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Interleukin (IL)-6 is chronically elevated in type 2 diabetes but also during exercise. However, the exact metabolic role, and hence the physiological significance, has not been elucidated. The objective of this study was to investigate the in vivo effect of recombinant human (rh) IL-6 on human fat and glucose metabolism and signaling of both adipose tissue and skeletal muscle. Eight healthy postabsorptive males were infused with either rhIL-6 or saline for 4 h, eliciting IL-6 levels of ~40 and ~1 pg/ml, respectively. Systemic, skeletal muscle, and adipose tissue fat and glucose metabolism was assessed before, during, and 2 h after cessation of the infusion. Glucose metabolism was unaffected by rhIL-6. In contrast, rhIL-6 increased systemic fatty acid oxidation approximately twofold after 60 min, and it remained elevated even 2 h after the infusion. The increase in oxidation was followed by an increase in systemic lipolysis. Adipose tissue lipolysis and fatty acid kinetics were unchanged with rhIL-6 compared with saline infusion. Conversely, rhIL-6 infusion caused an increase in skeletal muscle unidirectional fatty acid and glycerol release, indicative of an increase in lipolysis. The increased lipolysis in muscle could account for the systemic changes. Skeletal muscle signaling increased after 1 h of rhIL-6 infusion, indicated by a fourfold increase in the phosphorylated signal transducer and activator of transcription (STAT) 3-to-STAT3 ratio, whereas no changes in phosphorylated AMP-activated protein kinase or acetyl-CoA carboxylase levels could be observed. Our findings suggest that an acute increase in IL-6 at a normophysiological level selectively stimulates lipolysis in skeletal muscle, whereas adipose tissue is unaffected. integrative physiology; interleukin-6; metabolism; skeletal muscle; adipose tissue doi: 10.1152/ajpendo.00328.2010.

It was investigated whether skeletal muscle [K.sup.+] release is linked to the degree of anaerobic energy production. Six subjects performed an incremental bicycle exercise test in normoxic and hypoxic conditions prior to and after 2 and 8 wk of acclimatization to 4,100 m. The highest workload completed by all subjects in all trials was 260 W. With acute hypoxic exposure prior to acclimatization, venous plasma [[K.sup.+]] was lower (P < 0.05) in normoxia (4.9 [+ or -] 0.1 mM) than hypoxia (5.2 [+ or -] 0.2 mM) at 260 W, but similar at exhaustion, which occurred at 400 [+ or -] 9 W and 307 [+ or -] 7 W (P < 0.05), respectively. At the same absolute exercise intensity, leg net [K.sup.+] release was unaffected by hypoxic exposure independent of acclimatization. After 8 wk of acclimatization, no difference existed in venous plasma [[K.sup.+]] between the normoxic and hypoxic trial, either at submaximal intensities or at exhaustion (360 [+ or -] 14 W vs. 313 [+ or -] 8 W; P < 0.05). At the same absolute exercise intensity, leg net [K.sup.+] release was less (P < 0.001) than prior to acclimatization and reached negative values in both hypoxic and normoxic conditions after acclimatization. Moreover, the reduction in plasma volume during exercise relative to rest was less (P < 0.01) in normoxic than hypoxic conditions, irrespective of the degree of acclimatization (at 260 W prior to acclimatization: -4.9 [+ or -] 0.8% in normoxia and -10.0 [+ or -] 0.4% in hypoxia). It is concluded that leg net [K.sup.+] release is unrelated to anaerobic energy production and that acclimatization reduces leg net [K.sup.+] release during exercise. acclimatization; plasma volume; fatigue; cycling doi: 10.1152/ajpregu.00062.2010.

Individuals born with low birth weight (LBW) are at risk of developing type 2 diabetes mellitus (T2D), which may be precipitated by physical inactivity. Twenty-two LBW subjects and twenty-three controls were studied before and after bed rest by the hyperinsulinemic euglycemic clamp combined with indirect calorimetry and infusion of stable isotope tracers and preceded by an intravenous glucose tolerance test. LBW subjects had a similar body mass index but elevated abdominal obesity compared with controls. The basal rate of whole body lipolysis (WBL) was elevated in LBW subjects with and without correction for abdominal obesity before and after bed rest (all P = 0.01). Skeletal muscle hormone-sensitive lipase (HSL) protein expression and phosphorylation at Ser565 were similar in the two groups. Bed rest resulted in a decrease in WBL and an increased skeletal muscle HSL Ser565 phosphorylation indicating a decreased HSL activity in both groups. All subjects developed peripheral insulin resistance in response to bed rest (all P < 0.0001) with no differences between groups. LBW subjects developed hepatic insulin resistance in response to bed rest. In conclusion, increased WBL may contribute to the development of hepatic insulin resistance when exposed to bed rest in LBW subjects. Nine days of bed rest causes severe peripheral insulin resistance and reduced WBL and skeletal muscle HSL activity, as well as a compensatory increased insulin secretion, with no differences in LBW subjects and controls. physical inactivity; insulin resistance; prediabetic subjects doi:10.1152/ajpendo.00223.2009.

Exercise stimulates muscle protein fractional synthesis rate (FSR), but the importance of contractile intensity and whether it interplays with feeding is not understood. This was investigated following two distinct resistance exercise (RE) contraction intensities using an intrasubject design in the fasted (n = 10) and fed (n = 10) states. RE consisted of 10 sets of knee extensions. One leg worked against light load (LL) at 16% of one-repetition maximum (IRM), the other leg against heavy load (HL) at 70% 1RM, with intensities equalized for total lifted load. Males were infused with [[sup.13]C]leucine, and vastus lateralis biopsies were obtained bilaterally at rest as well as 0.5, 3, and 5.5 h after RE. Western blots were run on muscle lysates and phosphospecific antibodies used to detect phosphorylation status of targets involved in regulation of FSR. The intramuscular collagen FSR was evenly increased following LL- and HL-RE and was not affected by feeding. Myofibrillar FSR was unaffected by LL-RE, whereas HL-RE resulted in a delayed improvement (0.14 _+ 0.02%/h, P < 0.05). Myofibrillar FSR was increased at rest by feeding (P < 0.05) and remained elevated late in the postexercise period compared with the fasting condition. The Rp-s6k-4E-binding protein-1 (BP1) and the mitogenactivated protein kinase (MAPk) pathways were activated by the HL intensity and were suggested to be responsible for regulating myofibrillar FSR in response to adequate contractile activity. Feeding predominantly affected Rp-s6k and eukaryotic elongation factor 2 phospborylations in correspondence with the observed changes in myofibrillar FSR, whereas 4E-BP1 remained to respond only to the HL contraction intensity. Thus the study design allows us to conclude that the MAPk- and mammalian target of rapamycin-dependent signaling responds to contractile activity, whereas elongation mainly was found to respond to feeding. Furthermore, although functionally linked, the contractile and the supportive matrix structures upregulate their protein synthesis rate quite differently in response to feeding and contractile activity and intensity. gas chromatography-combustion-isotope ratio mass spectrometry; protein turnover; molecular signaling; exercise; nutrition doi: 10.1152/ajpendo.00609.2009

To determine whether conditions for [O.sub.2] utilization and [O.sub.2] off-loading from the hemoglobin are different in exercising arms and legs, six cross-country skiers participated in this study. Femoral and subclavian vein blood flow and gases were determined during skiing on a treadmill at ~76% maximal [O.sub.2] uptake (V[O.sub.2 max]) and at V[O.sub.2 max] with different techniques: diagonal stride (combined arm and leg exercise), double poling (predominantly arm exercise), and leg skiing (predominantly leg exercise). The percentage of [O.sub.2] extraction was always higher for the legs than for the arms. At maximal exercise (diagonal stride), the corresponding mean values were 93 and 85% (n = 3; P < 0.05). During exercise, mean arm [O.sub.2] extraction correlated with the P[O.sub.2] value that causes hemoglobin to be 50% saturated ([P.sub.50]: r = 0.93, P < 0.05), but for a given value of [P.sub.50], [O.sub.2] extraction was always higher in the legs than in the arms. Mean capillary muscle [O.sub.2] conductance of the arm during double poling was 14.5 (SD 2.6) ml x [min.sup.-1] x mm[Hg.sup.-1], and mean capillary P[o.sub.2] was 47.7 (SD 2.6) mmHg. Corresponding values for the legs during maximal exercise were 48.3 (SD 13.0) ml x [min.sup.-1]. mm[Hg.sup.-1] and 33.8 (SD 2.6) mmHg, respectively. Because conditions for [O.sub.2] off-loading from the hemoglobin are similar in leg and arm muscles, the observed differences in maximal arm and leg [O.sub.2] extraction should be attributed to other factors, such as a higher heterogeneity in blood flow distribution, shorter mean transit time, smaller diffusing area, and larger diffusing distance, in arms than in legs. diffusing capacity; fatigue; oxygen extraction; performance; training

The present study examined the role of the cytokine IL-6 in the regulation of fatty acid metabolism during exercise in humans. Six well-trained males completed three trials of 120 min of cycle ergometry at 70% peak [O.sub.2] consumption (V[O.sub.2 peak]; MOD) and 40% V[O.sub.2 peak] with (LOW + IL-6) and without (LOW) infusion of recombinant human (rh)IL-6. The dose of rhIL-6 during LOW + IL-6 elicited IL-6 concentration similar to those during OD but without altering the circulating hormonal milieu seen in MOD. Palmitate rate of appearance ([R.sub.a]), rate of disappearance ([R.sub.d]), and oxidation were measured by means of a constant infusion of [U-[sup.13]C]palmitate (0.015 [micro]mol* [kg.sup.-1]*[min.sup.-1], prime NaHC[O.sub.3], 1 [micro]mol/kg). Palmitate [R.sub.a], [R.sub.d], and oxidation were not affected by rhIL-6 infusion, remaining similar to LOW at all times. Palmitate [R.sub.a] and oxidation were significantly greater in the MOD trial (P < 0.05) compared with the LOW + IL-6 and LOW trials. Our data show that a low dose of rhIL-6, administered during low-intensity exercise without altering the hormonal milieu, does not alter fatty acid metabolism. These data suggest that the increase in fatty acid utilization seen during exercise at moderate compared with low intensity is not mediated via alterations in plasma IL-6. cytokine; metabolism

Pulmonary gas exchange at maximal exercise in Danish lowlanders during 8 wk of acclimatization to 4,100 m and in high-altitude Aymara natives. Am J Physiol Regul Integr Comp Physiol 287: R1202-R1208, 2004. First published June 10, 2004; doi:10.1152/ajpregu.00725.2003.--We aimed to test effects of altitude acclimatization on pulmonary gas exchange at maximal exercise. Six lowlanders were studied at sea level, in acute hypoxia (AH), and after 2 and 8 wk of acclimatization to 4,100 m (2W and 8W) and compared with Aymara high-altitude natives residing at this altitude. As expected, alveolar [Po.sub.2] was reduced during AH but increased gradually during acclimatization (61 [+ or -] 0.7, 69 [+ or -] 0.9, and 72 [+ or -] 1.4 mmHg in AH, 2W, and 8W, respectively), reaching values significantly higher than in Aymaras (67 [+ or -] 0.6 mmHg). Arterial [Po.sub.2] ([MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII.]) also decreased during exercise in AH but increased significantly with acclimatization (51 [+ or -] 1.1, 58 [+ or -] 1.7, and 62 [+ or -] 1.6 mmHg in AH, 2W, and 8W, respectively). [MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII.] in lowlanders reached levels that were not different from those in high-altitude natives (66 [+ or -] 1.2 mmHg). Arterial [O.sub.2] saturation ([MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII.]) decreased during maximum exercise compared with rest in AH and after 2W and 8W: 73.3 [+ or -] 1.4, 76.9 [+ or -] 1.7, and 79.3 [+ or -] 1.6%, respectively. After 8W, [MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII.] in lowlanders was not significantly different from that in Aymaras (82.7 [+ or -] 1%). An improved pulmonary gas exchange with acclimatization was evidenced by a decreased ventilatory equivalent of [O.sub.2] after 8W: 59 [+ or -] 4, 58 [+ or -] 4, and 52 [+ or -] 4 l*min*l [O.sub.-2.sup.-1], respectively. The ventilatory equivalent of [O.sub.2] reached levels not different from that of Aymaras (51 [+ or -] 3 l*min*l [O.sub.2.sup.-1]). However, increases in exercise alveolar [Po.sub.2] and [MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII.] with acclimatization had no net effect on alveolar-arterial [Po.sub.2] difference in lowlanders (10 [+ or -] 1.3, 11 [+ or -] 1.5, and 10 [+ or -] 2.1 mmHg in AH, 2W, and 8W, respectively), which remained significantly higher than in Aymaras (1 [+ or -] 1.4 mmHg). In conclusion, lowlanders substantially improve pulmonary gas exchange with acclimatization, but even acclimatization for 8 wk is insufficient to achieve levels reached by high-altitude natives. chronic hypoxia; acute normoxia; ventilation

We assessed the hypothesis that the epinephrine surge present during sepsis accelerates aerobic glycolysis and lactate production by increasing activity of skeletal muscle [Na.sup.+]-[K.sup.+]-ATPase. Healthy volunteers received an intravenous bolus of endotoxin or placebo in a randomized order on two different days. Endotoxemia induced a response resembling sepsis. Endotoxemia increased plasma epinephrine to a maximum at t = 2 h of 0.7 [+ or -] 0.1 vs. 0.3 [+ or -] 0.1 nmol/l (P < 0.05, n = 6-7). Endotoxemia reduced plasma [K.sup.+] reaching a nadir at t = 5 h of 3.3 [+ or -] 0.1 vs. 3.8 [+ or -] 0.1 mmol/l (P < 0.01, n = 6-7), followed by an increase to placebo level at t = 7-8 h. During the declining plasma [K.sup.+], a relative accumulation of [K.sup.+] was seen reaching a maximum at t = 6 h of 8.7 [+ or -] 3.8 mmol/leg (P < 0.05). Plasma lactate increased to a maximum at t = 1 h of 2.5 [+ or -] 0.5 vs. 0.9 [+ or -] 0.1 mmol/l (P < 0.05, n = 8) in association with increased release of lactate from the legs. These changes were not associated with hypoperfusion or hypoxia. During the first 24 h after endotoxin infusion, renal [K.sup.+] excretion was 27 [+ or -] 7 mmol, i.e., 58% higher than after placebo. Combination of the well-known stimulatory effect of catecholamines on skeletal muscle [Na.sup.+]-[K.sup.+]-ATPase activity, with the present confirmation of an expected [Na.sup.+]-[K.sup.+]-ATPase-induced decline in plasma [K.sup.+], suggests that the increased lactate release was due to increased [Na.sup.+]-[K.sup.+]-ATPase activity, supporting our hypothesis. Thus increased lactate levels in acutely and severely ill patients should not be managed only from the point of view that it reflects hypoxia. [K.sup.+] homeostasis; sepsis; glycolysis

To study the role of muscle mass and muscle activity on lactate and energy kinetics during exercise, whole body and limb lactate, glucose, and fatty acid fluxes were determined in six elite cross-country skiers during roller-skiing for 40 min with the diagonal stride (Continuous Arm + Leg) followed by 10 min of double poling and diagonal stride at 72-76% maximal [O.sub.2] uptake. A high lactate appearance rate ([R.sub.a] 184 [+ or -] 17 [micro]mol*[kg.sup.-1]*[min.sup.-1]) but a low arterial lactate concentration (~2.5 mmol/l) were observed during Continuous Arm + Leg despite a substantial net lactate release by the arm of ~2.1 mmol/min, which was balanced by a similar net lactate uptake by the leg. Whole body and limb lactate oxidation during Continuous Arm + Leg was ~45% at rest and ~95% of disappearance rate and limb lactate uptake, respectively. Limb lactate kinetics changed multiple times when exercise mode was changed. Whole body glucose and glycerol turnover was unchanged during the different skiing modes; however, limb net glucose uptake changed severalfold. In conclusion, the arterial lactate concentration can be maintained at a relatively low level despite high lactate [R.sub.a], during exercise with a large muscle mass because of the large capacity of active skeletal muscle to take up lactate, which is tightly correlated with lactate delivery. The limb lactate uptake during exercise is oxidized at rates far above resting oxygen consumption, implying that lactate uptake and subsequent oxidation are also dependent on an elevated metabolic rate. The relative contribution of whole body and limb lactate oxidation is between 20 and 30% of total carbohydrate oxidation at rest and during exercise under the various conditions. Skeletal muscle can change its limb net glucose uptake severalfold within minutes, causing a redistribution of the available glucose because whole body glucose turnover was unchanged. lactate dehydrogenase; cross-country skiing; tracers

We hypothesized that reliance on lactate as a means of energy distribution is higher after a prolonged period of acclimatization (9 wk) than it is at sea level due to a higher lactate [R.sub.a] and disposal from active skeletal muscle. To evaluate this hypothesis, six Danish lowlanders (25 [+ or -] 2 yr) were studied at rest and during 20 min of bicycle exercise at 146 W at sea level (SL) and after 9 wk of acclimatization to 5,260 m (Alt). Whole body glucose [R.sub.a] was similar at SL and Alt at rest and during exercise. Lactate [R.sub.a] was also similar for the two conditions at rest; however, during exercise, lactate [R.sub.a] was substantially lower at SL (65 [micro]mol*[min.sup.-1]*kg body [wt.sup.-1]) than it was at Alt (150 [micro]mol*[min.sup.-l]*kg body [wt.sup.-1]) at the same exercise intensity. During exercise, net lactate release was ~6-fold at Alt compared with SL, and related to this, tracer-calculated leg lactate uptake and release were both 3- or 4-fold higher at Alt compared with SL. The contribution of the two legs to glucose disposal was similar at SL and Alt; however, the contribution of the two legs to lactate [R.sub.a] was significantly lower at rest and during exercise at SL (27 and 81%) than it was at Alt (45 and 123%). In conclusion, at rest and during exercise at the same absolute workload, CHO and blood glucose utilization were similar at SL and at Alt. Leg net lactate release was severalfold higher, and the contribution of leg lactate release to whole body lactate [R.sub.a] was higher at Alt compared with SL. During exercise, the relative contribution of lactate oxidation to whole body CHO oxidation was substantially higher at Alt compared with SL as a result of increased uptake and subsequent oxidation of lactate by the active skeletal muscles. glucose; isotopes; [1-[sup.13]C]lactate

Muscle protein turnover following resistance exercise and amino acid availability are relatively well described. By contrast, the beneficial effects of different sources of intact proteins in relation to exercise need further investigation. Our objective was to compare muscle anabolic responses to a single bolus intake of whey or casein after performance of heavy resistance exercise. Young male individuals were randomly assigned to participate in two protein trials (n = 9) or one control trial (n = 8). Infusion of l-[1-13C]leucine was carried out, and either whey, casein (0.3 g/kg lean body mass), or a noncaloric control drink was ingested immediately after exercise. l-[1-13C]leucine-labeled whey and casein were used while muscle protein synthesis (MPS) was assessed. Blood and muscle tissue samples were collected to measure systemic hormone and amino acid concentrations, tracer enrichments, and myofibrillar protein synthesis. Western blots were used to investigate the Akt signaling pathway. Plasma insulin and branched-chain amino acid concentrations increased to a greater extent after ingestion of whey compared with casein. Myofibrillar protein synthesis was equally increased 1-6 h postexercise after whey and casein intake, both of which were higher compared with control (P < 0.05). Phosphorylation of Akt and p70S6K was increased after exercise and protein intake (P < 0.05), but no differences were observed between the types of protein except for total 4E-BP1, which was higher after whey intake than after casein intake (P < 0.05). In conclusion, whey and casein intake immediately after resistance exercise results in an overall equal MPS response despite temporal differences in insulin and amino acid concentrations and 4E-BP1. [ABSTRACT FROM AUTHOR]

It was investigated whether skeletal muscle K+ release is linked to the degree of anaerobic energy production. Six subjects performed an incremental bicycle exercise test in normoxic and hypoxic conditions prior to and after 2 and 8 wk of acclimatization to 4,100 m. The highest workload completed by all subjects in all trials was 260 W. With acute hypoxic exposure prior to acclimatization, venous plasma [K+] was lower (P < 0.05) in normoxia (4.9 ± 0.1 mM) than hypoxia (5.2 ± 0.2 mM) at 260 W, but similar at exhaustion, which occurred at 400 ± 9 W and 307 ± 7 W (P < 0.05), respectively. At the same absolute exercise intensity, leg net K+ release was unaffected by hypoxic exposure independent of acclimatization. After 8 wk of acclimatization, no difference existed in venous plasma [K+] between the normoxic and hypoxic trial, either at submaximal intensities or at exhaustion (360 ± 14 W vs. 313 ± 8 W; P < 0.05). At the same absolute exercise intensity, leg net K+ release was less (P < 0.001) than prior to acclimatization and reached negative values in both hypoxic and normoxic conditions after acclimatization. Moreover, the reduction in plasma volume during exercise relative to rest was less (P < 0.01) in normoxic than hypoxic conditions, irrespective of the degree of acclimatization (at 260 W prior to acclimatization: -4.9 ± 0.8% in normoxia and -10.0 ± 0.4% in hypoxia). It is concluded that leg net K+ release is unrelated to anaerobic energy production and that acclimatization reduces leg net K+ release during exercise. [ABSTRACT FROM AUTHOR]

We assessed the hypothesis thai the epinephrine surge present during sepsis accelerates aerobic glycolysis and lactate production by increasing activity of skeletal muscle Na[sup +]-K[sup +]-ATPase. Healthy volunteers received an intravenous bolus of endotoxin or placebo in a randomized order on two different days. Endotoxemia induced a response resembling sepsis. Endotoxemia increased plasma epinephrine to a maximum at t = 2 h of 0.7 ± 0.1 vs. 0.3 ± 0.1 nmol/1 (P < 0.05, n = 6-7). Endotoxemia reduced plasma K[sup +] reaching a nadir at t = 5 h of 3.3 ± 0.1 vs. 3.8 ± 0.1 mmol/1 (P < 0.01, n = 6-7), followed by an increase to placebo level at t = 7-8 h. During the declining plasma K[sup +], a relative accumulation of K[sup +] was seen reaching a maximum at t = 6 h of 8.7 ± 3.8 mmol/leg (P < 0.05). Plasma lactate increased to a maximum at t = 1 h of 2.5 ± 0.5 vs. 0.9 ± 0.1 mmol/l (P < 0.05, n = 8) in association with increased release of lactate from the legs. These changes were not associated with hypoperfusion or hypoxia. During the first 24 h after endotoxin infusion, renal K[sup +] excretion was 27 ± 7 mmol, i.e., 58% higher than after placebo. Combination of the well-known stimulatory effect of catecholamines on skeletal muscle Na[sup +]-K[sup +]-ATPase activity, with the present confirmation of an expected Na[sup +]-K[sup +]ATPase-induced decline in plasma K[sup +], suggests that the increased lactate release was due to increased Na[sup +]K[sup +]-ATPase activity, supporting our hypothesis. Thus increased lactate levels in acutely and severely ill patients should not be managed only from the point of view that it reflects hypoxia. [ABSTRACT FROM AUTHOR]