Henning B. Nielsen

Blood lactate is an important energy source for the human brain

Lactate is a potential energy source for the brain. The aim of this study was to establish whether systemic lactate is a brain energy source. We measured in vivo cerebral lactate kinetics and oxidation rates in 6 healthy individuals at rest with and without 90 mins of intravenous lactate infusion (36 μmol per kg bw per min), and during 30mins of cycling exercise at 75% of maximal oxygen uptake while the lactate infusion continued to establish arterial lactate concentrations of 0.89 ± 0.08, 3.9 ± 0.3, and 6.9 ± 1.3 mmol/L, respectively. At rest, cerebral lactate utilization changed from a net lactate release of 0.06 ± 0.01 to an uptake of 0.16 ± 0.07 mmol/min during lactate infusion, with a concomitant decrease in the net glucose uptake. During exercise, the net cerebral lactate uptake was further increased to 0.28 ± 0.16 mmol/min. Most 13C-label from cerebral [1-13C]lactate uptake was released as 13CO2 with 100% ± 24%, 86% ± 15%, and 87% ± 30% at rest with and without lactate infusion and during exercise, respectively. The contribution of systemic lactate to cerebral energy expenditure was 8% ± 2%, 19% ± 4%, and 27% ± 4% for the respective conditions. In conclusion, systemic lactate is taken up and oxidized by the human brain and is an important substrate for the brain both under basal and hyperlactatemic conditions.

Cerebral desaturation during exercise reversed by O2 supplementation

The combined effects of hyperventilation and arterial desaturation on cerebral oxygenation (ScO2) were determined using near-infrared spectroscopy. Eleven competitive oarsmen were evaluated during a 6-min maximal ergometer row. The study was randomized in a double-blind fashion with an inspired O2 fraction of 0.21 or 0.30 in a crossover design. During exercise with an inspired O2 fraction of 0.21, the arterial CO2 pressure (35 +/- 1 mmHg; mean +/- SE) and O2 pressure (77 +/- 2 mmHg) as well as the hemoglobin saturation (91.9 +/- 0.7%) were reduced (P < 0.05). ScO2 was reduced from 80 +/- 2 to 63 +/- 2% (P < 0.05), and the near-infrared spectroscopy-determined concentration changes in deoxy- (DeltaHb) and oxyhemoglobin (DeltaHbO2) of the vastus lateralis muscle increased 22 +/- 3 microM and decreased 14 +/- 3 microM, respectively (P < 0.05). Increasing the inspired O2 fraction to 0.30 did not affect ventilation (174 +/- 4 l/min), but arterial CO2 pressure (37 +/- 2 mmHg), O2 pressure (165 +/- 5 mmHg), and hemoglobin O2 saturation (99 +/- 0.1%) increased (P < 0. 05). ScO2 remained close to the resting level during exercise (79 +/- 2 vs. 81 +/- 2%), and although the muscle DeltaHb (18 +/- 2 microM) and DeltaHbO2 (-12 +/- 3 microM) were similar to those established without O2 supplementation, work capacity increased from 389 +/- 11 to 413 +/- 10 W (P < 0.05). These results indicate that an elevated inspiratory O2 fraction increases exercise performance related to maintained cerebral oxygenation rather than to an effect on the working muscles.The combined effects of hyperventilation and arterial desaturation on cerebral oxygenation ([Formula: see text]) were determined using near-infrared spectroscopy. Eleven competitive oarsmen were evaluated during a 6-min maximal ergometer row. The study was randomized in a double-blind fashion with an inspired O2 fraction of 0.21 or 0.30 in a crossover design. During exercise with an inspired O2 fraction of 0.21, the arterial CO2 pressure (35 ± 1 mmHg; mean ± SE) and O2 pressure (77 ± 2 mmHg) as well as the hemoglobin saturation (91.9 ± 0.7%) were reduced ( P < 0.05).[Formula: see text] was reduced from 80 ± 2 to 63 ± 2% ( P < 0.05), and the near-infrared spectroscopy-determined concentration changes in deoxy- (ΔHb) and oxyhemoglobin (ΔHbO2) of the vastus lateralis muscle increased 22 ± 3 μM and decreased 14 ± 3 μM, respectively ( P < 0.05). Increasing the inspired O2fraction to 0.30 did not affect ventilation (174 ± 4 l/min), but arterial CO2 pressure (37 ± 2 mmHg), O2 pressure (165 ± 5 mmHg), and hemoglobin O2saturation (99 ± 0.1%) increased ( P < 0.05).[Formula: see text] remained close to the resting level during exercise (79 ± 2 vs. 81 ± 2%), and although the muscle ΔHb (18 ± 2 μM) and ΔHbO2 (-12 ± 3 μM) were similar to those established without O2 supplementation, work capacity increased from 389 ± 11 to 413 ± 10 W ( P < 0.05). These results indicate that an elevated inspiratory O2fraction increases exercise performance related to maintained cerebral oxygenation rather than to an effect on the working muscles.

Glucose ingestion attenuates interleukin-6 release from contracting skeletal muscle in humans

To examine whether glucose ingestion during exercise affects the release of interleukin‐6 (IL‐6) from the contracting limb, seven men performed 120 min of semi‐recumbent cycling on two occasions while ingesting either 250 ml of a 6.4 % carbohydrate (GLU trial) or sweet placebo (CON trial) beverage at the onset of, and at 15 min intervals throughout, exercise. Muscle biopsies obtained before and immediately after exercise were analysed for glycogen and IL‐6 mRNA expression. Blood samples were simultaneously obtained from a brachial artery and a femoral vein prior to and during exercise and leg blood flow was measured by thermodilution in the femoral vein. Net leg IL‐6 release, and net leg glucose and free fatty acid (FFA) uptake, were calculated from these measurements. The arterial IL‐6 concentration was lower (P < 0.05) after 120 min of exercise in GLU, but neither intramuscular glycogen nor IL‐6 mRNA were different when comparing GLU with CON. However, net leg IL‐6 release was attenuated (P < 0.05) in GLU compared with CON. This corresponded with an enhanced (P < 0.05) glucose uptake and a reduced (P < 0.05) FFA uptake in GLU. These results demonstrate that glucose ingestion during exercise attenuates leg IL‐6 release but does not decrease intramuscular expression of IL‐6 mRNA.

Exercise induces hepatosplanchnic release of heat shock protein 72 in humans

Physical exercise results in the appearance of heat shock protein (HSP) 72 in the circulation that precedes any increase in gene or protein expression in contracting skeletal muscle. In rodents, exercise increases liver HSP72 expression and the hepatosplanchnic viscera are known to release many acute phase proteins. In the present study, we tested the hypothesis that the splanchnic tissue beds release HSP72 during exercise. Seven male subjects performed 120 min of semi‐recumbent cycling at 62 ± 2 % of maximal oxygen uptake. Blood samples were obtained simultaneously from a brachial artery, a femoral vein and the hepatic vein prior to and at 30, 60 and 120 min of exercise. Leg blood flow (LBF) was measured by thermodilution in the femoral vein, and hepatosplanchnic blood flow (HBL) was measured using indocyanine green dye. Net leg and net hepatosplanchnic HSP72 balance were calculated as the product of LBF and femoral venous‐arterial HSP72 difference and the product of HBF and hepatic venous‐arterial HSP72 difference, respectively. Arterial plasma HSP72 was only detected in one subject at rest but progressively appeared in the arterial samples throughout exercise such that at 120 min it was detected in all subjects (0.88 ± 0.35 pg l−1; P < 0.05 compared with rest). The contracting muscle did not, however, contribute to this increase since there was no difference in the femoral venous‐arterial HSP72 concentration at any time. Rather, the increase in arterial HSP72 was accounted for, at least in part, by release from the hepatosplanchnic viscera with values increasing (P < 0.05) from undetectable levels at rest to 5.2 ± 0.2 pg min−1 after 120 min. These data demonstrate that the splanchnic tissues release HSP72 during exercise and this release is responsible, in part, for the elevated systemic concentration of this protein during exercise.

Mesenteric, coeliac and splanchnic blood flow in humans during exercise

1 Exercise reduces splanchnic blood flow, but the mesenteric contribution to this response is uncertain. 2 In nineteen humans, superior mesenteric and coeliac artery flows were determined by duplex ultrasonography during fasting and postprandial submaximal cycling and compared with the splanchnic blood flow as assessed by the Indocyanine Green dye‐elimination technique. 3 Cycling increased arterial pressure, heart rate and cardiac output, while it reduced total vascular resistance. These responses were not altered in the postprandial state. During fasting, cycling increased mesenteric, coeliac and splanchnic resistances by 76, 165 and 126%, respectively, and it reduced corresponding blood flows by 32, 50 and 43% (by 0.18 ± 0.04, 0.42 ± 0.03 and 0.60 ± 0.04 l min−1). Postprandially, mesenteric and splanchnic vascular resistances decreased, thereby elevating regional blood flow, while the coeliac circulation was not influenced. Postprandial cycling did not influence the mesenteric resistance significantly, but its blood flow decreased by 22% (0.46 ± 0.28 l min−1). Coeliac and splanchnic resistance increased by 150 and 63%, respectively, and the corresponding regional blood flow decreased by 51 and 31% (0.49 ± 0.07 and 0.96 ± 0.28 l min−1). Splanchnic blood flow values assessed by duplex ultrasound and by dye‐elimination techniques were correlated (r= 0.70; P < 0.01). 4 During submaximal exercise in humans, splanchnic resistance increases and blood flow is reduced following a 50% reduction in the hepato‐splenic and a 25% reduction in the mesenteric blood flow.

Lymphocyte proliferation in response to exercise

Abstract Lymphocyte proliferative responses are often used to evaluate the functional capacity of the immune system in response to exercise. Blood mononuclear cells (BMNC) are stimulated in vitro with polyclonal mitogens and the incorporation of 3H-thymidine into the DNA reflects cell proliferation. The BMNC are most often stimulated with either phytohaemagglutinin (PHA), poke weed mitogen (PWM), concanavalin A (Con-A), interleukin-2 (IL-2), or purified derivative of tuberculin (PPD). The literature concerning lymphocyte proliferation and exercise is reviewed with respect to the type and intensity of exercise, and also the effect of training status. The proliferative responses to exercise are highly heterogeneous, the most consistent finding being that PHA-stimulated cell responses decrease during exercise which may reflect a decreased fraction of CD3+ cells. In contrast, reduced, elevated or even unchanged lymphocyte proliferative response to PHA, PWM, Con-A, IL-2 and PPD have been demonstrated in the recovery period following exercise. Also variable responses are present in trained athletes compared to less fit subjects. Even though this may reflect that the time of 3H-thymidine incorporation into lymphocytes varies, we conclude that a functional evaluation of the immune system in response to exercise cannot be based solely upon measurements of lymphocyte proliferation.

Cerebral oxygenation decreases during exercise in humans with beta‐adrenergic blockade

Aim:  Beta‐blockers reduce exercise capacity by attenuated increase in cardiac output, but it remains unknown whether performance also relates to attenuated cerebral oxygenation.

Arterial desaturation during exercise in man: implication for O2 uptake and work capacity

Exercise‐induced arterial hypoxaemia is defined as a reduction in the arterial O2 pressure (PaO2) by more than 1 kPa and/or a haemoglobin O2 saturation (SaO2) below 95%. With blood gas analyses ideally reported at the actual body temperature, desaturation is a consistent finding during maximal ergometer rowing. Arterial desaturation is most pronounced at the end of a maximal exercise bout, whereas the reduction in PaO2 is established from the onset of exercise. Exercise‐induced arterial hypoxaemia is multifactorial. The ability to maintain a high alveolar O2 pressure (PAO2) is critical for blood oxygenation and this appears to be difficult in large individuals. A large lung capacity and, in turn, diffusion capacity seem to protect PaO2. A widening of the PAO2–PaO2 difference does indicate that a diffusion limitation, a ventilation–perfusion mismatch and/or a shunt influence the transport of O2 from alveoli to the pulmonary capillaries. An inspired O2 fraction of 0.30 reduces the widened PAO2–PaO2 difference by 75% and prevents a reduction of PaO2 and SaO2. With a marked increase in cardiac output, diffusion limitation combined with a fast transit time dominates the O2 transport problem. Furthermore, a postexercise reduction in pulmonary diffusion capacity suggests that the alveolo‐capillary membrane is affected. An antioxidant attenuates oxidative burst by neutrophilic granulocytes, but it does not affect PaO2, SaO2 or O2 uptake (VO2), and the ventilatory response to maximal exercise also remains the same. It is proposed, though, that increased concentration of certain cytokines correlates to exercise‐induced hypoxaemia as cytokines stimulate mast cells and basophilic granulocytes to degranulate histamine. The basophil count increases during maximal rowing. Equally, histamine release is associated with hypoxaemia and when the release of histamine is prevented, the reduction in PaO2 is attenuated.

Cerebral perfusion, oxygenation and metabolism during exercise in young and elderly individuals

•  The influence of normative ageing on cerebral perfusion, oxygenation and metabolism during exercise is not well known. •  This study assessed cerebral perfusion and concentration differences for oxygen, glucose and lactate across the brain, in young and elderly individuals at rest and during incremental exercise to exhaustion. •  We observed that during submaximal exercise (at matched relative intensities) and during maximal exercise, cerebral perfusion was reduced in older individuals compared with young individuals, while the cerebral metabolic rate for oxygen and uptake of glucose and lactate were similar. •  The results indicate that the age‐related reduction in cerebral perfusion during exercise does not affect brain uptake of lactate and glucose.

Hypoxia and exercise provoke both lactate release and lactate oxidation by the human brain

Lactate is shuttled between organs, as demonstrated in the Cori cycle. Although the brain releases lactate at rest, during physical exercise there is a cerebral uptake of lactate. Here, we evaluated the cerebral lactate uptake and release in hypoxia, during exercise and when the two interventions were combined. We measured cerebral lactate turnover via a tracer dilution method ([1‐13C]lactate), using arterial to right internal jugular venous differences in 9 healthy individuals (5 males and 4 females), at rest and during 30 min of submaximal exercise in normoxia and hypoxia (Fio2 10%, arterial oxygen saturation 72±10%, mean±sd). Whole‐body lactate turnover increased 3.5‐fold and 9‐fold at two workloads in normoxia and 18‐fold during exercise in hypoxia. Although middle cerebral artery mean flow velocity increased during exercise in hypoxia, calculated cerebral mitochondrial oxygen tension decreased by 13 mmHg (P<0.001). At the same time, cerebral lactate release increased from 0.15 ± 0.1 to 0.8 ± 0.6 mmol min−1 (P<0.05), corresponding to ∼10% of cerebral energy consumption. Concurrently, cerebral lactate uptake was 1.0 ± 0.9 mmol min−1 (P<0.05), of which 57 ± 9% was oxidized, demonstrating that lactate oxidation may account for up to ∼33% of the energy substrate used by the brain. These results support the existence of a cell‐cell lactate shuttle that may involve neurons and astrocytes.— Overgaard, M., Rasmussen, P., Bohm, A. M., Seifert, T., Brassard, P., Zaar, M., Homann, P., Evans, K. A., Nielsen, H. B., Secher, N. H. Hypoxia and exercise provoke both lactate release and lactate oxidation by the human brain. FASEB J. 26, 3012–3020 (2012). www.fasebj.org