Increased insulin-stimulated glucose uptake in both leg and arm muscles after sprint interval and moderate-intensity training in subjects with type 2 diabetes or prediabetes.

We investigated the effects of sprint interval training (SIT) and moderate-intensity continuous training (MICT) on glucose uptake (GU) during hyperinsulinemic euglycemic clamp and fatty acid uptake (FAU) at fasting state in thigh and arm muscles in subjects with type 2 diabetes (T2D) or prediabetes. Twenty-six patients (age 49, SD 4; 10 women) were randomly assigned into two groups: SIT (n=13) and MICT (n=13). The exercise in the SIT group consisted of 4-6×30 s of all-out cycling with 4- minute recovery and in the MICT group 40- to 60- minute cycling at 60% of VO2peak . Both groups completed six training sessions within two weeks. GU and FAU were measured before and after the intervention with positron emission tomography in thigh (quadriceps femoris, QF; and hamstrings) and upper arm (biceps and triceps brachii) muscles. Whole-body insulin-stimulated GU increased significantly by 25% in both groups, and this was accompanied with significantly increased insulin-stimulated GU in all thigh and upper arm muscles and significantly increased FAU in QF. Within QF, insulin-stimulated GU improved more by SIT than MICT in rectus femoris (P = .01), but not differently between the training modes in the other QF muscles. In individuals with T2D or prediabetes, both SIT and MICT rapidly improve insulin-stimulated GU in whole body and in the thigh and arm muscles as well as FAU in the main working muscle QF. These findings highlight the underused potential of exercise in rapidly restoring the impaired skeletal muscle metabolism in subjects with impaired glucose metabolism.

Autonomic Function Predicts Fitness Response to Short-Term High-Intensity Interval Training.

We tested the hypothesis that baseline cardiac autonomic function and its acute response to all-out interval exercise explains individual fitness responses to high-intensity interval training (HIT). Healthy middle-aged sedentary men performed HIT (n=12, 4-6×30 s of all-out cycling efforts with 4-min recovery) or aerobic training (AET, n=9, 40-60 min at 60% of peak workload in exercise test [Loadpeak]), comprising 6 sessions within 2 weeks. Low (LF) and high frequency (HF) power of R-R interval oscillation were analyzed from data recorded at supine and standing position (5+5 min) every morning during the intervention. A significant training effect (p< 0.001), without a training*group interaction, was observed in Loadpeak and peak oxygen consumption (VO2peak). Pre-training supine LF/HF ratio, an estimate of sympathovagal balance, correlated with training outcome in Loadpeak (Spearman's rho [rs]=-0.74, p=0.006) and VO2peak (rs=- 0.59, p=0.042) in the HIT but not the AET group. Also, the mean change in the standing LF/HF ratio in the morning after an acute HIT exercise during the 1(st) week of intervention correlated with training response in Loadpeak (rs=- 0.68, p=0.014) and VO2peak (rs=-0.60, p=0.039) with HIT but not with AET. In conclusion, pre-training cardiac sympathovagal balance and its initial alterations in response to acute HIT exercise were related to fitness responses to short-term HIT.

Regional differences in blood flow, glucose uptake and fatty acid uptake within quadriceps femoris muscle during dynamic knee-extension exercise.

The purpose of the present study was to investigate the regional differences in glucose and fatty acid uptake within skeletal muscle during exercise. Blood flow (BF), glucose uptake (GU) and free fatty acid uptake (FFAU) were measured in four different regions (vastus lateralis, VL; rectus femoris, RF; vastus intermedius, VI; and vastus medialis, VM) of the quadriceps femoris (QF) muscle during low-intensity, knee-extension exercise using positron emission tomography. BF was higher in VI than in VL, RF and VM (P < 0.05). FFAU was higher in VI (P < 0.001) but also in VM (P < 0.05) compared with VL and RF. In contrast, GU was higher in RF compared with VL (P < 0.05) but was not significantly different to VM or VI (both P = NS). FFAU within these four muscle regions correlated significantly with BF (r = 0.951, P < 0.05), whereas no significant relationship was observed between GU and BF (r = 0.352, P = NS). Therefore, skeletal muscle FFAU, but not GU, appears to be associated with BF during low-intensity exercise. The present results also indicate considerable regional differences in substrate use within working QF muscle. As such, an important methodological outcome from these results is that one sample from a specific part of the QF muscle does not represent the response in the entire QF muscle group.

Myocardial and peripheral vascular functional adaptation to exercise training.

Exercise training seems to restore impaired vascular function in both peripheral and myocardial vessels in patients with coronary artery and peripheral vascular disease or in patients with risk factors for these diseases. However, the results on the effects of exercise training on vascular function in apparently healthy subjects are controversial. We studied the effects of long-term volitionally increased physical activity on peripheral and myocardial vascular function in nine young healthy male monozygotic twin pairs discordant for physical activity and fitness. The brothers were divided into more (MAG) and less active groups according to physical activity and fitness. The difference between groups in VO(2max) was 18+/-10% (P<0.001). Myocardial perfusion at rest, during adenosine-induced vasodilatation and during cold-pressor test and myocardial oxygen consumption were measured with positron emission tomography. In addition, endothelial function was measured using ultrasound in brachial and left anterior descending coronary arteries, and standard echocardiographic measures were taken. No differences were observed in myocardial perfusion measurements between groups. MAG tended to have a lower oxygen extraction fraction (P=0.06), but oxygen consumption was similar between the groups. No differences were found in coronary artery, myocardial resistance vessel or peripheral endothelial function between groups. These results suggest that when the effects of heredity are controlled, myocardial perfusion reserve and endothelial function, both in peripheral arteries and myocardial vessels, are not enhanced by increased physical activity and fitness in young healthy adult men.

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

Fabry disease (McKusick 301500) is an X-linked lysosomal storage disorder secondary to deficient alpha-galactosidase A activity which leads to the widespread accumulation of globotriaosylceramide (Gb(3)) 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 alpha-galactosidase A (Fabrazyme, Genzyme). Plasma Gb(3) 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 Gb(3) 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.

Effects of exhaustive stretch-shortening cycle exercise on muscle blood flow during exercise.

AIM: The influence of exhaustive stretch-shortening cycle exercise (SSC) on skeletal muscle blood flow (BF) during exercise is currently unknown. METHODS: Quadriceps femoris (QF) BF was measured in eight healthy men using positron emission tomography before and 3 days after exhaustive SSC exercise. The SSC protocol consisted of maximal and submaximal drop jumps with one leg. Needle biopsies of the vastus lateralis muscles were taken immediately and 2 days after SSC for muscle endothelial nitric oxide synthase (eNOS) and interleukin-1-beta (IL-1beta) mRNA level determinations. RESULTS: All subjects reported subjective muscle soreness after SSC (P < 0.001), which was well in line with a decrease in maximal isometric contraction force (MVC) and increase in serum creatine kinase activity (CK) (P = 0.018). After SSC muscle BF was 25% higher in entire QF (P = 0.043) and in its deep and superficial muscle regions, whereas oxygen uptake remained unchanged (P = 0.893). Muscle biopsies revealed increased IL-1beta (30 min: 152 +/- 75%, P = 0.012 and 2 days: 108 +/- 203%, P = 0.036) but decreased or unchanged eNOS (30 min; -21 +/- 57%, P = 0.050 and 2 days: +101 +/- 204%, P = 0.779) mRNA levels after SSC. CONCLUSION: It was concluded that fatiguing SSC exercise induces increased muscle BF during exercise, which is likely to be associated with pro-inflammatory processes in the exercised muscle.

Low-intensity tensile loading increases intratendinous glucose uptake in the Achilles tendon.

The metabolic activity of tendinous tissues has traditionally been considered to be of limited magnitude. However, recent studies have suggested that glucose uptake increases in the force-transmitting tissues as a response to contractile loading, which in turn indicates an elevated tissue metabolism. The purpose of the present study was to investigate whether such a mechanism could be observed for the human Achilles tendon following tensile loading. Six subjects participated in the study. Unilateral Achilles tendon loading was applied by 25-min intermittent voluntary plantar flexor contractions. A radioactive tracer ([18F]-2-fluoro-2-deoxy-D-glucose) was administered during muscle action, and glucose uptake was measured by use of PET. Regions of interest were defined on the PET images corresponding to the cross section of Achilles tendon at two longitudinally separated sites (insertion and free tendon). Glucose uptake index was determined within respective regions of interest for the active and resting leg. Tendon force during voluntary contractions was approximately 13% of maximal voluntary contraction force. Tendon loading induced an elevated glucose uptake index compared with that of the contralateral resting tendon in the region of tendon insertion (0.13 +/- 0.05 vs. 0.09 +/- 0.02; P < 0.05) and at the free tendon (0.12 +/- 0.01 vs. 0.08 +/- 0.02; P < 0.05). The present data suggest that tissue metabolism is elevated in the human Achilles tendon in response to low-intensity loading.

In vivo measurements of glucose uptake in human Achilles tendon during different exercise intensities.

Muscular contraction and loading of adjacent tendons has been demonstrated to cause increased blood flow and metabolic activity in the peritendinous region. However, it is poorly known to what extent the human tendon itself takes up glucose during exercise. Thus, the purpose of this study was to measure tendon glucose uptake with increasing exercise intensity and to compare it to muscle glucose uptake at the same intensities. Eight young men were examined on three separate days during which they performed 35 min of cycling at 30, 55 and 75 % of VO2max, respectively. Glucose uptake was measured directly by positron emission tomography (PET) with 2-[ (18)F]fluoro-2-deoxyglucose ([18F]FDG). [18F]FDG was injected after 10 min of exercise that was continued for a further 25 min after the injection. PET scanning of the thigh and Achilles region was performed after the exercise. Glucose uptake of the Achilles tendon (AT) remained unchanged (7.1 +/- 1.5, 6.6 +/- 1.1, and 6.0 +/- 1.1 micromol.kg(-1).min(-1)) with the increasing workload, although the glucose uptake in m. quadriceps femoris simultaneously clearly increased (48 +/- 35, 120 +/- 35, and 152 +/- 74 micromol.kg(-1).min(-1), p < 0.05). In conclusion, the AT takes up glucose during exercise but in significantly smaller amounts than the skeletal muscle does. Furthermore, glucose uptake in the AT is not increased with the increasing exercise intensity. This may be partly explained by the cycle ergometry exercise used in the present study, which probably causes only a little increase in strain to the AT with increasing exercise intensity.

Impaired myocardial perfusion reserve but preserved peripheral endothelial function in patients with Fabry disease.

Fabry disease (McKusick 301500) is an X-linked lysosomal storage disorder due to deficient alpha-galactosidase A activity, which leads to accumulation of glycosphingolipids, especially in vascular smooth-muscle and endothelial cells. The effect of this accumulation on peripheral and cardiac vascular function is poorly known. We studied 15 Fabry patients (mean age 35 years and mean BMI 24.8 kg/m2) and 30 age- and BMI-matched healthy controls to examine whether myocardial perfusion reserve and peripheral artery endothelial function are altered. Myocardial perfusion was measured at rest and during dipyridamole-induced hyperaemia by positron emission tomography and H2(15)O. Myocardial blood flow reserve was calculated as the ratio between the dipyridamole-induced maximal blood flow and resting blood flow. Peripheral artery endothelial function was assessed by measuring the brachial artery flow-mediated dilatation using ultrasound at rest and during reactive hyperaemia. The myocardial perfusion reserve was significantly lower in Fabry patients than in controls (3.3+/-1.2 vs 4.4+/-1.6, p=0.02), while the brachial artery flow-mediated dilatation was similar (5.9%+/-3.9% vs 4.5%+/-3.6%, p=0.27). Thus, inFabry disease, myocardial perfusion reserve is reduced while the peripheral artery endothelial function is preserved.

Perfusion distribution between and within muscles during intermittent static exercise in endurance-trained and untrained men.

We have recently shown that muscle perfusion varies between different quadriceps femoris muscles during submaximal exercise in humans. In animals, endurance training changes perfusion distribution between muscles during exercise. Whether the same is observed in humans is currently unknown. Therefore, we compared perfusion levels between different parts of the quadriceps femoris muscle group during one-legged intermittent static exercise in seven endurance-trained and seven untrained men. Muscle perfusion was measured using positron emission tomography with [ 15O]-H 2 O. In addition, relative dispersion of perfusion (standard deviation within a region/mean within a region x 100 %) within each muscle region was calculated as an index of perfusion heterogeneity within the muscles. Muscle perfusion tended to be lower in endurance-trained men (p = 0.16) and it was also different between the regions (p < 0.001). However, perfusion distributed similarly between the groups (p = 0.51). Relative dispersion of perfusion within the muscles was lower in endurance-trained men (p = 0.01) and it was also different between muscles (p < 0.001). These results suggest that endurance training does not alter perfusion distribution between muscles, but it decreases perfusion heterogeneity within the muscles.

Perfusion heterogeneity in human skeletal muscle: fractal analysis of PET data.

Muscle blood flow has been shown to be heterogeneous at the voxel by voxel level in positron emission tomography (PET) studies using oxygen-15 labelled water. However, the limited spatial resolution of the imaging device does not allow direct measurement of true vascular flow heterogeneity. Fractal dimension (D) obtained by fractal analysis describes the relationship between the relative dispersion and the size of the region studied, and has been used for the assessment of perfusion heterogeneity in microvascular units. This study was undertaken to evaluate fractal characteristics of PET perfusion data and to estimate perfusion heterogeneity in microvascular units. Skeletal muscle blood flow was measured in healthy subjects using [15O]water PET and the fractal characteristics of blood flow in resting and exercising skeletal muscle were analysed. The perfusion heterogeneity in microvascular units was estimated using the measured heterogeneity (relative dispersion, RD = SD/mean) and D values. Heterogeneity due to methodological factors was estimated with phantoms and subtracted from the flow data. The number of aggregated voxels was inversely correlated with RD both in phantoms (Pearson r = -0.96-0.97) and in muscle (Pearson r = -0.94) when both parameters were expressed using a logarithmic scale. Fractal dimension was similar between exercising (1.13) and resting (1.14) muscles and significantly lower than the values in the phantoms with different activity levels (1.27-1.29). Measured flow heterogeneity values were 20% +/- 6% (exercise) and 27% +/- 5% (rest, P < 0.001), whereas estimated flow heterogeneity values in microvascular units (1 mm3) were 35% +/- 14% (exercise) and 49% +/- 14% (rest, P < 0.01). In conclusion, these results show that it is feasible to apply fractal analysis to PET perfusion data. When microvascular flow heterogeneity is estimated using fractals, perfusion appears to be more heterogeneous in microvascular units than when obtained by routine spatial analysis of PET data. Analysis of flow heterogeneity using PET and fractals could provide new insight into physiological conditions and diseases associated with changes in peripheral vascular function.

Enhanced oxygen extraction and reduced flow heterogeneity in exercising muscle in endurance-trained men.

The aim of this study was to investigate the effects of endurance training on skeletal muscle hemodynamics and oxygen consumption. Seven healthy endurance-trained and seven untrained subjects were studied. Oxygen uptake, blood flow, and blood volume were measured in the quadriceps femoris muscle group by use of positron emission tomography and [15O]O2, [15O]H2O, and [15O]CO during rest and one-legged submaximal intermittent isometric exercise. The oxygen extraction fraction was higher (0.49 +/- 0.14 vs. 0.29 +/- 0.12; P = 0.017) and blood transit time longer (0.6 +/- 0.1 vs. 0.4 +/- 0.1 min; P = 0.04) in the exercising muscle of the trained compared with the untrained subjects. The flow heterogeneity by means of relative dispersion was lower for the exercising muscle in the trained (50 +/- 9%) compared with the untrained subjects (65 +/- 13%, P = 0.025). In conclusion, oxygen extraction is higher, blood transit time longer, and perfusion more homogeneous in endurance-trained subjects compared with untrained subjects at the same workload. These changes may be associated with improved exercise efficiency in the endurance-trained subjects.

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

Blood flow is the main regulator of skeletal muscle's 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 H2(15)O 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 x (kg muscle)(-1) x min(-1) at rest and 146 (54) ml x (kg muscle)(-1) x 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.