The Muscle Fiber Profiles, Mitochondrial Content, and Enzyme Activities of the Exceptionally Well-Trained Arm and Leg Muscles of Elite Cross-Country Skiers.

As one of the most physically demanding sports in the Olympic Games, cross-country skiing poses considerable challenges with respect to both force generation and endurance during the combined upper- and lower-body effort of varying intensity and duration. The isoforms of myosin in skeletal muscle have long been considered not only to define the contractile properties, but also to determine metabolic capacities. The current investigation was designed to explore the relationship between these isoforms and metabolic profiles in the arms (triceps brachii) and legs (vastus lateralis) as well as the range of training responses in the muscle fibers of elite cross-country skiers with equally and exceptionally well-trained upper and lower bodies. The proportion of myosin heavy chain (MHC)-1 was higher in the leg (58 ± 2% [34-69%]) than arm (40 ± 3% [24-57%]), although the mitochondrial volume percentages [8.6 ± 1.6 (leg) and 9.0 ± 2.0 (arm)], and average number of capillaries per fiber [5.8 ± 0.8 (leg) and 6.3 ± 0.3 (arm)] were the same. In these comparable highly trained leg and arm muscles, the maximal citrate synthase (CS) activity was the same. Still, 3-hydroxy-acyl-CoA-dehydrogenase (HAD) capacity was 52% higher (P < 0.05) in the leg compared to arm muscles, suggesting a relatively higher capacity for lipid oxidation in leg muscle, which cannot be explained by the different fiber type distributions. For both limbs combined, HAD activity was correlated with the content of MHC-1 (r2 = 0.32, P = 0.011), whereas CS activity was not. Thus, in these highly trained cross-country skiers capillarization of and mitochondrial volume in type 2 fiber can be at least as high as in type 1 fibers, indicating a divergence between fiber type pattern and aerobic metabolic capacity. The considerable variability in oxidative metabolism with similar MHC profiles provides a new perspective on exercise training. Furthermore, the clear differences between equally well-trained arm and leg muscles regarding HAD activity cannot be explained by training status or MHC distribution, thereby indicating an intrinsic metabolic difference between the upper and lower body. Moreover, trained type 1 and type 2A muscle fibers exhibited similar aerobic capacity regardless of whether they were located in an arm or leg muscle.

Pronounced limb and fibre type differences in subcellular lipid droplet content and distribution in elite skiers before and after exhaustive exercise.

KEY POINTS: Although lipid droplets in skeletal muscle are an important energy source during endurance exercise, our understanding of lipid metabolism in this context remains incomplete. Using transmission electron microscopy, two distinct subcellular pools of lipid droplets can be observed in skeletal muscle - one beneath the sarcolemma and the other between myofibrils. At rest, well-trained leg muscles of cross-country skiers contain 4- to 6-fold more lipid droplets than equally well-trained arm muscles, with a 3-fold higher content in type 1 than in type 2 fibres. During exhaustive exercise, lipid droplets between the myofibrils but not those beneath the sarcolemma are utilised by both type 1 and 2 fibres. These findings provide insight into compartmentalisation of lipid metabolism within skeletal muscle fibres. ABSTRACT: Although the intramyocellular lipid pool is an important energy store during prolonged exercise, our knowledge concerning its metabolism is still incomplete. Here, quantitative electron microscopy was used to examine subcellular distribution of lipid droplets in type 1 and 2 fibres of the arm and leg muscles before and after 1 h of exhaustive exercise. Intermyofibrillar lipid droplets accounted for 85-97% of the total volume fraction, while the subsarcolemmal pool made up 3-15%. Before exercise, the volume fractions of intermyofibrillar and subsarcolemmal lipid droplets were 4- to 6-fold higher in leg than in arm muscles (P < 0.001). Furthermore, the volume fraction of intermyofibrillar lipid droplets was 3-fold higher in type 1 than in type 2 fibres (P < 0.001), with no fibre type difference in the subsarcolemmal pool. Following exercise, intermyofibrillar lipid droplet volume fraction was 53% lower (P = 0.0082) in both fibre types in arm, but not leg muscles. This reduction was positively associated with the corresponding volume fraction prior to exercise (R2  = 0.84, P < 0.0001). No exercise-induced change in the subsarcolemmal pool could be detected. These findings indicate clear differences in the subcellular distribution of lipid droplets in the type 1 and 2 fibres of well-trained arm and leg muscles, as well as preferential utilisation of the intermyofibrillar pool during prolonged exhaustive exercise. Apparently, the metabolism of lipid droplets within a muscle fibre is compartmentalised.

The effect of nitric oxide synthase inhibition with and without inhibition of prostaglandins on blood flow in different human skeletal muscles.

PURPOSE: Animal studies suggest that the inhibition of nitric oxide synthase (NOS) affects blood flow differently in different skeletal muscles according to their muscle fibre type composition (oxidative vs glycolytic). Quadriceps femoris (QF) muscle consists of four different muscle parts: vastus intermedius (VI), rectus femoris (RF), vastus medialis (VM), and vastus lateralis (VL) of which VI is located deep within the muscle group and is generally regarded to consist mostly of oxidative muscle fibres. METHODS: We studied the effect of NOS inhibition on blood flow in these four different muscles by positron emission tomography in eight young healthy men at rest and during one-leg dynamic exercise, with and without combined blockade with prostaglandins. RESULTS: At rest blood flow in the VI (2.6 ± 1.1 ml/100 g/min) was significantly higher than in VL (1.9 ± 0.6 ml/100 g/min, p = 0.015) and RF (1.7 ± 0.6 ml/100 g/min, p = 0.0015), but comparable to VM (2.4 ± 1.1 ml/100 g/min). NOS inhibition alone or with prostaglandins reduced blood flow by almost 50% (p < 0.001), but decrements were similar in all four muscles (drug × muscle interaction, p = 0.43). During exercise blood flow was also the highest in VI (45.4 ± 5.5 ml/100 g/min) and higher compared to VL (35.0 ± 5.5 ml/100 g/min), RF (38.4 ± 7.4 ml/100 g/min), and VM (36.2 ± 6.8 ml/100 g/min). NOS inhibition alone did not reduce exercise hyperemia (p = 0.51), but combined NOS and prostaglandin inhibition reduced blood flow during exercise (p = 0.002), similarly in all muscles (drug × muscle interaction, p = 0.99). CONCLUSION: NOS inhibition, with or without prostaglandins inhibition, affects blood flow similarly in different human QF muscles both at rest and during low-to-moderate intensity exercise.

Oxidative capacity and glycogen content increase more in arm than leg muscle in sedentary women after intense training.

The hypothesis that the adaptive capacity is higher in human upper- than lower-body skeletal muscle was tested. Furthermore, the hypothesis that more pronounced adaptations in upper-body musculature can be achieved by "low-volume high-intensity" compared with "high-volume low-intensity" exercise training was evaluated. A group of sedentary premenopausal women aged 45 ± 6 yr (± SD) with expected high adaptive potential in both upper- and lower-extremity muscle groups participated. After random allocation to high-intensity swimming (HIS, n = 21), moderate-intensity swimming (MOS, n = 21), soccer (SOC, n = 21) or a nontraining control group (CON, n = 20), the training groups completed three workouts per week for 15 wk. Resting muscle biopsies were obtained from the vastus lateralis muscle and deltoideus muscle before and after the intervention. After the training intervention, a larger (P < 0.05) increase existed in deltoideus muscle of the HIS group compared with vastus lateralis muscle of the SOC group for citrate synthase maximal activity (95 ± 89 vs. 27 ± 34%), citrate synthase protein expression (100 ± 29 vs. 31 ± 44%), 3-hydroxyacyl-CoA dehydrogenase maximal activity (35 ± 43 vs. 3 ± 25%), muscle glycogen content (63 ± 76 vs. 20 ± 51%), and expression of mitochondrial complex II, III, and IV. Additionally, HIS caused higher (P < 0.05) increases than MOS in deltoideus muscle citrate synthase maximal activity, citrate synthase protein expression, and muscle glycogen content. In conclusion, the deltoideus muscle has a higher adaptive potential than the vastus lateralis muscle in sedentary women, and "high-intensity low-volume" training is a more efficient regime than "low-intensity high-volume" training for increasing the aerobic capacity of the deltoideus muscle.

Algogenic substances and metabolic status in work-related Trapezius Myalgia: a multivariate explorative study.

BACKGROUND: This study compares the levels of algesic substances between subjects with trapezius myalgia (TM) and healthy controls (CON) and explores the multivariate correlation pattern between these substances, pain, and metabolic status together with relative blood flow changes reported in our previous paper (Eur J Appl Physiol 108:657-669, 2010). METHODS: 43 female workers with (TM) and 19 females without (CON) trapezius myalgia were - using microdialysis - compared for differences in interstitial concentrations of interleukin-6 (IL-6), bradykinin (BKN), serotonin (5-HT), lactate dehydrogenas (LDH), substance P, and N-terminal propeptide of procollagen type I (PINP) in the trapezius muscle at rest and during repetitive/stressful work. These data were also used in multivariate analyses together with previously presented data (Eur J Appl Physiol 108:657-669, 2010): trapezius muscle blood flow, metabolite accumulation, oxygenation, and pain development and sensitivity. RESULTS: Substance P was significantly elevated in TM (p=0.0068). No significant differences were found in the classical algesic substances (p: 0.432-0.926). The multivariate analysis showed that blood flow related variables, interstitial concentrations of metabolic (pyruvate), and algesic (BKN and K+) substances were important for the discrimination of the subjects to one of the two groups (R2: 0.19-0.31, p<0.05). Pain intensity was positively associated with levels of 5-HT and K+ and negatively associated with oxygenation indicators and IL-6 in TM (R2: 0.24, p<0.05). A negative correlation existed in TM between mechanical pain sensitivity of trapezius and BKN and IL-6 (R2: 0.26-0.39, p<0.05). CONCLUSION: The present study increased understanding alterations in the myalgic muscle. When considering the system-wide aspects, increased concentrations of lactate, pyruvate and K+ and decreased oxygenation characterized TM compared to CON. There are three major possible explanations for this finding: the workers with pain had relatively low severity of myalgia, metabolic alterations preceded detectable alterations in levels of algesics, or peripheral sensitization and other muscle alterations existed in TM. Only SP of the investigated algesic substances was elevated in TM. Several of the algesics were of importance for the levels of pain intensity and mechanical pain sensitivity in TM. These results indicate peripheral contribution to maintenance of central nociceptive and pain mechanisms and may be important to consider when designing treatments.

Regulation of the skeletal muscle blood flow in humans.

In humans, skeletal muscle blood flow is regulated by an interaction between several locally formed vasodilators, including NO and prostaglandins. In plasma, ATP is a potent vasodilator that stimulates the formation of NO and prostaglandins and, very importantly, can offset local sympathetic vasoconstriction. Adenosine triphosphate is released into plasma from erythrocytes and endothelial cells, and the plasma concentration increases in both the feed artery and the vein draining the contracting skeletal muscle. Adenosine also stimulates the formation of NO and prostaglandins, but the plasma adenosine concentration does not increase during exercise. In the skeletal muscle interstitium, there is a marked increase in the concentration of ATP and adenosine, and this increase is tightly coupled to the increase in blood flow. The sources of interstitial ATP and adenosine are thought to be skeletal muscle cells and endothelial cells. In the interstitium, both ATP and adenosine stimulate the formation of NO and prostaglandins, but ATP has also been suggested to induce vasoconstriction and stimulate afferent nerves that signal to increase sympathetic nerve activity. Adenosine has been shown to contribute to exercise hyperaemia, whereas the role of ATP remains uncertain due to lack of specific purinergic receptor blockers for human use. The purpose of this review is to address the interaction between vasodilator systems and to discuss the multiple proposed roles of ATP in human skeletal muscle blood flow regulation.

Exercise training modulates functional sympatholysis and α-adrenergic vasoconstrictor responsiveness in hypertensive and normotensive individuals.

Essential hypertension is linked to an increased sympathetic vasoconstrictor activity and reduced tissue perfusion. We investigated the role of exercise training on functional sympatholysis and postjunctional α-adrenergic responsiveness in individuals with essential hypertension. Leg haemodynamics were measured before and after 8 weeks of aerobic training (3-4 times per week) in eight hypertensive (47 ± 2 years) and eight normotensive untrained individuals (46 ± 1 years) during arterial tyramine infusion, arterial ATP infusion and/or one-legged knee extensions. Before training, exercise hyperaemia and leg vascular conductance (LVC) were lower in the hypertensive individuals (P < 0.05) and tyramine lowered exercise hyperaemia and LVC in both groups (P < 0.05). Training lowered blood pressure in the hypertensive individuals (P < 0.05) and exercise hyperaemia was similar to the normotensive individuals in the trained state. After training, tyramine did not reduce exercise hyperaemia or LVC in either group. When tyramine was infused at rest, the reduction in blood flow and LVC was similar between groups, but exercise training lowered the magnitude of the reduction in blood flow and LVC (P < 0.05). There was no difference in the vasodilatory response to infused ATP or in muscle P2Y2 receptor content between the groups before and after training. However, training lowered the vasodilatory response to ATP and increased skeletal muscle P2Y2 receptor content in both groups (P < 0.05). These results demonstrate that exercise training improves functional sympatholysis and reduces postjunctional α-adrenergic responsiveness in both normo- and hypertensive individuals. The ability for functional sympatholysis and the vasodilator and sympatholytic effect of intravascular ATP appear not to be altered in essential hypertension.

Exercise performance and cardiovascular health variables in 70-year-old male soccer players compared to endurance-trained, strength-trained and untrained age-matched men.

The aim was to investigate performance variables and indicators of cardiovascular health profile in elderly soccer players (SP, n = 11) compared to endurance-trained (ET, n = 8), strength-trained (ST, n = 7) and untrained (UT, n = 7) age-matched men. The 33 men aged 65-85 years underwent a testing protocol including measurements of cycle performance, maximal oxygen uptake (VO2max) and body composition, and muscle fibre types and capillarisation were determined from m. vastus lateralis biopsy. In SP, time to exhaustion was longer (16.3 ± 2.0 min; P < 0.01) than in UT (+48%) and ST (+41%), but similar to ET (+1%). Fat percentage was lower (P < 0.05) in SP (-6.5% points) than UT but not ET and ST. Heart rate reserve was higher (P < 0.05) in SP (104 ± 16 bpm) than UT (+21 bpm) and ST (+24 bpm), but similar to ET (+2 bpm), whereas VO2max was not significantly different in SP (30.2 ± 4.9 ml O2 · min(-1) · kg(-1)) compared to UT (+14%) and ST (+9%), but lower (P < 0.05) than ET (-22%). The number of capillaries per fibre was higher (P < 0.05) in SP than UT (53%) and ST (42%) but similar to ET. SP had less type IIx fibres than UT (-12% points). In conclusion, the exercise performance and cardiovascular health profile are markedly better for lifelong trained SP than for age-matched UT controls. Incremental exercise capacity and muscle aerobic capacity of SP are also superior to lifelong ST athletes and comparable to endurance athletes.

High-intensity strength training improves function of chronically painful muscles: case-control and RCT studies.

AIM: This study investigates consequences of chronic neck pain on muscle function and the rehabilitating effects of contrasting interventions. METHODS: Women with trapezius myalgia (MYA, n = 42) and healthy controls (CON, n = 20) participated in a case-control study. Subsequently MYA were randomized to 10 weeks of specific strength training (SST, n = 18), general fitness training (GFT, n = 16), or a reference group without physical training (REF, n = 8). Participants performed tests of 100 consecutive cycles of 2 s isometric maximal voluntary contractions (MVC) of shoulder elevation followed by 2 s relaxation at baseline and 10-week follow-up. RESULTS: In the case-control study, peak force, rate of force development, and rate of force relaxation as well as EMG amplitude were lower in MYA than CON throughout all 100 MVC. Muscle fiber capillarization was not significantly different between MYA and CON. In the intervention study, SST improved all force parameters significantly more than the two other groups, to levels comparable to that of CON. This was seen along with muscle fiber hypertrophy and increased capillarization. CONCLUSION: Women with trapezius myalgia have lower strength capacity during repetitive MVC of the trapezius muscle than healthy controls. High-intensity strength training effectively improves strength capacity during repetitive MVC of the painful trapezius muscle.

Moderate intensity supine exercise causes decreased cardiac volumes and increased outer volume variations: a cardiovascular magnetic resonance study.

BACKGROUND: The effects on left and right ventricular (LV, RV) volumes during physical exercise remains controversial. Furthermore, no previous study has investigated the effects of exercise on longitudinal contribution to stroke volume (SV) and the outer volume variation of the heart. The aim of this study was to determine if LV, RV and total heart volumes (THV) as well as cardiac pumping mechanisms change during physical exercise compared to rest using cardiovascular magnetic resonance (CMR). METHODS: 26 healthy volunteers (6 women) underwent CMR at rest and exercise. Exercise was performed using a custom built ergometer for one-legged exercise in the supine position during breath hold imaging. Cardiac volumes and atrio-ventricular plane displacement were determined. Heart rate (HR) was obtained from ECG. RESULTS: HR increased during exercise from 60±2 to 94±2 bpm, (p<0.001). LVEDV remained unchanged (p=0.81) and LVESV decreased with -9±18% (p<0.05) causing LVSV to increase with 8±3% (p<0.05). RVEDV and RVESV decreased by -7±10% and -24±14% respectively, (p<0.001) and RVSV increased 5±17% during exercise although not statistically significant (p=0.18). Longitudinal contribution to RVSV decreased during exercise by -6±15% (p<0.05) but was unchanged for LVSV (p=0.74). THV decreased during exercise by -4±1%, (p<0.01) and total heart volume variation (THVV) increased during exercise from 5.9±0.5% to 9.7±0.6% (p<0.001). CONCLUSIONS: Cardiac volumes and function are significantly altered during supine physical exercise. THV becomes significantly smaller due to decreases in RVEDV whilst LVEDV remains unchanged. THVV and consequently radial pumping increases during exercise which may improve diastolic suction during the rapid filling phase.

Effect of nitric oxide synthase inhibition on the exchange of glucose and fatty acids in human skeletal muscle.

BACKGROUND: The role of nitric oxide in controlling substrate metabolism in humans is incompletely understood. METHODS: The present study examined the effect of nitric oxide blockade on glucose uptake, and free fatty acid and lactate exchange in skeletal muscle of eight healthy young males. Exchange was determined by measurements of muscle perfusion by positron emission tomography and analysis of arterial and femoral venous plasma concentrations of glucose, fatty acids and lactate. The measurements were performed at rest and during exercise without (control) and with blockade of nitric oxide synthase (NOS) with NG-monomethyl-l-arginine (L-NMMA). RESULTS: Glucose uptake at rest was 0.40 ± 0.21 µmol/100 g/min and increased to 3.71 ± 2.53 µmol/100 g/min by acute one leg low intensity exercise (p < 0.01). Prior inhibition of NOS by L-NMMA did not affect glucose uptake, at rest or during exercise (0.40 ± 0.26 and 4.74 ± 2.69 µmol/100 g/min, respectively). In the control trial, there was a small release of free fatty acids from the limb at rest (-0.05 ± 0.09 µmol/100 g/min), whereas during inhibition of NOS, there was a small uptake of fatty acids (0.04 ± 0.05 µmol/100 g/min, p < 0.05). During exercise fatty acid uptake was increased to (0.89 ± 1.07 µmol/100 g/min), and there was a non-significant trend (p = 0.10) for an increased FFA uptake with NOS inhibition 1.23 ± 1.48 µmol/100 g/min) compared to the control condition. Arterial concentrations of all substrates and exchange of lactate over the limb at rest and during exercise remained unaltered during the two conditions. CONCLUSION: In conclusion, inhibition of nitric oxide synthesis does not alter muscle glucose uptake during low intensity exercise, but affects free fatty acid exchange especially at rest, and may thus be involved in the modulation of energy metabolism in the human skeletal muscle.

Aerobic capacity reference data in 3816 healthy men and women 20-90 years.

PURPOSE: To provide a large reference material on aerobic fitness and exercise physiology data in a healthy population of Norwegian men and women aged 20-90 years. METHODS: Maximal and sub maximal levels of VO2, heart rate, oxygen pulse, and rating of perceived exertion (Borg scale: 6-20) were measured in 1929 men and 1881 women during treadmill running. RESULTS: The highest VO2max and maximal heart rate among men and women were observed in the youngest age group (20-29 years) and was 54.4±8.4 mL·kg(-1)·min(-1) and 43.0±7.7 mL·kg(-1)·min(-1) (sex differences, p<0.001) and 196±10 beats·min(-1) and 194±9 beats·min(-1) (sex differences, p<0.05), respectively, with a subsequent reduction of approximately 3.5 mL·kg(-1)·min(-1) and 6 beats·min(-1) per decade. The highest oxygen pulses were observed in the 3 youngest age groups (20-29 years, 30-39 years, 40-49 years) among men and women; 22.3 mL·beat(-1)±3.6 and 14.7 mL·beat(-1)±2.7 (sex differences, p<0.001), respectively, with no significant difference between these age groups. After the age of 50 we observed an 8% reduction per decade among both sexes. Borg scores appear to give a good estimate of the relative exercise intensity, although observing a slightly different relationship than reported in previous reference material from small populations. CONCLUSION: This is the largest European reference material of objectively measured parameters of aerobic fitness and exercise-physiology in healthy men and women aged 20-90 years, forming the basis for an easily accessible, valid and understandable tool for improved training prescription in healthy men and women.

Skeletal muscle signaling and the heart rate and blood pressure response to exercise: insight from heart rate pacing during exercise with a trained and a deconditioned muscle group.

Endurance training lowers heart rate and blood pressure responses to exercise, but the mechanisms and consequences remain unclear. To determine the role of skeletal muscle for the cardioventilatory response to exercise, 8 healthy young men were studied before and after 5 weeks of 1-legged knee-extensor training and 2 weeks of deconditioning of the other leg (leg cast). Hemodynamics and muscle interstitial nucleotides were determined during exercise with the (1) deconditioned leg, (2) trained leg, and (3) trained leg with atrial pacing to the heart rate obtained with the deconditioned leg. Heart rate was ≈ 15 bpm lower during exercise with the trained leg (P<0.05), but stroke volume was higher (P<0.05) and cardiac output was similar. Arterial and central venous pressures, rate-pressure product, and ventilation were lower during exercise with the trained leg (P<0.05), whereas pulmonary capillary wedge pressure was similar. When heart rate was controlled by atrial pacing, stroke volume decreased (P<0.05), but cardiac output, peripheral blood flow, arterial pressures, and pulmonary capillary wedge pressure remained unchanged. Circulating [norepinephrine], [lactate] and [K(+)] were lower and interstitial [ATP] and pH were higher in the trained leg (P<0.05). The lower cardioventilatory response to exercise with the trained leg is partly coupled to a reduced signaling from skeletal muscle likely mediated by K(+), lactate, or pH, whereas the lower cardiac afterload increases stroke volume. These results demonstrate that skeletal muscle training reduces the cardioventilatory response to exercise without compromising O2 delivery, and it can therefore be used to reduce the load on the heart during physical activity.

Exercise training and work task induced metabolic and stress-related mRNA and protein responses in myalgic muscles.

The aim was to assess mRNA and/or protein levels of heat shock proteins, cytokines, growth regulating, and metabolic proteins in myalgic muscle at rest and in response to work tasks and prolonged exercise training. A randomized controlled trial included 28 females with trapezius myalgia and 16 healthy controls. Those with myalgia performed ~7 hrs repetitive stressful work and were subsequently randomized to 10 weeks of specific strength training, general fitness training, or reference intervention. Muscles biopsies were taken from the trapezius muscle at baseline, after work and after 10 weeks intervention. The main findings are that the capacity of carbohydrate oxidation was reduced in myalgic compared with healthy muscle. Repetitive stressful work increased mRNA content for heat shock proteins and decreased levels of key regulators for growth and oxidative metabolism. In contrast, prolonged general fitness as well as specific strength training decreased mRNA content of heat shock protein while the capacity of carbohydrate oxidation was increased only after specific strength training.

Ex vivo measures of muscle mitochondrial capacity reveal quantitative limits of oxygen delivery by the circulation during exercise.

Muscle mitochondrial respiratory capacity measured ex vivo provides a physiological reference to assess cellular oxidative capacity as a component in the oxygen cascade in vivo. In this article, the magnitude of muscle blood flow and oxygen uptake during exercise involving a small-to-large fraction of the body mass will be discussed in relation to mitochondrial capacity measured ex vivo. These analyses reveal that as the mass of muscle engaged in exercise increases from one-leg knee extension, to 2-arm cranking, to 2-leg cycling and x-country skiing, the magnitude of blood flow and oxygen delivery decrease. Accordingly, a 2-fold higher oxygen delivery and oxygen uptake per unit muscle mass are seen in vivo during 1-leg exercise compared to 2-leg cycling indicating a significant limitation of the circulation during exercise with a large muscle mass. This analysis also reveals that mitochondrial capacity measured ex vivo underestimates the maximal in vivo oxygen uptake of muscle by up to ∼2-fold. This article is part of a Directed Issue entitled: Bioenergetic dysfunction, adaptation and therapy.

Inefficient functional sympatholysis is an overlooked cause of malperfusion in contracting skeletal muscle.

Contracting skeletal muscle can overcome sympathetic vasoconstrictor activity (functional sympatholysis), which allows for a blood supply that matches the metabolic demand. This ability is thought to be mediated by locally released substances that modulate the effect of noradrenaline (NA) on the α-receptor. Tyramine induces local NA release and can be used in humans to investigate the underlying mechanisms and physiological importance of functional sympatholysis in the muscles of healthy and diseased individuals as well as the impact of the active muscles' training status. In sedentary elderly men, functional sympatholysis and muscle blood flow are impaired compared to young men, but regular physical activity can prevent these age related impairments. In young subjects, two weeks of leg immobilization causes a reduced ability for functional sympatholysis, whereas the trained leg maintained this function. Patients with essential hypertension have impaired functional sympatholysis in the forearm, and reduced exercise hyperaemia in the leg, but this can be normalized by aerobic exercise training. The effect of physical activity on the local mechanisms that modulate sympathetic vasoconstriction is clear, but it remains uncertain which locally released substance(s) block the effect of NA and how this is accomplished. NO and ATP have been proposed as important inhibitors of NA mediated vasoconstriction and presently an inhibitory effect of ATP on NA signalling via P2 receptors appears most likely.

Opposing effects of nitric oxide and prostaglandin inhibition on muscle mitochondrial Vo(2) during exercise.

Nitric oxide (NO) and prostaglandins (PG) together play a role in regulating blood flow during exercise. NO also regulates mitochondrial oxygen consumption through competitive binding to cytochrome-c oxidase. Indomethacin uncouples and inhibits the electron transport chain in a concentration-dependent manner, and thus, inhibition of NO and PG synthesis may regulate both muscle oxygen delivery and utilization. The purpose of this study was to examine the independent and combined effects of NO and PG synthesis blockade (L-NMMA and indomethacin, respectively) on mitochondrial respiration in human muscle following knee extension exercise (KEE). Specifically, this study examined the physiological effect of NO, and the pharmacological effect of indomethacin, on muscle mitochondrial function. Consistent with their mechanism of action, we hypothesized that inhibition of nitric oxide synthase (NOS) and PG synthesis would have opposite effects on muscle mitochondrial respiration. Mitochondrial respiration was measured ex vivo by high-resolution respirometry in saponin-permeabilized fibers following 6 min KEE in control (CON; n = 8), arterial infusion of N(G)-monomethyl-L-arginine (L-NMMA; n = 4) and Indo (n = 4) followed by combined inhibition of NOS and PG synthesis (L-NMMA + Indo, n = 8). ADP-stimulated state 3 respiration (OXPHOS) with substrates for complex I (glutamate, malate) was reduced 50% by Indo. State 3 O(2) flux with complex I and II substrates was reduced less with both Indo (20%) and L-NMMA + Indo (15%) compared with CON. The results indicate that indomethacin reduces state 3 mitochondrial respiration primarily at complex I of the respiratory chain, while blockade of NOS by L-NMMA counteracts the inhibition by Indo. This effect on muscle mitochondria, in concert with a reduction of blood flow accounts for in vivo changes in muscle O(2) consumption during combined blockade of NOS and PG synthesis.

GLUT4 and glycogen synthase are key players in bed rest-induced insulin resistance.

To elucidate the molecular mechanisms behind physical inactivity-induced insulin resistance in skeletal muscle, 12 young, healthy male subjects completed 7 days of bed rest with vastus lateralis muscle biopsies obtained before and after. In six of the subjects, muscle biopsies were taken from both legs before and after a 3-h hyperinsulinemic euglycemic clamp performed 3 h after a 45-min, one-legged exercise. Blood samples were obtained from one femoral artery and both femoral veins before and during the clamp. Glucose infusion rate and leg glucose extraction during the clamp were lower after than before bed rest. This bed rest-induced insulin resistance occurred together with reduced muscle GLUT4, hexokinase II, protein kinase B/Akt1, and Akt2 protein level, and a tendency for reduced 3-hydroxyacyl-CoA dehydrogenase activity. The ability of insulin to phosphorylate Akt and activate glycogen synthase (GS) was reduced with normal GS site 3 but abnormal GS site 2+2a phosphorylation after bed rest. Exercise enhanced insulin-stimulated leg glucose extraction both before and after bed rest, which was accompanied by higher GS activity in the prior-exercised leg than the rested leg. The present findings demonstrate that physical inactivity-induced insulin resistance in muscle is associated with lower content/activity of key proteins in glucose transport/phosphorylation and storage.

Metabolic profile in two physically active Inuit groups consuming either a western or a traditional Inuit diet.

OBJECTIVES: To evaluate the effect of regular physical activity on metabolic risk factors and blood pressure in Inuit with high BMI consuming a western diet (high amount of saturated fatty acids and carbohydrates with a high glycemic index). STUDY DESIGN: Cross sectional study, comparing Inuit eating a western diet with Inuit eating a traditional diet. METHODS: Two physically active Greenland Inuit groups consuming different diet, 20 eating a traditional diet (Qaanaaq) and 15 eating a western diet (TAB), age (mean (range)); 38, (22-58) yrs, BMI; 28 (20-40) were subjected to an oral glucose tolerance test (OGTT), blood sampling, maximal oxygen uptake test, food interview/collection and monitoring of physical activity. RESULTS: All Inuit had a normal OGTT. Fasting glucose (mmol/l), HbA1c (%), total cholesterol (mmol/l) and HDL-C (mmol/l) were for Qaanaaq women: 4.8±0.2, 5.3±0.1, 4.96±0.42, 1.34±0.06, for Qaanaaq men: 4.9±0.1, 5.7±0.1, 5.08±0.31, 1.28±0.09, for TAB women: 5.1±0.2, 5.3±0.1, 6.22±0.39, 1.86±0.13, for TAB men: 5.1±0.2, 5.3±0.1, 6.23±0.15, 1.60±0.10. No differences were found in systolic or diastolic blood pressure between the groups. There was a more adverse distribution of small dense LDL-C particles and higher total cholesterol and HDL-C concentration in the western diet group. CONCLUSIONS: Diabetes or impaired glucose tolerance was not found in the Inuit consuming either the western or the traditional diet, and this could, at least partly, be due to the high amount of regular daily physical activity. However, when considering the total cardio vascular risk profile the Inuit consuming a western diet had a less healthy profile than the Inuit consuming a traditional diet.