Kari K. Kalliokoski

High intensity exercise decreases global brain glucose uptake in humans

Physiological activation increases glucose uptake locally in the brain. However, it is not known how high intensity exercise affects regional and global brain glucose uptake. The effect of exercise intensity and exercise capacity on brain glucose uptake was directly measured using positron emission tomography (PET) and [18F]fluoro‐deoxy‐glucose ([18F]FDG). Fourteen healthy, right‐handed men were studied after 35 min of bicycle exercise at exercise intensities corresponding to 30, 55 and 75% of on three separate days. [18F]FDG was injected 10 min after the start of the exercise. Thereafter exercise was continued for another 25 min. PET scanning of the brain was conducted after completion of the exercise. Regional glucose metabolic rate (rGMR) decreased in all measured cortical regions as exercise intensity increased. The mean decrease between the highest and lowest exercise intensity was 32% globally in the brain (38.6 ± 4.6 versus 26.1 ± 5.0 μmol (100 g)−1 min−1, P < 0.001). Lactate availability during exercise tended to correlate negatively with the observed brain glucose uptake. In addition, the decrease in glucose uptake in the dorsal part of the anterior cingulate cortex (37%versus 20%, P < 0.05 between 30% and 75% of ) was significantly more pronounced in subjects with higher exercise capacity. These results demonstrate that brain glucose uptake decreases with increase in exercise intensity. Therefore substrates other than glucose, most likely lactate, are utilized by the brain in order to compensate the increased energy needed to maintain neuronal activity during high intensity exercise. Moreover, it seems that exercise training could be related to adaptive metabolic changes locally in the frontal cortical regions.

Myocardial and skeletal muscle glucose uptake during exercise in humans

The purpose of this study was to investigate the effects of exercise on myocardial glucose uptake and whether the pattern of glucose uptake is the same as in skeletal muscle. Glucose uptake was measured using positron emission tomography (PET) and 2‐[18F]fluoro‐2‐deoxy‐D‐glucose ([18F]FDG). Twelve healthy men were studied during rest, while 14 subjects were studied after 35 min of bicycle exercise corresponding to 30, 55 and 75 % of maximal oxygen consumption (V̇O2,max) on three separate days. [18F]FDG was injected 10 min after the start of exercise and exercise continued for a further 25 min. Myocardial and skeletal muscle PET scanning was commenced directly after the completion of the exercise bout. As compared to the resting state, exercise doubled myocardial glucose uptake at the 30 % (P= 0.056) and 55 % intensity levels (P < 0.05), while at the 75 % intensity level glucose uptake was reduced significantly compared to the lower exercise intensities. There was no significant difference between the highest intensity level and the resting state (P= 0.18). At rest and during low‐intensity exercise, myocardial glucose uptake was inversely associated with circulating levels of free fatty acids. However, during higher exercise intensities when plasma lactate concentrations increased significantly, this association disappeared. In contrast to myocardial responses, skeletal muscle glucose uptake rose in parallel with exercise intensity from rest to 30 % and then 55 % V̇O2,max (P < 0.001) and tended to increase further at the intensity of 75 % V̇O2,max (P= 0.065). In conclusion, these results demonstrate that myocardial glucose uptake is increased during mild‐ and moderate‐intensity exercise, but is decreased during high‐intensity exercise. This finding suggests that the increased myocardial energy that is needed during high‐intensity exercise is supplied by substrates other than glucose.

Exercise training improves biventricular oxidative metabolism and left ventricular efficiency in patients with dilated cardiomyopathy.

OBJECTIVES The aim of this study was to determine the effect of exercise training on myocardial oxidative metabolism and efficiency in patients with idiopathic dilated cardiomyopathy (DCM) and mild heart failure (HF). BACKGROUND Exercise training is known to improve exercise tolerance and quality of life in patients with chronic HF. However, little is known about how exercise training may influence myocardial energetics. METHODS Twenty clinically stable patients with DCM (New York Heart Association classes I through III) were prospectively separated into a training group (five-month training program; n = 9) and a non-trained control group (n = 11). Oxidative metabolism in both the right and left ventricles (RV and LV) was measured using [(11)C]acetate and positron emission tomography. Myocardial work power was measured using echocardiography. Myocardial efficiency for forward work was calculated as myocardial work power per mass/LV oxidative metabolism. RESULTS Significant improvements were noted in exercise capacity (VO(2)) and ejection fraction in the training group, whereas no changes were observed in the non-trained group. Exercise training reduced both RV and LV oxidative metabolism and elicited a significant increase in LV forward work efficiency, although no significant changes were observed in the non-trained group. CONCLUSIONS Exercise training improves exercise tolerance and LV function. This is accompanied by a decrease in biventricular oxidative metabolism and enhanced forward work efficiency. Therefore, exercise training elicits an energetically favorable improvement in myocardial function and exercise tolerance in patients with DCM.

Muscle blood flow and flow heterogeneity during exercise studied with positron emission tomography in humans

Abstract Blood flow is the main regulator of skeletal muscles oxygen supply, and several studies have shown heterogeneous blood flow among and within muscles. However, it remains unclear whether exercise changes the heterogeneity of flow in exercising human skeletal muscle. Muscle blood flow and spatial flow heterogeneity were measured simultaneously in exercising and in the contralateral resting quadriceps femoris (QF) muscle in eight healthy men using H152O and positron emission tomography. The relative dispersion (standard deviation/mean) of blood flow was calculated as an index of spatial flow heterogeneity. Average muscle blood flow in QF was 29 (10) ml · (kg muscle)−1 · min−1 at rest and 146 (54) ml · (kg muscle)−1 · min−1 during exercise (P=0.008 for the difference). Blood flow was significantly (P < 0.001) higher in the vastus medialis and the vastus intermedius than in the vastus lateralis and the rectus femoris, both in the resting and the exercising legs. Flow was more homogeneous in the exercising vastus medialis and more heterogeneous (P < 0.001) in the exercising vastus lateralis (P=0.01) than in the resting contralateral muscle. Flow was more homogeneous (P < 0.001) in those exercising muscles in which flow was highest (vastus intermedius and vastus medialis) as compared to muscles with the lowest flow (vastus lateralis and the rectus femoris). These data demonstrate that muscle blood flow varies among different muscles in humans both at rest and during exercise. Muscle perfusion is spatially heterogeneous at rest and during exercise, but responses to exercise are different depending on the muscle.

Local heating, but not indirect whole body heating, increases human skeletal muscle blood flow.

For decades it was believed that direct and indirect heating (the latter of which elevates blood and core temperatures without directly heating the area being evaluated) increases skin but not skeletal muscle blood flow. Recent results, however, suggest that passive heating of the leg may increase muscle blood flow. Using the technique of positron-emission tomography, the present study tested the hypothesis that both direct and indirect heating increases muscle blood flow. Calf muscle and skin blood flows were evaluated from eight subjects during normothermic baseline, during local heating of the right calf [only the right calf was exposed to the heating source (water-perfused suit)], and during indirect whole body heat stress in which the left calf was not exposed to the heating source. Local heating increased intramuscular temperature of the right calf from 33.4 ± 1.0°C to 37.4 ± 0.8°C, without changing intestinal temperature. This stimulus increased muscle blood flow from 1.4 ± 0.5 to 2.3 ± 1.2 ml·100 g⁻¹·min⁻¹ (P < 0.05), whereas skin blood flow under the heating source increased from 0.7 ± 0.3 to 5.5 ± 1.5 ml·100 g⁻¹·min⁻¹ (P < 0.01). While whole body heat stress increased intestinal temperature by ∼1°C, muscle blood flow in the calf that was not directly exposed to the water-perfused suit (i.e., indirect heating) did not increase during the whole body heat stress (normothermia: 1.6 ± 0.5 ml·100 g⁻¹·min⁻¹; heat stress: 1.7 ± 0.3 ml·100 g⁻¹·min⁻¹; P = 0.87). Whole body heating, however, reflexively increased calf skin blood flow (to 4.0 ± 1.5 ml·100 g⁻¹·min⁻¹) in the area not exposed to the water-perfused suit. These data show that local, but not indirect, heating increases calf skeletal muscle blood flow in humans. These results have important implications toward the reconsideration of previously accepted blood flow distribution during whole body heat stress.

Evidence of skeletal muscle damage following electrically stimulated isometric muscle contractions in humans.

It is unknown whether muscle damage at the level of the sarcomere can be induced without lengthening contractions. To investigate this, we designed a study where seven young, healthy men underwent 30 min of repeated electrical stimulated contraction of m. gastrocnemius medialis, with the ankle and leg locked in a fixed position. Two muscle biopsies were collected 48 h later: one from the stimulated muscle and one from the contralateral leg as a control. The biopsies were analyzed immunohistochemically for inflammatory cell infiltration and intermediate filament disruption. Ultrastructural changes at the level of the z-lines were investigated by transmission electron microscopy. Blood samples were collected for measurement of creatine kinase activity, and muscle soreness was assessed in the days following stimulation. The biopsies from the stimulated muscle revealed macrophage infiltration and desmin-negative staining in a small percentage of myofibers in five and four individuals, respectively. z-Line disruption was evident at varying magnitudes in all subjects and displayed a trend toward a positive correlation (r = 0.73, P = 0.0663) with the force produced by stimulation. Increased muscle soreness in all subjects, combined with a significant increase in creatine kinase activity (P < 0.05), is indirectly suggestive of muscle damage, and the novel findings of the present study, i.e., 1) macrophages infiltration, 2) lack of desmin staining, and 3) z-line disruption, provide direct evidence of damage at the myofiber and sarcomere levels. These data support the hypothesis that muscle damage at the level of the sarcomere can be induced without lengthening muscle contractions.

Skeletal muscle glucose uptake response to exercise in trained and untrained men.

PURPOSE Endurance training enhances skeletal muscle glucose uptake at rest, but the responses to different exercise intensities are unknown. In the present study, we tested whether glucose uptake is enhanced in trained men during low-, moderate-, and high-intensity exercise as compared with untrained men. METHODS Seven trained and untrained men were studied without any dietary manipulation during bicycle exercise at relative intensities of 30%, 55%, and 75% of maximal oxygen consumption ([OV0312]O(2max)) on three separate days. Glucose uptake in the quadriceps femoris muscle was directly measured using positron emission tomography (PET) and 18F-fluoro-deoxy-glucose ([18F]FDG). [18F]FDG was injected 10 min after the start of the exercise. Thereafter exercise was continued for another 25 min. PET scanning was conducted immediately after completion of the exercise. The measured glucose uptake values reflect the situation during exercise due to chemical characteristics of the [18F]FDG. RESULTS Muscle glucose uptake increased from 30% to 55% [OV0312]O(2max) intensity exercise similarly in both groups (P < 0.05). However, from 55% to 75% [OV0312]O(2max) intensity exercise, only athletes were able to further enhance glucose uptake. Furthermore, at highest intensity, glucose uptake was significantly higher in trained than in untrained men (236.6 +/- 29.6 vs 176.3 +/- 22.4 micromol.kg-1.min-1, P < 0.05). There were no differences in plasma glucose, insulin, or lactate in any time point at 75% [OV0312]O(2max) intensity between groups. CONCLUSIONS These results show that skeletal muscle glucose uptake is higher in trained than in untrained men at high relative exercise intensity, although at lower relative exercise intensities no differences are observed. Thus, endurance training improves the capacity of contraction-induced glucose uptake in skeletal muscle.

Intermuscular force transmission between human plantarflexor muscles in vivo

The exact mechanical function of synergist muscles within a human limb in vivo is not well described. Recent studies indicate the existence of a mechanical interaction between muscle actuators that may have functional significance and further play a role for injury mechanisms. The purpose of the present study was to investigate if intermuscular force transmission occurs within and between human plantarflexor muscles in vivo. Seven subjects performed four types of either active contractile tasks or passive joint manipulations: passive knee extension, voluntary isometric plantarflexion, voluntary isometric hallux flexion, passive hallux extension, and selective percutaneous stimulation of the gastrocnemius medialis (MG). In each experiment plantar- and hallux flexion force and corresponding EMG activity were sampled. During all tasks ultrasonography was applied at proximal and distal sites to assess task-induced tissue displacement (which is assumed to represent loading) for the plantarflexor muscles [MG, soleus (SOL), and flexor hallucis longus (FHL)]. Selective MG stimulation and passive knee extension resulted in displacement of both the MG and SOL muscles. Minimal displacement of the triceps surae muscles was seen during passive hallux extension. Large interindividual differences with respect to deep plantarflexor activation during voluntary contractions were observed. The present results suggest that force may be transmitted between the triceps surae muscles in vivo, while only limited evidence was provided for the occurrence of force transfer between the triceps surae and the deeper-lying FHL.

The effect of 12-month enzyme replacement therapy on myocardial perfusion in patients with Fabry disease.

SummaryFabry disease (McKusick 301500) is an X-linked lysosomal storage disorder secondary to deficient α-galactosidase A activity which leads to the widespread accumulation of globotriaosylceramide (Gb3) and related glycosphingolipids, especially in vascular smooth-muscle and endothelial cells. We have recently shown that the myocardial perfusion reserve of Fabry patients is significantly decreased. Thus, in the present study we investigated, whether it can be improved with enzyme replacement therapy (ERT). Ten patients (7 male, 3 female; mean age 34, range 19–49 years) with confirmed Fabry disease were approved for this uncontrolled, open-label study. Myocardial perfusion was measured at rest and during dipyridamole-induced hyperaemia by positron emission tomography and radiowater. Myocardial perfusion reserve was calculated as the ratio between maximal and resting perfusion. Perfusion measurements were performed before and after 6 and 12 months of ERT by recombinant human α-galactosidase A (Fabrazyme, Genzyme). Plasma Gb3 concentration decreased significantly and the patients reported that they felt better and suffered less pain after the ERT. However, neither resting or dipyridamole-stimulated myocardial perfusion nor myocardial perfusion reserve changed during the ERT. Pretreatment relative wall thickness correlated negatively with posttreatment changes in flow reserve (r = −0.76, p = 0.05) and positively with posttreatment changes in minimal coronary resistance (r = 0.80, p = 0.03). This study shows that 12 months of ERT does not improve myocardial perfusion reserve, although the plasma Gb3 concentration decreases. However, individual variation in the response to therapy was large and the results suggest that the success of the therapy may depend on the degree of cardiac hypertrophy.

Regulation of human skeletal muscle perfusion and its heterogeneity during exercise in moderate hypoxia

Although many effects of both acute and chronic hypoxia on the circulation are well characterized, the distribution and regulation of blood flow (BF) heterogeneity in skeletal muscle during systemic hypoxia is not well understood in humans. We measured muscle BF within the thigh muscles of nine healthy young men using positron emission tomography during one-leg dynamic knee extension exercise in normoxia and moderate physiological systemic hypoxia (14% O(2) corresponding to approximately 3,400 m of altitude) without and with local adenosine receptor inhibition with femoral artery infusion of aminophylline. Systemic hypoxia reduced oxygen extraction of the limb but increased muscle BF, and this flow increment was confined solely to the exercising quadriceps femoris muscle. Exercising muscle BF heterogeneity was reduced from rest (P = 0.055) but was not affected by hypoxia. Adenosine receptor inhibition had no effect on capillary BF during exercise in either normoxia or hypoxia. Finally, one-leg exercise increased muscle BF heterogeneity both in the resting posterior hamstring part of the exercising leg and in the resting contralateral leg, whereas mean BF was unchanged. In conclusion, the results show that increased BF during one-leg exercise in moderate hypoxia is confined only to the contracting muscles, and the working muscle hyperemia appears not to be directly mediated by adenosine. Increased flow heterogeneity in noncontracting muscles likely reflects sympathetic nervous constraints to curtail BF increments in areas other than working skeletal muscles, but this effect is not potentiated in moderate systemic hypoxia during small muscle mass exercise.