Muscle VO2max Research Articles

Impact of O2 Availability on Convective and Diffusive O2 Transport and Skeletal Muscle Intracellular PO2 at VO2max

Cross‐sectional evidence suggests that maximal O2 uptake (VO2max) is the consequence of well‐matched O2 supply and demand in untrained skeletal muscle (symmorphosis) and in trained skeletal muscle is limited, not by mitochondrial O2 capacity, but, by convective and diffusive O2 transport (dysmorphosis). However, it is unknown if, longitudinally, aerobic exercise training transitions skeletal muscle VO2max from a sym‐ to a dys‐morphosis of O2 transport and utilization capacities. The purpose of this study was to test the hypothesis that, compared to normoxia, hyperoxia would increase skeletal muscle mean capillary PO2 (capPO2) and intracellular PO2 (iPO2) both pre‐ and post‐training, but would only increase VO2max post‐training. We tested this in 5 healthy sedentary males (mean±SD; age: 27±5 yrs, height: 175±6 cm, mass: 73±7 kg, cycle VO2max: 33±4 ml/kg/min) using the unique combination of human quadriceps single‐leg knee‐extensor exercise (KE), directly measured arterial and femoral PO2, thermodilution measured leg blood flow (LBF), and 1H nuclear magnetic resonance spectroscopy measurement of myoglobin (Mb) desaturation at 100% maximal work rate in randomized conditions of hypoxia, normoxia, and hyperoxia (12, 21, and 100 % O2, respectively). Mb desaturation was converted to iPO2 using an O2 half‐saturation pressure of 3.2 mmHg. All measurements were made pre‐ and post‐training, which consisted of eight weeks of KE (1 hour/visit, 3 visits/week). Pre‐training, increasing inspired O2 increased capPO2 (33.0±4.8, 41.4±4.1, and 49.6±8.7 mmHg, all p<0.019), Mb desaturation decreased from hypoxia to normoxia (46±4 and 31±4 %, p=0.004), but not from normoxia to hyperoxia (29±14 %, p=0.79), iPO2 increased from hypoxia to normoxia (3.8±0.6 and 7.2±1.4 mmHg, p=0.009), but not from normoxia to hyperoxia (10.0±6.6 mmHg, p=0.375), and VO2max was not altered by inspired O2 (0.47±0.10, 0.52±0.13, and 0.54±.01 l/min, all p>0.285). Post‐training, increasing inspired O2 increased capPO2 (32.8±2.6, 39.6±2.8, and 47.5±6.1 mmHg, all p<0.010), did not decrease Mb desaturation (79±20, 53±11, and 53±8 %, all p>0.050), iPO2 increased from hypoxia to normoxia (1.1±1.2 and 3.1±1.1 mmHg, p=0.019), but not from normoxia to hyperoxia (3.0±1.1 mmHg, p=0.954), and VO2max increased with greater inspired O2(0.59±0.11, 0.68±0.11, and 0.76±0.09 l/min, all p<0.044). There was a pre‐ to post‐training difference within all three inspired O2 conditions for VO2max (all p<0.010) and in hypoxia and normoxia for both Mb desaturation (both p<0.020) and iPO2 (both p<0.011). When untrained, the concomitant increase in capPO2 and iPO2, with no change in VO2max, from normoxia to hyperoxia infers a mitochondrial O2 capacity limited skeletal muscle VO2max. In trained skeletal muscle, the concomitant increase in capPO2 and VO2max, with minimal changes in iPO2, from normoxia to hyperoxia infers an O2 transport limited VO2max.

Oxygen Delivery Limitations And Muscle Mitochondrial Oxygen Consumption At VO2max

It is unclear whether the full oxygen (O2) consuming capacity of skeletal muscle mitochondria (mitoVO2max) is utilized during whole-body, maximal aerobic exercise. PURPOSE: We sought to determine if muscle O2 delivery limitations during cycling exercise prevent mitochondria from reaching mitoVO2max and if augmenting mass-specific O2 delivery, by reducing the amount of exercising muscle with single leg knee extension (KE), would allow muscle VO2max to reach mitoVO2max. METHODS: mitoVO2max (i.e convergent State 3 respiration) was assessed in permeabilized fibers biopsied from the vastus lateralis of 11 young males of varying aerobic fitness (pulmonary VO2max: 32-64 ml/kg/min). Muscle VO2max and O2 delivery during cycling and KE were determined with blood drawn from catheters placed in the femoral artery and vein and blood flow was simultaneously measured by Doppler ultrasound. Leg muscle mass was measured anthropometrically. RESULTS: During cycling exercise muscle O2 delivery (157± 17 ml/kg/min) failed to reach rates similar to mitoVO2max (551 ± 56 ml/kg/min; P<0.05) which yielded a muscle VO2max of 144 ± 7 ml/kg/min that was only to 29 ± 3% of mitoVO2max. During KE muscle O2 delivery was significantly elevated compared to cycling (512 ± 31 ml/kg/min; P<0.05) which resulted in a much greater muscle VO2max (385± 28 ml/kg/min; P<0.05). However, despite the augmented O2 delivery during KE muscle VO2max was still significantly less than mitoVO2max (73±7% of mitoVO2max, P<0.05). Interestingly, the greater a subject’s aerobic fitness, the less they utilized their full mitochondrial capacity (r=-0.60, P<0.05). CONCLUSIONS: Increasing mass-specific O2 delivery by switching from large to small muscle mass exercise within the same limb allowed muscle VO2max to approach mitoVO2max, suggesting that limited O2 delivery prevents mitochondria from maximally respiring during whole-body maximal aerobic exercise. Surprisingly, even during maximal KE, a modality reported to elicit the highest mass-specific rates of O2 consumption, much of the mitochondria’s potential to consume oxygen, especially among endurance-trained subjects, was left unrealized. The function of this untapped mitochondrial respiratory capacity is unclear, but may be related to substrate utilization and endurance performance.

Prolonged Exercise Training does not Preserve Mitochondrial Enzyme Activity in Senescent Rats

Skeletal muscle aerobic function (VO2max) and mitochondrial oxidative capacity decline with aging, particularly in senescence (SEN). Since exercise training improves muscle VO2max and oxidative capacity in young adult skeletal muscle, our objective was to determine if treadmill training from late middle age (LMA) into SEN would minimize the declines in skeletal muscle aerobic function and oxidative capacity seen in SEN. 62 male rats at late middle age (29 mo) were randomly separated into control and exercise groups. Exercise consisted of 60 m/day treadmill running, 5 d/week for 7 weeks and then decreased to 4 d/week for a total of 5 and 7 mo (until 34 and 36 mo of age respectively). Although running capacity was significantly higher in the trained groups (13% at 34 mo and 21% at 36 mo), muscle VO2max at matched muscle O2 delivery was not significantly greater in the trained groups compared to sedentary controls at either age. Similarly, citrate synthase and cytochrome oxidase activity in the plantaris, soleus and the heart muscle were not different in the trained vs the sedentary groups, suggesting no benefit of training for muscle oxidative capacity. The superior exercise capacity suggests a better overall level of function of the senescent rats; however, contrary to our hypothesis and prior observations in LMA rats, treadmill exercise training between LMA and SEN does not benefit muscle aerobic function or mitochondrial oxidative capacity.Supported by CIHR (AB, RT), CIHR Provincial Training Program in Bone and Joint Health (AB), AHFMR (RT) and NSERC (MT).

Training of late middle aged rats increases oxidative capacity without increasing mitochondrial content

There is some evidence that aged muscle does not increase mitochondrial protein content after exercise training, suggesting an improvement in mitochondrial quality rather than quantity. The purpose of this study was to determine if an improvement in oxidative capacity without an increase in mitochondrial content also occurs in a rat model, and to investigate one of the markers involved in mitochondrial biogenesis. Late middle aged (28 mo; 70% survival rate) Fisher 344-BN male rats performed treadmill running exercise 5 times/wk for 7 wk and were compared to an age-matched sedentary group. Muscle aerobic performance was assessed using a pump-perfused hindlimb model. Contralateral gastrocnemius and plantaris muscles were harvested for biochemical and molecular measurements. Endurance training increased muscle VO2 max (15%) and citrate synthase and complex IV activity (~25%) compared to the control group. CS protein content was not significantly different between training and sedentary groups, suggesting that mitochondrial content did not increase with training. PGC-1α protein but not mRNA was increased only in the plantaris muscle with training. These results show that endurance training of late middle aged rats increases oxidative enzyme activity without an increase in protein content. The training-induced improvement in mitochondrial function but not content may occur secondary to increased mitochondrial turnover. Supported by CIHR and the Alberta Provincial CIHR Training Program in Bone and Joint Health

SKELETAL MUSCLE VO2MAX DECLINES WITH AGING INDEPENDENT OF CONVECTIVE OXYGEN DELIVERY

It is well established that VO2max declines with age. Most studies examining this issue did so using whole body VO2. It is significant that during whole body exercise, O2 delivery to the working muscles declines from adulthood to old age and this alone can compromise aerobic performance. PURPOSE: To determine if muscle VO2max is reduced with aging independent of convective O2 delivery. METHODS: The distal muscles of a rat (Fisher 344 X Brown Norway F1 Hybrid) single hindlimb preparation perfused at matched rates of muscle convective O2 delivery, in young adult (8 mo old; mean ± SD, body mass: 416 ± 21 g) and late middle aged (28 mo old; 500 ± 58 g) animals, were electrically stimulated for 4 min (60 tetani min−1). Samples were drawn anaerobically every 30 s for measurement of O2 content in femoral arterial and venous blood. VO2max was determined by the product of blood flow and the arterio-venous O2 content difference across the hindlimb. Matching of muscle blood flow between each group was verified by examining the distribution of coloured microspheres infused after the experiment. RESULTS: Muscle O2 delivery was well matched between the 8 mo old (541 ± 96 μmol O2 min−1 100 g−1) and 28 mo old (532 ± 96 μmol O2 min−1 100 g−1) groups. VO2max was lower in the 28 mo old (308 ± 28 μmol O2 min−1 100 g−1) than the 8 mo old (388 ± 28 μmol O2, min−1 100 g−1; p < 0.05) rats. CONCLUSIONS: These results show that, at matched rates of muscle convective O2 delivery, VO2max is reduced with aging, suggesting that alterations in factors intrinsic to skeletal muscle (i.e., reduced capillarization, etc.) play a role in this response. Supported by CIHR (MOP 48185).

Oxygen transport to skeletal muscle working at VO 2max in acute hypoxia: theoretical predictions

The influence of acute hypoxia (30≤PaO 2≤100 mmHg) on the values of VO 2max and parameters of oxygen transport in muscle working at VO 2max was studied. We investigated muscle working under different values of blood flow F (60≤ F≤120 ml/min per 100 g), blood pH (7.0–7.6), and different diffusion conditions. Investigations were performed on a computer model of O 2 delivery to and O 2 consumption in the working muscle. VO 2max, PvO 2, pO 2- and VO 2-distribution in muscle fiber were calculated. It was shown that the greater the degree of arterial hypoxemia, the lower the muscle VO 2max and blood pO 2 values. When working at VO 2max, the average and minimal values of tissue pO 2 depend on PaO 2. The greater the blood flow through muscle, the greater the VO 2max. However, with an increasing degree of arterial hypoxemia, the effect of F and blood pH on the value of VO 2max is weakened. The diffusion conditions produced a powerful influence on the VO 2max value. At reduced PaO 2 they are the most important limiting factors of O 2 supply to muscle working at maximal effort.

Skeletal muscle: microcirculatory adaptation to metabolic demand.

The issue of whether skeletal muscle is master or slave of the cardiovascular system depends on frame of reference. Acute manipulations of convective O2 delivery clearly show that O2 supply sets the upper limit of muscle VO2max. However, studies of adaptation to chronic conditions such as training and hypoxia show that skeletal muscle has a remarkable capacity to meet changes in metabolic demand. Moreover, there are several lines of evidence that these adaptations are essential to changes in VO2max. Studies show that with training, electrical stimulation, and chronic hypoxia, the ratio of capillary surface per fiber surface and fiber mitochondrial volume/fiber length is preserved, suggesting a primary regulated feature in skeletal muscle is matching the structural capacity for O2 flux to mitochondrial metabolic demand. Adaptations in both capillarity and mitochondrial respiratory capacity have also been shown to be important components in the adaptive increase in VO2max with training. Collectively, this evidence argues against skeletal muscle being simply a slave to the cardiovascular system.

Effects of F(I)O2 on leg VO2 during cycle ergometry in sedentary subjects.

In a recent study of completely sedentary normal young subjects, leg VO2max was reduced by hypoxia in proportion to mean capillary PO2 as F(I)O2 was reduced from 0.15 to 0.12. However, the increase in VO2max from F(I)O2 = 0.15 to 0.21 was less than expected for the increase in mean capillary PO2. This finding has led us to hypothesize that in sedentary subjects breathing room air, VO2max is not limited by O2 supply but rather by oxidative capacity of mitochondria. The present study sought to obtain further evidence for or against this hypothesis in sedentary subjects by assessing leg VO2max (VO2leg) breathing 100% O2, as well as in normoxia and hypoxia. Data from 18 subjects studied at F(I)O2 = 0.12, 0.15, and 0.21 and from six more studied at 0.12, 0.15, and 1.00 were analyzed. In all 24 we measured VO2leg by arterial and venous blood sampling and thermodilution leg blood flow during maximal cycle ergometry at each F(I)O2. VO2leg was not increased by room air or 100% O2 breathing relative to that observed at F(I)O2 = 0.15, but it was reduced while breathing 12% O2. The data at F(I)O2 = 0.12 and 0.15 conformed to the predictions of O2 supply limitation of maximal VO2 as previously. These results confirm and extend our prior observations that in sedentary, as opposed to trained subjects, muscle VO2max is O2 supply limited only in hypoxia.

Hemodynamic Responses to Peak Arm-Crank Exercise in Thoracic Level Paraplegics 483

It has long been debated in the literature as to whether upper body exercise is limited centrally or peripherally. It has been suggested that aerobic capacity in the spinal cord injured (SCI) may be limited by the relatively greater intramuscular pressure generated during upper body exercise. Brechue et al. (1995) concluded that “skeletal muscle VO2max is limited by O2 delivery secondary to a restriction of blood flow.” The purpose of this study was to measure the hemodynamic responses of paraplegics during a graded exercise test (GXT) to peak oxygen consumption and examine the relation of these responses to aerobic capacity(VO2peak). The subjects for this study were 10 thoracic level paraplegics. The GXT was performed on an arm-crank ergometer using an intermittent protocol. The following variables were measured: peak heart rate, peak systolic blood pressure (SBP), peak mean aterial pressure (MAP), and peak rate pressure product (RPP). Heart rate was measured by telemetry. Exercise blood pressures were measured by reducing the power output by one half and instructing the subject to continue cranking with one arm. Blood pressure was then measured on the free arm. These variables were then correlated with VO2peak with a significance level set at p*< 0.05:Table Results show a significant correlation between VO2peak and peak SBP. These findings are consistent with the hypothesis that aerobic capacity in the paraplegic population may be limited by the delivery of oxygen secondary to the ability to perfuse the exercising muscles.

HYPEROXIA INCREASES VO2max IN THE ISOLATED HUMAN QUADRICEPS1403

Under normoxic conditions maximal O2 delivery per 100g of active muscle mass in knee-extensor (KE) exercise is far greater than during cycle exercise (KE = 57 ml/min/100g (2.5 kg of muscle); cycling = 25 ml/min/100g(7.5 kg of muscle)). With such high levels of oxygen delivery KE exercise is an ideal model to test the hypothesis that O2 supply limits VO2 in maximally working muscle. To study this relationship five trained subjects performed maximum KE exercise in normoxia (21% O2), hypoxia (12% O2), and hyperoxia (100% O2) in a balanced order. The protocol was (after warm-up) a square wave to a previously determined maximum work rate followed by incremental stages to ensure a true maximum was achieved under each condition. Direct measures of arterial and venous blood [O2] in combination with a thermodilution blood flow technique allowed the determination of O2 delivery, and muscle VO2. Maximal O2 delivery increased with inspired O2: 12% O2=45 ± 5.21% O2=57 ± 8, and 100% O2 = 63 ± 11 ml/min/100g. Maximal work rate was significantly affected by variations in inspired O2 (-19% in 12% O2 and +14% in 100% O2 compared to normoxia) as was VO2max (12% O2 = 35.6 ± 2.1, 21% O2 = 44.0 ± 2.7, and 100%O2=48.4 ± 3.0 ml/min/100g). Calculated mean capillary PO2 also varied with inspired O2 (12%O2 = 29.5 ± 14.21%O2 = 35.8 ± 2.9, and 100%O2 = 42.0 ± 2.1 mmHg) and was proportionally related to changes in VO2max, supporting our previous finding that a decrease in O2 supply will proportionately decrease muscle VO2max. Because even in the isolated quadriceps (where normoxic O2 delivery is the highest recorded in man) an increase in O2 supply by hyperoxia allows the achievement of a greater VO2max, we conclude that in normoxic conditions of isolated KE exercise, KE VO2max is not limited by mitochondrial metabolic rate, but rather by O2 supply.

Determinants of maximal exercise VO2 during single leg knee-extensor exercise in humans.

Previously, a reduction in fractional inspired O2 (FIO2) during dynamic exercise of the human quadriceps muscles of one leg resulted in increased muscle blood flow (Q) and a fall in femoral venous O2 tension (PO2) but no change in peak O2 uptake (VO2). These data can be interpreted as reflecting an increase in muscle O2 diffusive capacity (DO2) in hypoxia or, alternatively, that maximum O2 uptake (VO2max) was not reached for these muscles when air was breathed, in which case the theory of diffusion limitation to VO2max is not applicable to these data. Therefore, the primary goal of this study was to test the hypothesis that VO2max would be reduced in hypoxia as a result of the decreased O2 supply and a constant diffusional conductance from blood to exercising muscle. To resolve this, five trained men were studied performing single leg incremental knee-extensor exercise to VO2max while breathing air (N) and again while breathing 12% O2 (H). The maximum work rate (WRmax) was 30-50 W greater and produced even greater associated maximum leg Q (N = 9.1 +/- 0.61 and H = 8.2 +/- 0.65 l/min, P < 0.05) and leg O2 than in previous studies. Hypoxia reduced quadriceps muscle VO2max (N = 1.4 +/- 0.1 and H = 1.1 +/- 0.1 l/min, P < 0.05). In the two conditions the relationships between 1) measured femoral venous PO2 (N = 18 +/- 0.5 and H = 13 +/- 0.5 Torr) and VO2max and 2) calculated mean capillary PO2 (N = 37 +/- 0.4 and H = 28 +/- 0.8 Torr) and VO2max were each one of proportionality.(ABSTRACT TRUNCATED AT 250 WORDS)

Increased peak oxygen consumption of trained muscle requires increased electron flux capacity

The importance of the training-induced increase in mitochondrial capacity in realizing the increase in maximal O2 consumption (VO2max) of trained muscle was evaluated using an isolated perfused rat hindlimb preparation at a high blood flow (approximately 80 ml.min-1.100 g-1) during tetanic contractions. Rats trained for 8-12 wk by treadmill running exhibited an approximately 25% increase in muscle VO2max (5.62 +/- 0.31 to 7.06 +/- 0.64 mumol.min-1.g-1), an increase in mitochondrial enzyme activity (approximately 70% for cytochrome oxidase and approximately 55% for NADH cytochrome-c reductase), and an increase in tissue capillarity (14%) that is expected to increase the O2 exchange capacity of the tissue. Muscle VO2max of sedentary (n = 34) and trained (n = 30) animals was determined, and electron transport capacity was acutely managed with myxothiazol, a tight-binding inhibitor of complex III. Inhibition of complex III was similar among 1) the low- and high-oxidative fibers and 2) the superficial and deep mitochondrial populations within muscle. Inhibition of NADH cytochrome-c reductase activity resulted in reductions in muscle VO2max with similar dose responses (mean effective dose of approximately 0.2 microM) of myxothiazol added to the perfusion medium. The extraction of O2 by the contracting muscle decreased as VO2max declined. The increase in muscle VO2max observed in the muscle of trained animals was eliminated when its electron transport capacity was reduced to that observed in normal sedentary rat muscle. Thus, the exercise-induced adaptation of an increased muscle mitochondrial content appears to be essential for trained muscle to exhibit its increased O2 flux capacity. The results of the present experiment illustrate the importance of mitochondrial adaptations in muscle remodeled by exercise training.

Effect of low dose oxygent added to blood on muscle VO2max.

Federspiel et al.1 have suggested that the plasma space between red blood cells in capillaries does not contribute significantly to diffusive O2 transport out of the muscle vasculature due to the low plasma solubility of O2. To test this, we pump-perfused in situ isolated canine gastrocnemius muscle stimulated electrically to produce VO2 max under two conditions [with blood flow 120 ml 100 gm−1 min−1, [Hb] 8.7 gm dl−1 and PaO2 ~ 500 torr in each case]: A) control, and B) with Oxygent (perflubron emulsion, Alliance) added at 6 gm perflubron/70 ml. Total plasma O2 solubility was taken to be 0.003 ml 100 ml−1 torr−1 in A) and computed to be 0.005 ml 100 ml−1 torr−1 in B) from the increase in total [O2] in B) compared to A).KeywordsTotal PlasmaDiffuse CapacityBlood Flow RatePlasma SpaceFlow ExtractionThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.