (see below), and has already been rebutted by the bulk of canine evidence on this topic, which in line with unequivocal data in healthy humans does not indicate any regulatory role for O2 diffusion from microvessels into muscle at (Lundby & Montero, 2015). In fact Wagner (2015) omits that his own cited work demonstrates identical muscle O2 uptake despite having elevated P50 experimentally (Richardson et al. 1998).

Endurance training facilitates myoglobin desaturation during muscle contraction in rat skeletal muscle.

At onset of muscle contraction, myoglobin (Mb) immediately releases its bound O2 to the mitochondria. Accordingly, intracellular O2 tension (PmbO2) markedly declines in order to increase muscle O2 uptake (mO2). However, whether the change in PmbO2 during muscle contraction modulates mO2 and whether the O2 release rate from Mb increases in endurance-trained muscles remain unclear. The purpose of this study was, therefore, to determine the effect of endurance training on O2 saturation of Mb (SmbO2) and PmbO2 kinetics during muscle contraction. Male Wistar rats were subjected to a 4-week swimming training (Tr group; 6 days per week, 30 min × 4 sets per day) with a weight load of 2% body mass. After the training period, deoxygenated Mb kinetics during muscle contraction were measured using near-infrared spectroscopy under hemoglobin-free medium perfusion. In the Tr group, the mO2peak significantly increased by 32%. Although the PmbO2 during muscle contraction did not affect the increased mO2 in endurance-trained muscle, the O2 release rate from Mb increased because of the increased Mb concentration and faster decremental rate in SmbO2 at the maximal twitch tension. These results suggest that the Mb dynamics during muscle contraction are contributing factors to faster O2 kinetics in endurance-trained muscle.

Effects of lung ventilation-perfusion and muscle metabolism-perfusion heterogeneities on maximal O2 transport and utilization.

We expanded a prior model of whole-body O2 transport and utilization based on diffusive O2 exchange in the lungs and tissues to additionally allow for both lung ventilation-perfusion and tissue metabolism-perfusion heterogeneities, in order to estimate V̇O2 and mitochondrial PO2 (PmO2) during maximal exercise. Simulations were performed using data from (a) healthy fit subjects exercising at sea level and at altitudes up to the equivalent of Mount Everest and (b) patients with mild and severe chronic obstructive pulmonary disease (COPD) exercising at sea level. Heterogeneity in skeletal muscle may affect maximal O2 availability more than heterogeneity in lung, especially if mitochondrial metabolic capacity (V̇ MAX ) is only slightly higher than the potential to deliver O2 , but when V̇ MAX is substantially higher than O2 delivery, the effect of muscle heterogeneity is comparable to that of lung heterogeneity. Skeletal muscle heterogeneity may result in a wide range of potential mitochondrial PO 2 values, a range that becomes narrower as V̇ MAX increases; in regions with a low ratio of metabolic capacity to blood flow, PmO2 can exceed that of mixed muscle venous blood. The combined effects of lung and peripheral heterogeneities on the resistance to O2 flow in health decreases with altitude. Previous models of O2 transport and utilization in health considered diffusive exchange of O2 in lung and muscle, but, reasonably, neglected functional heterogeneities in these tissues. However, in disease, disregarding such heterogeneities would not be justified. Here, pulmonary ventilation-perfusion and skeletal muscle metabolism-perfusion mismatching were added to a prior model of only diffusive exchange. Previously ignored O2 exchange in non-exercising tissues was also included. We simulated maximal exercise in (a) healthy subjects at sea level and altitude, and (b) COPD patients at sea level, to assess the separate and combined effects of pulmonary and peripheral functional heterogeneities on overall muscle O2 uptake (V̇O2) and on mitochondrial PO2 (PmO2). In healthy subjects at maximal exercise, the combined effects of pulmonary and peripheral heterogeneities reduced arterial PO2 (PaO2) at sea level by 32mmHg, but muscle V̇O2 by only 122mlmin(-1) (-3.5%). At the altitude of Mt Everest, lung and tissue heterogeneity together reduced PaO2 by less than 1mmHg and V̇O2 by 32mlmin(-1) (-2.4%). Skeletal muscle heterogeneity led to a wide range of potential PmO2 among muscle regions, a range that becomes narrower asV̇ MAX increases, and in regions with a low ratio of metabolic capacity to blood flow, PmO2 can exceed that of mixed muscle venous blood. For patients with severe COPD, peak V̇O2 was insensitive to substantial changes in the mitochondrial characteristics for O2 consumption or the extent of muscle heterogeneity. This integrative computational model of O2 transport and utilization offers the potential for estimating profiles of PmO2 both in health and in diseases such as COPD if the extent for both lung ventilation-perfusion and tissue metabolism-perfusion heterogeneity is known.

Oxygen cost of exercise hyperpnea is greater in women compared to men (882.3)

We tested the hypothesis that the O2 cost of exercise hyperpnea is greater in women compared to men. Healthy subjects (8M, 7F) first performed a maximal step cycle exercise test with esophageal and gastric balloon instrumentation followed by a hyperpnea familiarization trial on a separate day. Cardiorespiratory parameters were measured and flow‐ and pressure‐volume loops were constructed from the same breaths (~n=10) for each exercise stage. Days 3 and 4 involved exercise hyperpnea mimicking over 5 ventilatory levels while in the cycling position. Mimicking trials were repeated (n=4) for each ventilatory level. End‐tidal CO2 was controlled to a level corresponding to each exercise stage. Respiratory muscle O2 uptake (VO2rm) was linearly related to work of breathing (WOB) in men (r=0.94, P&lt;0.001) and women (r=0.88, P&lt;0.001). The VO2rm to VE relationship was assessed by fitting a regression accounting for viscous and resistive work. There was no difference in viscous work (P=0.45); however, the resistive component was ~13x greater in women (P&lt;0.05). At maximal ventilation the absolute VO2rm was similar between sexes (0.39 vs. 0.42 l min‐1, P=0.52) despite men having a greater VE (108 vs. 169 l min‐1); but the VO2rm represented a greater fraction of whole‐body VO2 in women (14.6 vs. 9.8%, P&lt;0.05). In conclusion, the O2 cost of exercise hyperpnea is greater in women owing to a greater resistive WOB.Grant Funding Source: Natural Sciences and Engineering Research Council of Canada

A validated model of oxygen uptake and circulatory dynamic interactions at exercise onset in humans

At the onset of muscular exercise, the kinetics of pulmonary O2 uptake (Vo2P) reflect the integrated dynamic responses of the ventilatory, circulatory, and neuromuscular systems for O2 transport and utilization. Muscle O2 uptake (Vo2m) kinetics, however, are dissociated from Vo2P kinetics by intervening O2 capacitances and the dynamics of the circulation and ventilation. We developed a multicompartment computational model (MCM) to investigate these dynamic interactions and optimized and validated the MCM using previously published, simultaneously measured Vo2m, alveolar O2 uptake (Vo2A), and muscle blood flow (Qm) in healthy young men during cycle ergometry. The model was used to show that 1) the kinetics of Vo2A during exercise transients are very sensitive to preexercise blood flow distribution and the absolute value of Qm, 2) a low preexercise Qm exaggerates the magnitude of the transient fall in venous O2 concentration for any given Vo2m kinetics, necessitating a tighter coupling of Qm/Vo2m (or a reduction in the available work rate range) during the exercise transient to avoid limits to O2 extraction, and 3) information regarding exercise-related alterations in O2 uptake and blood flow in nonexercising tissues and their effects on mixed venous O2 concentration is required to accurately predict Vo2A kinetics from knowledge of Vo2m and Qm dynamics. Importantly, these data clearly demonstrate that Vo2A kinetics are nonexponential, nonlinear distortions of Vo2m kinetics that can be explained in a MCM by interactions among circulatory and cellular respiratory control processes before and during exercise.

Influence of exercise intensity on skeletal muscle blood flow, O2 extraction and O2 uptake on-kinetics.

Following the start of low-intensity exercise in healthy humans, it has been established that the kinetics of skeletal muscle O(2) delivery is faster than, and does not limit, the kinetics of muscle O(2) uptake (V(O(2)(m))). Direct data are lacking, however, on the question of whether O(2) delivery might limit (V(O(2)(m))) kinetics during high-intensity exercise. Using multiple exercise transitions to enhance confidence in parameter estimation, we therefore investigated the kinetics of, and inter-relationships between, muscle blood flow (Q(m)), a-(V(O(2))) difference and (V(O(2)(m))) following the onset of low-intensity (LI) and high-intensity (HI) exercise. Seven healthy males completed four 6 min bouts of LI and four 6 min bouts of HI single-legged knee-extension exercise. Blood was frequently drawn from the femoral artery and vein during exercise and Q(m), a-(V(O(2))) difference and (V(O(2)(m))) were calculated and subsequently modelled using non-linear regression techniques. For LI, the fundamental component mean response time (MRT(p)) for Q(m) kinetics was significantly shorter than (V(O(2)(m))) kinetics (mean ± SEM, 18 ± 4 vs. 30 ± 4 s; P < 0.05), whereas for HI, the MRT(p) for Q(m) and (V(O(2)(m))) was not significantly different (27 ± 5 vs. 29 ± 4 s, respectively). There was no difference in the MRT(p) for either Q(m) or (V(O(2)(m))) between the two exercise intensities; however, the MRT(p)for a-(V(O(2)) difference was significantly shorter for HI compared with LI (17 ± 3 vs. 28 ± 4 s; P < 0.05). Excess O(2), i.e. oxygen not taken up (Q(m) x (V(O(2))), was significantly elevated within the first 5 s of exercise and remained unaltered thereafter, with no differences between LI and HI. These results indicate that bulk O(2) delivery does not limit (V(O(2)(m))) kinetics following the onset of LI or HI knee-extension exercise.

Faster O2 uptake kinetics in canine skeletal muscle in situ after acute creatine kinase inhibition

Creatine kinase (CK) plays a key role both in energy provision and in signal transduction for the increase in skeletal muscle O2 uptake () at exercise onset. The effects of acute CK inhibition by iodoacetamide (IA; 5 mm) on kinetics were studied in isolated canine gastrocnemius muscles in situ (n = 6) during transitions from rest to 3 min of electrically stimulated contractions eliciting ∼70% of muscle peak , and were compared to control (Ctrl) conditions. In both IA and Ctrl muscles were pump-perfused with constantly elevated blood flows. Arterial and venous [O2] were determined at rest and every 5-7 s during contractions. was calculated by Fick's principle. Muscle biopsies were obtained at rest and after ∼3 min of contractions. Muscle force was measured continuously. There was no fatigue in Ctrl (final force/initial force (fatigue index, FI) = 0.97 ± 0.06 (x ± s.d.)), whereas in IA force was significantly lower during the first contractions, slightly recovered at 15-20 s and then decreased (FI 0.67 ± 0.17). [Phosphocreatine] was not different in the two conditions at rest, and decreased during contractions in Ctrl, but not in IA. at 3 min was lower in IA (4.7 ± 2.9 ml 100 g-1 min-1) vs. Ctrl (16.6 ± 2.5 ml 100 g-1 min-1). The time constant (τ) of kinetics was faster in IA (8.1 ± 4.8 s) vs. Ctrl (16.6 ± 2.6 s). A second control condition (Ctrl-Mod) was produced by modelling a response that accounted for the 'non-square' force profile in IA, which by itself could have influenced kinetics. However, τ in IA was faster than in Ctrl-Mod (13.8 ± 2.8 s). The faster kinetics due to IA suggest that in mammalian skeletal muscle in situ, following contractions onset, temporal energy buffering by CK slows the kinetics of signal transduction for the activation of oxidative phosphorylation.

Blockade Of Prostaglandins And Nitric Oxide In-vivo Reduces State 3 Mitochondrial Respiration In Human Skeletal Muscle

Combined inhibition of nitric oxide (NO) and prostaglandins (PG) reduces skeletal muscle blood flow and oxygen delivery at rest and during exercise. It has recently been found that combined inhibition of NO and PG blockade reduces muscle oxygen uptake during exercise (Mortensen et al. 2007) suggesting a partial inhibition of aerobic metabolism or improved muscle efficiency of oxidative phosphorylation or actin-myosin cycling. PURPOSE: The purpose of this study was to examine in humans the independent and combined effect of NO and PG blockade with L-NMMA and Indomethacin (Indo) on mitochondrial respiration in muscle from biopsies of the vastus lateralis (VL) following knee extension (KE) exercise. METHODS: Mitochondrial respiration was measured ex-vivo by high resolution respirometry in saponin-permeabilized fibers following 6 min KE in control (CON, n=8), arterial infusion of LNMMA (n=4) and Indo (n=4) randomized in order, followed by combined inhibition of NO and PG (L-NMMA + Indo, n=8). RESULTS. ADP-stimulated state 3 respiration with substrates for complex I (glutamate, malate) was reduced 50% by Indo compared to CON. State 3 O2 flux with convergent electron input through both complex I and II with addition of succinate was equally reduced with Indo (20%) and L-NMMA + Indo (15%) compared to CON and LNMMA alone. Uncoupled O2 flux determined by titration of the ionophore FCCP was not increased above state 3 respiration with Indo suggesting tight coupling to oxidative phosphorylation. Graded titrations of L-NMMA into the respirometer in CON muscle reduced state 3 respiration by 12% only at a supra-physiological dose, while titration of Indo caused a linear reduction at all doses within and above the physiological range. CONCLUSION: The results indicate that inhibition of PG by indomethacin inhibits state 3 mitochondrial respiration primarily at complex I of the respiratory chain. This effect may in part explain the in-vivo reduction in muscle O2 uptake during exercise with double blockade of NO and PG, since blockade of NO by L-NMMA counteracts the inhibitory effect of Indo.

Improved Matching of Local O2 Delivery to Muscle VO2 is Related to Faster VO2 Kinetics

Improving the matching of local blood flow (Qm) to muscle O2 uptake (VO2m) is thought to be an important factor regulating the adjustment of Phase II pulmonary VO2 kinetics (tauVO2p). The degree to which Qm and VO2m are matched can be discerned from the ratio of changes in muscle deoxygenation ([HHb])-to-phase II VO2p. PURPOSE: To determine the relationship between [HHb]/VO2 and the rate of adjustment of VO2p in subjects presenting with slow and fast VO2p kinetics. METHODS: VO2p and muscle deoxygenation kinetics were examined during repeated step transitions from 20 W to moderate-intensity cycling (80-90% of estimated lactate threshold) in 37 young males (24 (4) yr; mean (±SD)). VO2p was measured breath-by-breath using a volume turbine and a mass spectrometer. Changes in [HHb] of the vastus lateralis muscle were measured by near-infrared spectroscopy. VO2p and [HHb] response profiles were modeled as a mono-exponential using non-linear regression, and later scaled to a relative % of the response (0-100%). The [HHb]-to-VO2 ratio for each individual was calculated as the average [HHb]/VO2 relative response from 20s to 120s during the exercise on-transient. RESULTS: Subjects were grouped based on tauVO2p <21s (very fast (VF); n=8); 21-30s (fast (F); n=12); 31-40s (moderate (M); n=10); >41s (slow (S); n=7). The corresponding [HHb]/VO2 were 0.98 (VF), 1.05 (F), 1.09 (M), and 1.22 (S). The larger [HHb]/VO2 observed in the groups with the slower rates of adjustment for VO2p resulted in the [HHb]/VO2 displaying a transient "overshoot" relative to the subsequent steady state level. That "overshoot" was progressively reduced as tauVO2 became smaller with a correlation between [HHb]/VO2 and tauVO2p of 0.91. CONCLUSION: When tauVO2p is greater than ∼20s, the rate of adjustment of phase 2 VO2p (muscle VO2) appears to be mainly constrained by the matching of local O2 delivery to muscle VO2 (i.e., microvascular blood flow distribution). In those with a shorter tauVO2 there is a reduced "overshoot" in the [HHb]/VO2 as represented by a lower [HHb]/VO2 ratio. These data experimentally support the idea that groups with progressively slower VO2 kinetics are O2 availability dependent, requiring a progressively greater O2 extraction during the on-transient of exercise.

The skeletal muscle VEGF mRNA response to acute exercise in patients with chronic heart failure

In seven patients with chronic heart failure (CHF) and six controls, we examined (a) resting and post-exercise muscle vascular endothelial growth factor (VEGF) mRNA levels and (b) their relationship with muscle structure and function. Muscle biopsies were taken after 30 min of single-leg knee-extensor exercise at 50% of maximum work rate (50% WRmax) from both the exercised and rested legs. Muscle blood flow and O2 uptake were measured during exercise. Resting VEGF mRNA levels were not different between patients and controls and both groups upregulated VEGF mRNA equally in response to acute exercise. Patients had lower , , and mitochondrial density but similar capillarity and fiber area. These findings reveal a normal basal level of muscle VEGF mRNA, its appropriate upregulation in response to acute exercise and, despite increased vascular resistance during exercise, a normal skeletal muscle vascular structure in patients with CHF.