The cerebral metabolic ratio is not affected by oxygen availability during maximal exercise in humans


Corresponding author S. Volianitis: Department of Health Science and Technology, Aalborg University, Denmark Fredrik Bajers Vej 7E4, DK-9220 Aalborg, Denmark. Email:


Intense exercise decreases the cerebral metabolic ratio of O2 to carbohydrates (glucose +½ lactate) and the cerebral lactate uptake depends on its arterial concentration, but whether these variables are influenced by O2 availability is not known. In six males, maximal ergometer rowing increased the arterial lactate to 21.4 ± 0.8 mm (mean ±s.e.m.) and arterial–jugular venous (a–v) difference from −0.03 ± 0.01 mm at rest to 2.52 ± 0.03 mm (P < 0.05). Arterial glucose was raised to 8.5 ± 0.5 mm and its a–v difference increased from 1.03 ± 0.01 to 1.86 ± 0.02 mm (P < 0.05) in the immediate recovery. During exercise, the cerebral metabolic ratio decreased from 5.67 ± 0.52 at rest to 1.70 ± 0.23 (P < 0.05) and remained low in the early recovery. Arterial haemoglobin O2 saturation was 92.5 ± 0.2% during exercise with room air, and it reached 87.6 ± 1.0% and 98.9 ± 0.2% during exercise with an inspired O2 fraction of 0.17 and 0.30, respectively. Whilst the increase in a–v lactate difference was attenuated by manipulation of cerebral O2 availability, the cerebral metabolic ratio was not affected significantly. During maximal rowing, the cerebral metabolic ratio reaches the lowest value with no effect by a moderate change in the arterial O2 content. These findings suggest that intense whole body exercise is associated with marked imbalance in the cerebral metabolic substrate preferences independent of oxygen availability.

At rest, cerebral metabolism is supported almost exclusively by carbohydrate oxidation, as indicated by a cerebral oxygen/glucose uptake ratio (or specifically, oxygen-to-glucose index; OGI) close to 6 (Dalsgaard et al. 2002). Whereas at rest the brain releases small amounts of lactate, during maximal exercise, where arterial lactate is elevated, there is substantial cerebral lactate uptake (Ide & Secher, 2000). Since lactate does not accumulate within the cerebrospinal fluid or brain tissue (Dalsgaard et al. 2004b), it is most probably metabolized and thus included in the calculation of the cerebral metabolic ratio (MR) as O2/(glucose +½ lactate). Similarly to other activities involving intense neuronal activity (Fox et al. 1988), carbohydrate uptake increases more than that of O2 and thus the MR decreases during exercise (Ide & Secher, 2000). Indeed, during maximal whole body exercise ∼50% of the carbohydrate taken up is not oxidized and thus the MR decreases to the lowest measured value of less than 3 (Dalsgaard & Secher, 2007), with lactate contributing 30–40% to this reduction (Ide & Secher, 2000; Dalsgaard et al. 2002).

One of the factors that contribute to the reduced MR during exercise is the magnitude of brain activation required for the simultaneous control of various muscle groups, as suggested by the reduction in MR in proportion to the active muscle mass (Dalsgaard et al. 2004b). Activation of a large muscle mass during maximal exercise also induces a marked increase in arterial lactate concentration that enhances cerebral lactate uptake (Dalsgaard et al. 2004b). However, the reduction of MR during exercise does not depend on the lactate taken up by the brain, as shown by the low MR values at exhaustion following prolonged exercise where arterial blood lactate accumulation is negligible and hence there is no cerebral lactate uptake (Nybo et al. 2003). Instead, the lactate taken up by the brain replaces glucose as the preferential cerebral substrate and thus glucose uptake decreases with increasing exercise intensity (Kemppainen et al. 2005). Arguably, the availability of oxygen could affect cerebral lactate uptake and thus the MR, as demonstrated in rats where cerebral hypoxia provokes a significant increase in lactate concentration and the lactate/pyruvate ratio, as well as a decrease in glucose levels (Zoremba et al. 2007). During whole body exercise in humans, metabolic acidosis contributes to the arterial haemoglobin O2 desaturation that, among other tissues, also compromises regional cerebral oxygenation (Nielsen et al. 1999). Rowing presents a worse case scenario where extreme metabolic acidosis, with pH as low as ∼6.8, is routinely manifested in arterial haemoglobin O2 saturation values below 90% (Nielsen, 1999). The effect of altered O2 availability on the MR during exercise is not known.

We hypothesized that oxygen availability would influence cerebral lactate uptake and thus modify the MR. We considered that compromised oxygen delivery would increase the glycolytic requirements of astrocytes and, thus, influence cerebral carbohydrate uptake and aggravate the MR, while, on the other hand, increased oxygen availability would reduce the disparity between carbohydrate and oxygen uptake and hence restore the MR. In order to test these hypotheses, we manipulated O2 availability (i.e. arterial haemoglobin O2 saturation, Sinline image) with normoxic, hypoxic and hyperoxic breathing during maximal ergometer rowing, while we sampled arterial and internal jugular venous blood simultaneously.


Six healthy males (mean ±s.e.m.; age, 32 ± 4 years; height, 180 ± 3 cm; weight, 75 ± 3 kg), following written informed consent, volunteered to the study that was approved by the Ethical Committee of Copenhagen and conformed to the standards set by the Declaration of Helsinki. All subjects were recruited from a local rowing club and were well familiarized with maximal ergometer rowing as they had been competing for a number of years (one was a current world champion and two others were members of the national team).

Experimental protocol

The subjects refrained from strenuous exercise, alcohol and caffeine for 24 h prior to the investigations and reported in the laboratory after an 8 h overnight fast. They performed on three occasions, separated by 1–2 weeks, a normoxic (inspiratory O2 fraction (Finline image), 0.21), a hypoxic (Finline image, 0.17) and a hyperoxic (Finline image, 0.30) trial in a randomised blinded order. The subjects were allowed an individualized warm-up for about 20 min and, after a short rest, they were instructed to perform on a wind-braked ergometer (Concept II, Morrisville, VT, USA) a 2000 m all-out row that simulates an on-water competition. Throughout exercise the subjects were encouraged and coached to ensure maximal effort.

Arterial and jugular venous blood samples were obtained from a retrograde catheter (14 gauge; 2.2 mm) in the right internal jugular vein, with the tip positioned below the basis of the skull, and another catheter (20 gauge; 1.1 mm) in the radial artery of the non-dominant arm. The catheters were reported to neither inflict pain nor hamper the ability to exercise. Blood samples were drawn anaerobically three times at rest, once after 500, 1000, 1500 m of rowing, immediately after and at 15 min post-exercise in heparinized syringes and immediately analysed for blood gasses, pH, electrolytes and plasma glucose and lactate (ABL 725; Radiometer, Copenhagen, Denmark). Mean arterial pressure (MAP) was measured from the artery through a transducer (Baxter, Uden, the Netherlands) connected to a monitor (Dialogue 2000, Danica Electronic, Copenhagen, Denmark) and heart rate (HR) was calculated from the arterial blood pressure curve (Windaq Waveform Browser, DATAQ Instruments, OH, USA).

The subjects breathed through a two-way low-resistance T valve (model 2700, Hans Rudolph, Kansas City, MO, USA) with humidified air delivered from a Douglas bag. After 5 min seated rest, designed to stabilize ventilation, the subjects breathed air with a Finline image of 0.17, 0.21 or 0.30 for 5 min prior to and during exercise. Breath-by-breath measurements of O2 consumption (inline image) and ventilation (inline image) were made with an online gas analyser (CPX/D, Medical Graphics, St Paul, MN, USA) and data were averaged every 30 s.


Blood oxygen content (Cinline image, ml l−1) was calculated as

display math

where [Hb] is the total haemoglobin concentration (g dl−1) and HbO2 is the fraction of HbO2 in blood. HbO2 was calculated as

display math

where O2 sat is the O2 saturation and COHb and MetHb are the fractions of carboxyhemoglobin and methemoglobin, respectively. Arterio-venous (a–v) difference was calculated by subtracting the venous from the arterial values.


Values are presented as mean ±s.e.m. A two-way analysis of variance (ANOVA) with repeated measures (time × trial) was used to reveal significant interactions and the Tukey post hoc test for paired data was used to locate differences. A P value of < 0.05 was considered significant.


The manipulation of Finline image provided a range of Sinline image values and therefore arterial Cinline image during exercise (Table 1). In normoxia, the subjects completed the 2000 m ergometer row in 6 min 56 ± 4 s and HR, MAP and gas exchange variables increased (P < 0.05, Table 1). The pH decreased in both arterial and venous blood (P < 0.05), and arterial O2 tension remained at resting level, while it decreased in jugular venous blood. The Sinline image value also decreased and the a–v difference for Sinline image was elevated by ∼28% (P < 0.05).

Table 1.  Effects of inspired O2 fraction of 0.17, 0.21 and 0.30 at rest and during ergometer rowing
 17% O221% O230% O2
  1. P inline image , oxygen tension; Pinline image, carbon dioxide tension; Sinline image, haemoglobin oxygen saturation; Cinline image, oxygen content; a–v difference, arterial–jugular venous difference; gluc, glucose; lac, lactate. *P < 0.05 compared with rest, †P < 0.05 compared with hypoxia, ‡P < 0.05 compared with normoxia. Data are mean ±s.e.m., N= 6.

HR (beats min−1)63 ± 3178 ± 3* 71 ± 5181 ± 2* 68 ± 2178 ± 2*
MAP (mmHg)91 ± 5107 ± 2* 96 ± 2104 ± 4* 94 ± 2109 ± 3*
inline image (l min−1)13 ± 1173 ± 5* 13 ± 1168 ± 3*13 ± 1172 ± 5*
inline image (l min−1) 0.4 ± 0.0 4.5 ± 0.2* 0.4 ± 0.0  4.7 ± 0.2*† 0.4 ± 0.0   5.2 ± 0.2*‡
Arterial blood
P inline image (mmHg)87 ± 264 ± 2*103 ± 2†  94 ± 2*†164 ± 3†161 ± 5†
P inline image (mmHg)38 ± 129 ± 1*39 ± 129 ± 1*39 ± 1 31 ± 1*
S inline image (%)96.7 ± 0.587.6 ± 1.0*98.3 ± 0.2 92.5 ± 0.2*†99.4 ± 0.1  98.9 ± 0.2†‡
C inline image (ml l−1)204 ± 6 186 ± 4* 212 ± 6 222 ± 5*†225 ± 5  238 ± 4†‡
Glucose (mm) 5.7 ± 0.3 7.6 ± 0.6* 6.0 ± 0.4 8.5 ± 0.5* 5.6 ± 0.2  7.3 ± 0.2*
Lactate (mm) 1.41 ± 0.4020.03 ± 1.52* 1.02 ± 0.11 21.43 ± 0.81*  1.0 ± 0.1 17.7 ± 1.7*
pH 7.36 ± 0.01 7.11 ± 0.02*  7.40 ± 0.01† 7.08 ± 0.03* 7.40 ± 0.01  7.12 ± 0.03*
a–v difference
S inline image (%)35.1 ± 2.844.1 ± 2.9*34.4 ± 1.647.5 ± 4.0*34.2 ± 2.3  34.0 ± 5.5†‡
C inline image (ml l−1)81 ± 896 ± 7*81 ± 6 95 ± 10*74 ± 8  85 ± 10*
Glucose (mm) 0.63 ± 0.02 1.43 ± 0.02* 1.03 ± 0.01 1.86 ± 0.02* 0.85 ± 0.01   1.20 ± 0.03*‡
Lactate (mm)−0.02 ± 0.01 1.68 ± 0.02*−0.03 ± 0.01   2.52 ± 0.03*† 0.10 ± 0.30   1.53 ± 0.02*‡
Glucose +½ lac. (mm) 0.63 ± 0.031.85 ± 0.02 0.50 ± 0.023.06 ± 0.13 0.90 ± 0.02 1.79 ± 0.16
Ratios of a–v difference
O2/glucose 5.70 ± 1.07 3.68 ± 0.53* 5.89 ± 0.51  2.89 ± 0.39*† 5.49 ± 0.34  2.79 ± 0.27*
O2/(gluc +½ lac) 5.81 ± 0.76 1.90 ± 0.47* 5.67 ± 0.52 1.70 ± 0.23* 5.42 ± 0.77  1.72 ± 0.36*

During exercise, arterial lactate was markedly increased compared with rest (P < 0.05, Table 1) contributing to the 24-fold increase in lactate a–v difference (P < 0.05). In the recovery, arterial lactate remained high and the lactate a–v difference was even larger than during exercise. In contrast, arterial glucose and glucose a–v difference did not increase during exercise but in the immediate recovery, arterial glucose was elevated by about 3 mm resulting in an elevated glucose a–v difference (Fig. 1).

Figure 1.

The arterial–internal jugular venous differences (upper) and the metabolic uptake ratio (lower) in response to maximal ergometer rowing in hypoxia (left), normoxia (middle) and hyperoxia (right)•, lactate; ○, glucose; pre-ex, after warm-up; post-ex, immediately after exercise; *different from rest, #different from hypoxia, +different from normoxia, P < 0.05. Data are mean ±s.e.m., N= 6.

The MR increased from 4.6 ± 0.8 at rest to 5.7 ± 0.6 after warm-up, while during exercise it reached its lowest value of 1.7 ± 0.1 (P < 0.05) and remained low in the recovery (Fig. 1). Similarly, the OGI increased by ∼40% after the warm-up, a value which was subsequently halved during exercise and only partially restored in the recovery (Table 1).

Hypoxia and hyperoxia

Hypoxia increased the time to complete the all-out row by 9 s (to 7 min 5 ± 5 s, P < 0.05), while there was no difference in performance time between the hyperoxic and normoxic trials. The change in Finline image did not affect HR or MAP significantly. During exercise in hyperoxia, Sinline image was higher than in normoxia and hypoxia (P < 0.05, Table 1), while the a–v difference for SO2 was only significantly lower in hyperoxia compared with normoxia and hyperoxia (P < 0.05). Hypoxia decreased Sinline image but the Sinline image a–v difference was not different from the level reached during the normoxic trial.

During both hypoxia and hyperoxia, the levels of lactate and glucose in arterial blood were similar to those established during exercise in normoxia. Also, during exercise in hyperoxia and hypoxia, the lactate a–v difference was lower than during exercise in normoxia, while the glucose a–v difference was not affected by the change in the inspired O2 fraction. During both hypoxic and hyperoxic exercise, the MR was not different from the value established during the normoxic exercise trial (Table 1, Fig. 1). The OGI during the hyperoxic trial was similar to that during the normoxic trial, while during the hypoxic trial it was ∼20% higher (P < 0.05, Table 1).


The main finding of this study is that the cerebral metabolic ratio during exercise is not determined by oxygen availability, as supported by its comparable reduction during exercise trials with moderate bilateral manipulation of Finline image. Secondly, during maximal ergometer rowing the cerebral metabolic ratio reaches 1.7, the lowest level reported during exercise (Dalsgaard, 2006).

In a balanced fuelled oxidative metabolism, the MR [O2/(glucose +½ lactate)] would be close to 6 since two molecules of lactate are equivalent to one molecule of glucose with regard to oxidative metabolism. During strenuous whole body exercise, the oxidative metabolism is far from balanced because the relative carbohydrate uptake is greater than the corresponding oxygen uptake, resulting in a drop in MR (Ide & Secher, 2000). Since carbohydrate availability determines cerebral fuel (Dienel et al. 2002), at rest oxidation of glucose is the primary source of energy for the neurones. However, during vigorous whole body exercise where cerebral energy consumption rises (Tashiro et al. 2001), and arterial lactate levels exceed those of the brain, cerebral lactate uptake becomes significant (Langemann et al. 2001) and its utilization may be as important as that of glucose (Dalsgaard & Secher, 2007). Maximal ergometer rowing, as confirmed in this study, leads to a markedly elevated blood lactate level (> 20 mm). Lactate is formed from the energy-producing conversion of pyruvate in the Embden–Meyerhof pathway and its production serves as communication between glycolysis in the cytoplasma and oxidative metabolism in the mitochondria. Following enhanced metabolic flux, the concentration in the cytosol increases and there is an outflow of lactate to the plasma that challenges the buffering capacity of blood and results in a parallel decrease in pH. Nevertheless, the extremely high arterial lactate concentration observed in response to maximal exercise does not only reflect production, but also impaired clearance from plasma. The conversion of lactate to glycogen in the liver (the Cori cycle) is markedly impaired since perfusion of the splanchnic area is reduced to an absolute minimum during intense exercise (Perko et al. 1998; Nielsen et al. 2007). Nevertheless, the increase in arterial glucose and glucose a–v difference in the recovery phase may be attributed to gluconeogenesis by pyruvate conversion, suggesting the possible restoration of the Cori cycle.

High arterial lactate leads to a noticeably increased cerebral lactate uptake. Based on the a–v difference over the brain, an increasing flux of lactate going into the brain is observed as the arterial concentration increases (Dalsgaard et al. 2004b). The rise in the lactate uptake does not show in the cerebrospinal fluid or within the brain, suggesting that the lactate taken up by the brain is metabolized (Dalsgaard et al. 2004a). The transport of lactate into neurones is facilitated by monocarboxylic transporters (MCT), which co-transport lactate with H+. The low affinity isoform MCT1 is expressed in astrocytes and in microvessel endothelial cells, whilst MCT4 is predominantly expressed in astrocytes and the high affinity MCT2 is abundant in neurones (Pellerin et al. 2005). The MCT1 mediates lactate transport from the blood to astrocytes and extracellular spaces, while the MCT4 and MCT2 mediate lactate transport out of the astrocytes and neuronal lactate uptake from extra-cellular spaces, respectively (Pierre & Pellerin, 2005). The MCT2 isoform is of interest because it is enhanced by catecholamines in mice neurone culture (Pierre et al. 2003) and, though not proved, MCT2 up-regulation could be similar in humans. Since rowing invokes a huge catecholamine response (Holmqvist et al. 1986), up-regulation of MCT2 could explain some of the increased cerebral lactate uptake observed in the present study during exercise.

In addition to lactate taken up from the circulation, neurones can be fuelled by lactate produced in the astrocytes, which are mainly glycolytic at the expense of astrocytic glycogen or arterial glucose (Pellerin & Magistretti, 1994). During brain stimulation, the capability of the astrocytes to instantaneously increase ATP production is required in order for the power requirements of millisecond neuronal firing to be met (Shulman et al. 2001). This acute anaerobic ATP production results in a temporal mismatch between cerebral O2 uptake and glucose utilization that leads to lactate accumulation and is manifested as a drop in MR. Subsequently, the lactate is consumed and oxidized (Madsen et al. 1999).

However, cerebral lactate uptake can explain only about half of the MR reduction, as other pathways, oxidative and biosynthetic, with different time courses and fluxes also contribute (Madsen et al. 1999). Furthermore, glycogen turnover in human astrocytes is slow (Oz et al. 2003) and functionally separated from the lactate produced from blood-borne glucose (Dienel et al. 2002). This notion suggests that it is arterial lactate that is increasingly utilized by the brain during exercise.

The larger increase in pulmonary O2 uptake in hyperoxia versus normoxia at comparable workload is in agreement with previous reports of only a small increase in work capacity with hyperoxia (Peltonen et al. 1995; Nielsen et al. 1998, 1999) and may be reflective of the complex physiological effect of hyperoxia. During maximal rowing, oxygenation of the leg muscles, determined by near-infrared spectroscopy, is not affected by an elevation in Sinline image (Nielsen et al. 1999). In that case, tissues other than those performing external work (e.g. the splanchnic organs) may benefit from the increased O2 availability. Furthermore, it has been suggested that maximal exercise may be limited by a failure of muscle contractility, independent of muscle tissue oxygenation (Noakes, 1988). Nevertheless, since the primary scope of the present study was to measure cerebral metabolism, is has to be considered that the invasive methods used may have hindered the subjects from performing at their capacity and thus result in an apparent dissociation between pulmonary O2 uptake and exercise performance.

We hypothesized that oxygen availability would influence cerebral lactate uptake and thus modify the MR. We considered that oxygen deprivation and arterial haemoglobin O2 desaturation would lead to increased glycolytic requirements of astrocytes and thus would influence cerebral carbohydrate uptake, while, on the other hand, increased O2 availability would reduce the displacement between carbohydrate and oxygen uptake. This, however, does not seem to be the case. As shown in this study, an Finline image between 0.17 and 0.30 does not change the MR significantly, suggesting that the availability of oxygen does not influence the cerebral uptake of lactate or glucose during exercise, at least not within the applied inspiratory partial oxygen tensions.

This study demonstrated that it is possible to reach a cerebral metabolic ratio below 2 during strenuous whole body exercise, while the reduction in cerebral metabolic ratio remains debated. Presumably, the increased uptake of arterial lactate plays an important role in the reduction of the metabolic ratio but its fate after cerebral uptake remains to be identified. As tested in this study, O2 availability does not affect the uptake of lactate, or the drop in MR, during exercise suggesting that short-term cerebral metabolism is unaffected by small changes in arterial O2 availability.