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. 2001 Jul 1;534(Pt 1):269–278. doi: 10.1111/j.1469-7793.2001.t01-1-00269.x

Adrenaline increases skeletal muscle glycogenolysis, pyruvate dehydrogenase activation and carbohydrate oxidation during moderate exercise in humans

Matthew J Watt *, Kirsten F Howlett *, Mark A Febbraio *, Lawrence L Spriet †, Mark Hargreaves *
PMCID: PMC2278696  PMID: 11433007

Abstract

  1. To evaluate the role of adrenaline in regulating carbohydrate metabolism during moderate exercise, 10 moderately trained men completed two 20 min exercise bouts at 58 ± 2 % peak pulmonary oxygen uptake (V̇O2,peak). On one occasion saline was infused (CON), and on the other adrenaline was infused intravenously for 5 min prior to and throughout exercise (ADR). Glucose kinetics were measured by a primed, continuous infusion of 6,6-[2H]glucose and muscle samples were obtained prior to and at 1 and 20 min of exercise.

  2. The infusion of adrenaline elevated (P < 0.01) plasma adrenaline concentrations at rest (pre-infusion, 0.28 ± 0.09; post-infusion, 1.70 ± 0.45 nmol l−1; means ±s.e.m.) and this effect was maintained throughout exercise. Total carbohydrate oxidation increased by 18 % and this effect was due to greater skeletal muscle glycogenolysis (P < 0.05) and pyruvate dehydrogenase (PDH) activation (P < 0.05, treatment effect). Glucose rate of appearance was not different between trials, but the infusion of adrenaline decreased (P < 0.05, treatment effect) skeletal muscle glucose uptake in ADR.

  3. During exercise muscle glucose 6-phosphate (G-6-P) (P = 0.055, treatment effect) and lactate (P < 0.05) were elevated in ADR compared with CON and no changes were observed for pyruvate, creatine, phosphocreatine, ATP and the calculated free concentrations of ADP and AMP.

  4. The data demonstrate that elevated plasma adrenaline levels during moderate exercise in untrained men increase skeletal muscle glycogen breakdown and PDH activation, which results in greater carbohydrate oxidation. The greater muscle glycogenolysis appears to be due to increased glycogen phosphorylase transformation whilst the increased PDH activity cannot be readily explained. Finally, the decreased glucose uptake observed during exercise in ADR is likely to be due to the increased intracellular G-6-P and a subsequent decrease in glucose phosphorylation.

Muscle glycogen degradation is catalysed by glycogen phosphorylase, which exists in a less active b and more active a form. During exercise, transformation of phosphorylase b to a is regulated by increases in cytosolic Ca2+, liberated during muscle contraction, and an adrenaline-mediated increase in 3′,5′-cyclic adenosine monophosphate (cAMP), thereby setting an upper limit for muscle glycogenolysis (Howlett et al. 1998). Factors linked to the energy state of the cell (e.g. AMP and IMP) or substrate (glycogen, inorganic phosphate − Pi) then ‘fine-tune’ the flux rate according to the metabolic demands (Ren & Hultman, 1990; Johnson, 1992).

Increased adrenaline often (Jansson et al. 1986; Spriet et al. 1988; Febbraio et al. 1998), but not always (Chesley et al. 1995; Wendling et al. 1996), results in increased muscle glycogen utilisation during exercise in man. The discrepancies in these studies may be related to the infusion of supraphysiological concentrations of adrenaline (Jansson et al. 1986; Spriet et al. 1988) and/or the marked differences in exercise intensity (Chesley et al. 1995; Febbraio et al. 1998). During exercise where the energy state of the cell is challenged (Chesley et al. 1995), factors such as increased Pi, and allosteric modulation via increased free AMP (AMPf) may maximally activate glycogenolysis, irrespective of further increases in adrenaline concentration. In contrast, when increases in the intramuscular concentrations of the allosteric activators are minimal the effect of adrenaline may become important in further stimulating glycogen breakdown (Febbraio et al. 1998). Thus, the first aim of this study was to further investigate the effect of increased adrenaline on muscle glycogen breakdown during moderate-intensity exercise.

Although the upper limit of glycolytic flux is regulated by glycogen phosphorylase, an increase in pyruvate flux must occur to facilitate higher carbohydrate (CHO) oxidation. Pyruvate dehydrogenase (PDH) regulates the entry of CHO into oxidative pathways by catalysing the decarboxylation of pyruvate to acetyl-CoA. The transformation of PDH to its active form (PDHa) is controlled by changes in the activation of PDH phosphatase (activating) and PDH kinase (inhibiting). PDH phosphatase is activated by increases in intracellular Ca2+ concentration (Wieland, 1983), whereas elevations of the mitochondrial acetyl CoA/CoA, NADH/NAD+ and ATP/ADP ratios increase and pyruvate decreases PDH kinase activity. Essentially, PDH activation is linked to exercise intensity, substrate availability and intrinsic regulators related to the energy state of the cell (Constantin-Teodosiu et al. 1991a; Putman et al. 1993; Howlett et al. 1998).

Based on the finding that CHO oxidation is greater with increased plasma adrenaline (Febbraio et al. 1998), PDH activity should be enhanced to facilitate greater flux of CHO-derived acetyl-CoA through the TCA cycle. Although an effect of adrenaline has been demonstrated in the isolated rat heart (McCormack & Denton, 1981), no such effect is evident in resting human skeletal muscle with adrenaline infusion (Constantin-Teodusiu et al. 1999). However, the effect of adrenaline on PDH activation may occur early in exercise and as such the absence of an early (< 30 min) muscle biopsy may preclude such an observation (Constantin-Teodusiu et al. 1999). Thus, a second aim of the present study was to investigate the effect of adrenaline on PDH activation and CHO oxidation during moderate exercise.

In contrast with the stimulatory effect of adrenaline on muscle glycogenolysis, recent evidence supports a role of adrenaline in inhibiting skeletal muscle glucose uptake. In exercising humans several studies have reported decreased glucose uptake with adrenaline infusion (Jansson et al. 1986; Howlett et al. 1999) although others have reported no such effect (Kreisman et al. 2000). The reduction in the rate of glucose disappearance (Rd) with increased adrenaline levels may be attributed to increased flux through glycogenolysis which may reduce the gradient for glucose diffusion across the plasma membrane via decrements in glucose phosphorylation induced by glucose 6-phosphate inhibition of hexokinase (Leuck & Fromm, 1974; Katz et al. 1991). Studies conducted in vitro support such a mechanism (Chiasson et al. 1981; Aslesen & Jensen, 1998). In contrast, most studies have observed that both insulin- (Lee et al. 1997; Aslesen & Jensen, 1998) and contraction- (Aslesen & Jensen, 1998) stimulated glucose transport in vitro are unaffected by β-adrenergic stimulation, although this remains equivocal (Bonen et al. 1992). Hence previous studies suggest a role for adrenaline in inhibiting glucose uptake via decreased glucose transport secondary to an inhibition of glucose phosphorylation. A third and final aim of the study was to examine the effect of adrenaline on glucose disposal during exercise in humans.

In the present study, we examined the combined effects of elevated plasma adrenaline and exercise on skeletal muscle glycogen degradation, glucose uptake and PDH activation. It was hypothesised that skeletal muscle glycogenolysis and PDH activation would be enhanced by adrenaline and glucose uptake inhibited due to an increase in G-6-P.

METHODS

Subjects

Ten recreationally active males (23.4 ± 1.0 years, 73.6 ± 4.5 kg; mean ±s.d.) volunteered as subjects for the experiment. The experimental procedure and possible risks associated with the study were explained to subjects both verbally and in writing, and all subjects provided their written consent. The experiment was approved by the Deakin University Ethics Committee and was conducted in accordance with the Declaration of Helsinki.

Pre-experimental protocol

Peak pulmonary oxygen uptake (V̇O2,peak) was determined during an incremental cycling test to volitional exhaustion on an electromagnetically braked cycle ergometer (Lode Instruments, Groningen, The Netherlands), and averaged 4.16 ± 0.17 l min−1. For the day preceding each trial, subjects were provided with a food parcel (14 MJ, 80 % CHO) and were required to abstain from exercise, caffeine and alcohol. On the morning of the trial subjects consumed 5 ml (kg body weight)−1 of water to ensure euhydration and arrived at the laboratory after an overnight fast (10 h). All trials were performed at an ambient temperature of 19-21 °C.

Experimental protocol

Subjects performed two cycle exercise trials for 20 min at a workload corresponding to 58 ± 2 % of V̇O2,peak. On one occasion adrenaline was infused 5 min prior to and throughout exercise (ADR); on the other, saline was infused at an identical rate (CON). The trials were blind, randomised and conducted at least 1 week apart. On arrival at the laboratory an indwelling catheter was positioned in the antecubital vein of one arm for blood sampling, and in the contralateral arm for infusion of 6,6-[2H]glucose (n = 8 for tracer infusion) and adrenaline solutions. After a blood sample was obtained for subsequent determination of background isotopic enrichment, a primed (3.3 mmol) continuous (40.6 ± 2.1 μmol min−1) infusion of 6,6-[2H]glucose (Cambridge Isotope Laboratories, Cambridge, MA, USA) was begun using a peristaltic pump (Minipuls 3, Gilson, Villiers Le Bel, France). Five minutes prior to the commencement of exercise a muscle sample (n = 8 for muscle sampling) was obtained from the vastus lateralis using the percutaneous needle biopsy technique with suction, and quickly frozen in liquid nitrogen for later analysis. An infusion of saline (CON) or adrenaline (ADR) was commenced and continued for 5 min, after which subjects moved to the cycle ergometer and commenced exercise. A syringe pump (IVAC P3000, IVAC Medical Systems, Hampshire, UK) was used to infuse the adrenaline solution at a rate of 0.00736 μg kg−1 min−1. After 1 min, exercise ceased and a second muscle sample was obtained while the subject remained on the cycle ergometer. The time delay between the cessation and recommencement of exercise was 1 min. Immediately upon completion of the exercise bout a final muscle sample was obtained. All muscle samples were analysed for glycogen, lactate, pyruvate, adenosine triphosphate (ATP), phosphocreatine (PCr), creatine, glucose 6-phosphate (G-6-P) and pyruvate dehydrogenase activity (PDHa).

Venous blood samples were obtained at 5 min intervals during the final 15 min of the rest period and throughout exercise for later determination of plasma glucose and [2H]glucose enrichment. Samples were obtained prior to adrenaline infusion and at 0, 10 and 20 min for the determination of plasma insulin and free fatty acids (FFAs). Additional samples obtained at −5, 0, 5, 10 and 20 min were analysed for plasma catecholamines. Blood for glucose, [2H]glucose, lactate and insulin was placed in lithium heparin tubes and rolled. For adrenaline, noradrenaline and FFAs 1.5 ml of whole blood was added to 30 μl of EGTA and reduced glutathione. Blood for glucagon was collected at 0, 10 and 20 min and added to a protease inhibitor. All blood was spun and the plasma stored at −20 °C. Plasma for catecholamine analysis was stored at −80 °C. Expired gases were collected on-line (Gould 2900 Metabolic System, OH, USA) for 5 min at 5 and 15 min of exercise with data from the final minute being recorded. Heart rate was measured continuously via telemetry (Polar sports tester, Polar Electro, Finland) and recorded every 5 min.

Analytic techniques

Plasma glucose and lactate were measured using an automated analyser (EML105, Radiometer, Denmark). Plasma adrenaline and noradrenaline were analysed using a single isotope (3H) radioenzymatic assay system (TRK995, Amersham, Buckinghamshire, UK) and plasma FFAs were analysed by using an enzymatic colormetric method (Wako NEFA C test kit, Wako Chemicals, VA, USA). Plasma insulin (Phadeseph, Pharmacia & Upjohn, Uppsala, Sweden) and glucagon (Alford et al. 1977) were measured by radioimmunoassay. For the determination of [2H]glucose isotopic enrichments, 50 μl of plasma was deproteinised with 0.3 m Ba(OH)2 and 0.3 m ZnSO4. After centrifugation 80 μl of supernate was removed and dried overnight at 60 °C. The samples were reconstituted using 100 μl of pyradine-acetic anhydride solution, added to 10 ml of scintillant and measured with a gas chromatograph-mass spectrometer (5890 series 2 gas chromatograph, 5971 mass spectrometer detector, Hewlett-Packard, Avondale, PA, USA). The rates of glucose appearance (Ra) and disappearance (Rd) were calculated from the changes in glucose percentage enrichment using a modified one-pool non-steady state model (Steele et al. 1956) assuming a pool fraction of 0.65 and estimating the apparent glucose space at 25 %. In the fasted state glucose Ra is equivalent to hepatic glucose production. The metabolic clearance rate (MCR) of glucose was calculated by dividing glucose Rd by the plasma glucose concentration.

A 15 mg portion of wet skeletal muscle was removed under liquid nitrogen and analysed for PDH activity using a radioisotopic method (Constantin-Teodosiu et al. 1991b) as modified by Putman et al. (1993). The coefficient of variation for repeated measurements of PDH activity in a muscle sample is 6.7 %. The remaining portion of muscle was freeze dried, dissected free of visible connective tissue and blood, and powdered. Muscle glycogen concentrations were determined on the first aliquot, which was extracted, neutralised, and analysed according to the methods of Passonneau & Lauderdale (1974). A second aliquot was extracted (Harris et al. 1974) and analysed for ATP, PCr, creatine, pyruvate and lactate by using enzymatic fluorometric techniques (Lowry & Passonneau, 1972). Muscle metabolites and PDHa were corrected to the highest total creatine content for each subject.

Calculations

Free ADP (ADPf) and AMP (AMPf) concentrations were calculated by assuming equilibrium of the creatine phosphokinase and adenylate kinase reactions. ADPf was calculated using the previously measured ATP, PCr and creatine contents and [H+] estimated from changes in pyruvate and lactate. AMPf was calculated from ATP and the estimated ADPf (Dudley et al. 1987). Free Pi content was calculated as the sum of the estimated resting free phosphate concentration (10.8 mmol (kg d.w.)−1) and ΔPCr-ΔG-6-P between rest and each time point. Skeletal muscle glycogenolysis at 1 min was calculated from the changes in G-6-P, lactate and pyruvate from rest.

Statistical analysis

The data from the two trials were compared by using a two-way analysis of variance (ANOVA) with repeated measures. Where appropriate, specific differences were located by using the Newman-Keuls post hoc test. All values are reported as means ±s.e.m.

RESULTS

Physiological responses

Oxygen uptake did not increase with exercise duration and averaged 2.40 ± 0.14 and 2.47 ± 0.13 l min−1 for CON and ADR, respectively (Table 1). Heart rate increased progressively throughout exercise in both trials (P < 0.01, time effect) and was elevated (P < 0.01, treatment effect) with adrenaline infusion (Table 1). The respiratory exchange ratio (RER) was higher throughout exercise during ADR (P < 0.01) compared with CON and remained unchanged with time (Table 1).

Table 1.

Physiological responses during 20 min exercise at 58 ± 2%V̇O2,peak with (ADR) and without (CON) adrenaline infusion

Variable Trial 10 20
V̇O2 (l min−1) CON 2.41 ± 0.14 2.40 ± 0.14
ADR 2.44 ± 0.13 2.49 ± 0.12
V̇E (l min−1) CON 58.1 ± 3.6 60.0 ± 4.5
ADR 64.9 ± 4.1 67.4 ± 4.8
RER CON 0.90 ± 0.01 0.89 ± 0.01
ADR 0.94 ± 0.01* 0.92 ± 0.01*
Heart rate (beats min−1) CON 142 ± 4.3 150 ± 4.6
ADR 152 ± 4.0 161 ± 4.2
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Values are means ±s.e.m., n = 10. V̇O2, oxygen uptake; V̇E, minute ventilation; RER, respiratory exchange ratio.

*

ADR significantly different from CON (P < 0.001).

Plasma hormones

Plasma adrenaline levels were similar between trials prior to the commencement of the infusion. The administration of adrenaline increased (P < 0.05) plasma adrenaline concentration at rest (pre-infusion, 0.28 ± 0.09; post-infusion, 1.70 ± 0.45 nmol l−1) and this effect was maintained throughout exercise (Fig. 1). Plasma noradrenaline rapidly increased at the onset of exercise (P < 0.01, time effect) and remained elevated thereafter. No differences for noradrenaline were observed between trials (Table 2). Plasma insulin and glucagon concentrations were not affected by exercise or the administration of adrenaline (Table 2).

Figure 1. Plasma adrenaline concentration at rest and during 20 min of exercise at 58 ± 2 %V̇O2,peak with (ADR) or without (CON) adrenaline infusion.

Figure 1

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Values are means ±s.e.m., n = 10. * Significantly different (P < 0.01) from CON.

Table 2.

Plasma metabolite and hormone levels during 20 min exercise at 58 ± 2%V̇O2,peak with (ADR) and without (CON) adrenaline infusion

Variable Trial 0 10 20
[Lactate] (mmol l−1) CON 1.15 ± 0.08 4.17 ± 0.50 4.45 ± 0.62
ADR 1.48 ± 0.20 6.15 ± 0.47* 7.12 ± 0.55*
[FFAs] (mmol l−1) CON 0.61 ± 0.10 0.46 ± 0.05 0.47 ± 0.05
ADR 0.71 ± 0.08 0.78 ± 0.07* 0.80 ± 0.10*
[Noradrenaline] (nmol l−1) CON 2.08 ± 0.26 6.13 ± 0.60† 7.90 ± 0.72†
ADR 2.17 ± 0.31 7.79 ± 0.98† 8.54 ± 1.05†
[Insulin] (pmol l−1) CON 32.8 ± 2.17 37.4 ± 2.90 34.1 ± 2.69
ADR 34.5 ± 1.92 41.0 ± 5.93 38.7 ± 5.59
[Glucagon] (ng l−1) CON 36.1 ± 5.0 38.6 ± 7.3 43.1 ± 6.9
ADR 31.9 ± 6.7 43.9 ± 9.4 52.3 ± 10.2
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Values are means ±s.e.m., n = 10.

*

Significantly different from CON (P < 0.05);

†

significantly different from rest (P < 0.05).

Plasma metabolites

Plasma glucose was similar at rest for both trials. Plasma glucose increased (P < 0.01) progressively during exercise in ADR (0 min, 5.4 ± 0.12; 20 min, 8.0 ± 0.52 mmol l−1) whilst no such change was observed in CON (Fig. 2). Plasma lactate concentrations were similar at rest but increased (P < 0.01) throughout exercise in ADR compared with CON (Table 2). Basal plasma FFA concentrations were not different between trials; however, the infusion of adrenaline resulted in higher (P < 0.05) plasma FFAs during exercise (Table 2).

Figure 2. Plasma glucose concentration (top) and glucose rate of appearance (Ra, bottom) at rest and during 20 min of exercise at 58 ± 2 %V̇O2,peak with (ADR) or without (CON) adrenaline infusion.

Figure 2

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Values are means ±s.e.m., n = 8. * Significantly different (P < 0.01) from CON.

Glucose Ra increased throughout exercise for both trials and no differences were observed between conditions (P = 0.23, Fig. 2). Glucose Rd increased (P < 0.01) progressively throughout exercise and matched glucose Ra in CON. In response to adrenaline infusion glucose Rd was lower (P < 0.05, treatment effect) in ADR (Fig. 3). Similarly, glucose MCR increased (P < 0.01) with exercise duration in both trials and was lower (P < 0.05, treatment effect) in ADR compared with CON (Fig. 3).

Figure 3. Whole body glucose uptake (Rd, top) and metabolic clearance rate of plasma glucose (MCR, bottom) at rest and during 20 min of exercise at 58 ± 2 %V̇O2,peak with (ADR) or without (CON) adrenaline infusion.

Figure 3

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Values are means ±s.e.m., n = 8. * Significantly different (P < 0.05, treatment effect) from CON.

Muscle metabolites

Muscle glycogen content was similar at rest and was lower (P < 0.05) in ADR compared to CON following 20 min exercise (Table 3). Estimated muscle glycogen utilisation in the first minute of exercise was higher in ADR (CON: 16 ± 1; ADR: 24 ± 3 mmol (kg d.w.)−1, P < 0.01) and when measured was approximately twofold greater (P < 0.01) throughout exercise in ADR (187 ± 31 mmol (kg d.w.)−1) compared with CON (96 ± 23 mmol (kg d.w.)−1, Fig. 4). Muscle G-6-P increased (P < 0.01) at the onset of exercise in both trials and tended (P = 0.055) to be elevated throughout exercise in ADR compared with CON. For CON, muscle lactate increased (P < 0.05) during the first minute of exercise and plateaued thereafter. Muscle lactate during exercise was higher (P < 0.01) in ADR compared with CON (Table 3). No differences between trials were observed for muscle pyruvate, creatine, PCr and ATP (Table 3). Exercise resulted in marked alterations in muscle metabolites, such that muscle creatine increased (P < 0.05) and PCr concentrations decreased (P < 0.05) during the first minute of exercise. These responses persisted throughout exercise. ATP and muscle pyruvate were unaffected by exercise. Even though the calculated ADPf contents increased twofold and AMPf increased fourfold with exercise, these values were not statistically different from rest. There were no differences between trials (Table 3). The calculated accumulation of Pi was greater (P < 0.01) at 1 min of exercise in CON, but this difference between trials was not evident at 20 min (Table 3).

Table 3.

Comparison of muscle metabolite concentrations during 20 min exercise at 58 ± 2%¨O2,peak with (ADR) and without (CON) adrenaline infusion

Variable Trial 0 1 20
Glycogen (mmol (kg d.w.)−1) CON 517 ± 30 — 421 ± 41
ADR 551 ± 32 — 366 ± 40
Lactate (mmol (kg d.w.)−1) CON 6.2 ± 0.8 18.6 ± 2.2 16.2 ± 5.4
ADR 4.9 ± 0.7 22.7 ± 3.3 33.5 ± 8.6*
Pyruvate (mmol (kg d.w.)−1) CON 0.13 ± 0.02 0.19 ± 0.01 0.18 ± 0.02
ADR 0.14 ± 0.01 0.18 ± 0.02 0.19 ± 0.02
G-6-P (mmol (kg d.w.)−1)) CON 0.94 ± 0.10 5.17 ± 0.86 4.22 ± 0.71
ADR 0.93 ± 0.13 8.20 ± 0.95 6.61 ± 0.65
Creatine (mmol (kg d.w.)−1)) CON 43.8 ± 4.0 60.6 ± 5.9 63.0 ± 8.1
ADR 45.7 ± 4.7 58.8 ± 5.9 69.7 ± 7.6
Phosphocreatine (mmol (kg d.w.)−1)) CON 85.3 ± 1.8 68.2 ± 4.1 63.5 ± 6.2
ADR 83.6 ± 1.6 71.4 ± 3.5 58.1 ± 6.4
ATP (mmol (kg d.w.)−1)) CON 28.0 ± 1.2 27.2 ± 1.0 27.1 ± 0.5
ADR 28.0 ± 1.0 27.3 ± 0.7 28.4 ± 1.0
ADPf (μmol (kg d.w.)−1)) CON 79.5 ± 8.8 126.4 ± 21.4 151.5 ± 32.2
ADR 79.3 ± 10.7 106.3 ± 9.8 165.5 ± 34.7
AMPf (μmol (kg d.w.)−1)) CON 0.23 ± 0.04 0.61 ± 0.20 1.04 ± 0.41
ADR 0.23 ± 0.06 0.45 ± 0.07 1.23 ± 0.63
Free Pi (mmol (kg d.w.)−1)) CON — 23.6 ± 4.3 29.3 ± 6.4
ADR — 15.7 ± 2.8* 30.6 ± 6.3
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Values are means ±s.e.m., n = 8.

*

Significantly different from corresponding value for CON (P < 0.05).

Figure 4. Muscle glycogen utilisation following 20 min of exercise at 58 ± 2 %V̇O2,peak with (ADR) or without (CON) adrenaline infusion.

Figure 4

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Values are means ±s.e.m., n = 8.* Significantly different (P < 0.05) from CON.

Resting PDH activity averaged 1.12 ± 0.2 and 1.02 ± 0.1 mmol acetyl CoA (kg wet wt)−1 min−1 for CON and ADR, increased (P < 0.01) during the first minute of exercise in both trials and remained elevated for the duration of exercise (2.86 ± 0.4 and 3.22 ± 0.3 for CON and ADR at 20 min, respectively). The infusion of adrenaline increased (P < 0.01, treatment effect) PDH activity during exercise compared with control conditions (Fig. 5).

Figure 5. Pyruvate dehydrogenase activity (PDHa) at rest and during 20 min of exercise at 58 ± 2 %V̇O2,peak with (ADR) or without (CON) adrenaline infusion.

Figure 5

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Values are means ±s.e.m., n = 8. * Significantly different (P < 0.01, treatment effect) from CON.

DISCUSSION

The present study demonstrates that carbohydrate metabolism is increased in human skeletal muscle with elevated adrenaline as a result of a twofold increase in glycogen utilisation and increased flux through PDH. Interestingly, both CHO oxidation and lactate accumulation were greater with adrenaline infusion. Glucose uptake during exercise was attenuated by adrenaline infusion and this response is likely to be due to a decrease in glucose phosphorylation.

The finding that CHO oxidation and glycogen utilisation are increased with elevated adrenaline during whole body exercise is in agreement with a previous result from our laboratory (Febbraio et al. 1998). These results also confirm earlier reports of an effect of high plasma adrenaline levels on muscle glycogenolysis during two-legged cycle exercise (Jansson et al. 1986) and electrical stimulation of the quadriceps (Spriet et al. 1988). They are also consistent with effects of adrenaline on muscle glycogenolysis in the perfused, contracting rat hindlimb (Richter et al. 1982). In contrast to these findings the absence of an effect of adrenaline on glycogenolysis has been demonstrated in exercising humans (Chesley et al. 1995; Wendling et al. 1996; Kjær et al. 2000). Although the exercise intensity used in the study by Wendling et al. (1996) was similar to that of the present study (65 vs. 58 %V̇O2,peak, respectively) it is likely that the adrenaline infusion elicited no effect on glycogenolysis due to the high concentrations of adrenaline observed in the control condition (2.35 nmol l−1 at 90 min vs. 1.4 nmol l−1 at 20 min in the present study). It has been demonstrated previously that elevation of plasma adrenaline to ≈2 nmol l−1 increases muscle glycogenolysis during moderate exercise (Febbraio et al. 1998) and as such, additional adrenaline may not further enhance glycogenolysis. Alternatively, comparisons between Wendling et al. (1996) and the present study are difficult to make due to the differences in exercise duration (90 and 20 min, respectively). The discrepancies in findings between the present study and those of Chesley et al. (1995) are most likely to be related to the marked differences in exercise intensity (58 vs. 83 %V̇O2,peak) and the subsequent effect on glycogen phosphorylase (PHOS), the key regulatory enzyme of glycogenolysis. During contraction, increased cytosolic [Ca2+] activates the transformation of PHOS from its b to its more active a isoform (Chasiotis et al. 1982). Thereafter, the activity of the enzyme is intimately coupled to the energy status of the cell (Ren & Hultman, 1990; Chesley et al. 1995; Howlett et al. 1998) and the availability of Pi (Chasiotis, 1988). PHOS transformation is also increased by adrenaline via a cAMP-dependant process. During contraction PHOS a is rapidly converted back to b in the absence of adrenaline (Conlee et al. 1979; Cartier & Gollnick, 1985) and this coincides with reduced glycogenolytic rates (Ren & Hultman, 1989). However, studies in rats and humans have demonstrated no such reduction in glycolytic rate in the presence of adrenaline (Rennie et al. 1982; Richter et al. 1982; Spriet et al. 1988), which suggests the likely mechanism responsible for the increased glycogenolysis is a reactivation of the active a form of PHOS (Rennie et al. 1982; Richter et al. 1982; Spriet et al. 1988).

Intense aerobic exercise is likely to fully activate glycogenolysis via increased calcium release, elevated plasma adrenaline and increased intramuscular concentrations of allosteric activators, irrespective of any further increase in adrenaline concentrations. Indeed, during heavy exercise (Chesley et al. 1995) Pi, ADPf and AMPf were all markedly elevated as compared with the present study (ADP: 450 vs. 160 μmol (kg d.w.)−1; AMP: 9 vs. 1.15 μmol (kg d.w.)−1; free Pi: 64.5 vs. 24.5 mmol (kg d.w.)−1 for 83 ± 1 and 58 ± 2 %V̇O2,peak, respectively). These increases in allosteric activators, together with an already high plasma adrenaline level, may minimise the effects of further increases in adrenaline level. In support of this observation, adrenaline infusion did not augment glycogenolysis in rat skeletal muscle during intense tetanic contractions (Chesley et al. 1994). Although we were unable to measure PHOS a activity in the present study, the absence of changes in the intramuscular concentration of post-transformational regulators of PHOS (AMPf, ADPf, Pi; Table 3) supports the hypothesis that an adrenaline-induced increase in PHOS transformation is the most likely mechanism responsible for the observed increase in glycogen utilisation during exercise in the present study. It is worth noting that previous studies have observed an increase in PHOS a activity with adrenaline infusion, although this was not accompanied by enhanced muscle glycogenolysis (Chesley et al. 1995; Kjær et al. 2000).

The novel finding is that adrenaline increased PDH activity in association with an increase in RER, and that the extra flux through PDH could account for the increased CHO oxidation that occurred in ADR. This observation is logical because the transformation of PDH to its active form permits the entry of CHO into the tricarboxylic acid cycle by catalysing the decarboxylation of pyruvate to acetyl CoA. In this study the infusion of adrenaline increased the calculated whole body CHO oxidation by ≈18 % (data not shown) and PDH activation by ≈14 % during 20 min of exercise. Assuming that the active muscle mass during cycling was 10 kg (Putman et al. 1993) and that changes in CHO oxidation during exercise occur primarily in active muscle, the calculated difference in CHO oxidation and PDH activity between ADR and CON was 0.38 mmol pyruvate (kg wet wt)−1 min−1 and 0.42 mmol acetyl CoA (kg wet wt)−1 min−1, respectively. Since previous studies have consistently demonstrated that flux through PDH is closely matched to PDH activation at various exercise intensities (Gibala et al. 1998; Howlett et al. 1998; Putman et al. 1993) our data suggest that the adrenaline-induced increase in PDH activity was adequate to account for the increased flux through PDH and the increased CHO oxidation.

The regulation of PDH transformation to the dephosphorylated active form is dependant on the balance between PDH phosphatase (activating) and PDH kinase (inhibiting) (Linn et al. 1969; Hultman, 1996). PDH phosphatase is stimulated by Ca2+ and PDH kinase is inhibited by pyruvate, and stimulated by high ATP/ADP, NADH/NAD+ and acetyl CoA/CoA ratios (for review see Hultman, 1996). The explanation for the elevated PDH activity with adrenaline in the present study is not readily apparent. The increase in PDHa cannot be explained by changes in muscle pyruvate and the ATP/ADP ratio and although the acetyl CoA/CoA ratio was not measured, previous investigations suggest that changes in the transformation of PDH are independent of the acetyl CoA/CoA ratio during exercise (Constantin-Teodosiu et al. 1992; Putman et al. 1993, 1995). Due to the technical limitations of measuring the mitochondrial redox state we did not measure the NADH/NAD ratio in the present study. However, there appears to be no consensus regarding the effect of mitochondrial redox state on PDH activation during exercise (Constantin-Teodosiu et al. 1992; Putman et al. 1995) and this relationship will remain unclear until a proven method for measuring mitochondrial redox state is established. Whether the stimulus for the increase in PDH activity is mediated by adrenaline-induced cAMP effects on PDH kinase or PDH phosphatase is not known. Studies in the isolated rat heart report increased PDH activity (McCormack & Denton, 1981) and demonstrate higher intramitochondrial Ca2+ concentrations (Crompton et al. 1983) when adrenaline is added to the perfusion medium. Similarly, β2-adrenergic stimulation of mouse skeletal muscle increases tetanic myoplasmic calcium concentration by enhancing sarcoplasmic calcium release (Cairns et al. 1993). Taken together, these data suggest that adrenaline may increase PDH activation via a calcium-stimulated activation of PDH phosphatase. Arguing against such a possibility, the infusion of exogenous adrenaline into resting men to levels observed during heavy exercise (≈4 nmol l−1) had no effect on PDH activity (Constantin-Teodosiu et al. 1999). Clearly, further studies investigating the role of adrenaline on the regulators of PDH in skeletal muscle are warranted.

As opposed to the stimulatory effect of adrenaline on muscle glycogenolysis, whole body glucose uptake was decreased with adrenaline infusion in the present study. It has been shown previously that the administration of adrenaline decreases glucose MCR in humans at rest (Rizza et al. 1980), but during exercise the data are less conclusive. Although it has been reported that Rd increases (Kreisman et al. 2000) with adrenaline, most data support a role for adrenaline in inhibiting glucose Rd during exercise. Infusion of adrenaline into adrenaline-deficient adrenalectomised humans decreased glucose Rd and MCR during moderate to heavy exercise (Howlett et al. 1999). In support of such an observation, the infusion of adrenaline into the femoral artery of one leg during two-legged cycle exercise resulted in an attenuation of the arterial-femoral venous difference for glucose in that leg (Jansson et al. 1986). Furthermore, α- and β-adrenergic blockade with islet clamp (Marker et al. 1991) and coeliac blockade (Kjær et al. 1993) resulted in increased glucose utilisation during moderate exercise when compared with control conditions.

The mechanism underlying the attenuated glucose uptake is most likely to be attributed to increases in glycolytic flux. According to this schema, an increase in muscle glycogenolysis results in G-6-P accumulation and a decrease in glucose phosphorylation since G-6-P is a strong inhibitor of hexokinase (Leuck & Fromm, 1974). Subsequent increases in intracellular glucose concentration would reduce the gradient for glucose diffusion across the plasma membrane (Leuck & Fromm, 1974; Katz et al. 1991). Studies conducted in vitro have shown that adrenaline increases intracellular glucose- and decreases insulin-stimulated (Chiasson et al. 1981; Aslesen & Jensen, 1998) and, to a lesser extent, contraction-stimulated (Aslesen & Jensen, 1998) glucose uptake by inhibiting phosphorylation. Indeed, in the present study muscle glycogen degradation and G-6-P accumulation were augmented, and glucose uptake was attenuated with elevated adrenaline.

It has also been proposed that adrenaline may inhibit glucose disposal via a direct effect on GLUT4. The administration of supra-physiological concentrations of adrenaline increases GLUT4 translocation and decreases 3-O-methyl glucose transport in perfused rat muscle, thus implying a decrease in GLUT4 intrinsic activity (Bonen et al. 1992). In contrast, β-adrenergic stimulation does not directly inhibit insulin-stimulated (Lee et al. 1997; Aslesen & Jensen, 1998) or contraction-stimulated (Aslesen & Jensen, 1998) glucose transport in vitro. Taken together, these findings suggest that adrenaline-mediated decreases in glucose uptake by skeletal muscle are likely to be due to a reduction in glucose phosphorylation and a subsequent inhibition of transport.

Another mechanism that may attenuate glucose uptake during moderate exercise is higher plasma FFA levels (Hargreaves et al. 1991). Although this has not been a consistent finding (Romijn et al. 1995; Odland et al. 1998), the possibility that such a mechanism was operating in the present study cannot be excluded since plasma FFAs were 41 % higher during exercise in ADR.

In summary, the results of the present study demonstrate that elevated plasma adrenaline increases total CHO oxidation via greater skeletal muscle glycogenolysis and PDH activation during moderate exercise. The increased glycogenolysis appears to be regulated by increased glycogen phosphorylase transformation, whilst the mechanism controlling the increased PDH transformation is unexplained, but may be related to an adrenaline-induced increase in cytosolic calcium content. Finally, the likely mechanism mediating the reduced glucose uptake with adrenaline infusion is a decrease in glucose phosphorylation.

Acknowledgments

The authors acknowledge the excellent medical assistance of Dr Andrew Garnham, School of Health Sciences, Deakin University, and thank Michael Christopher, Department of Endocrinology, St Vincent's Hospital, for performing the glucagon assays, and Dom Caridi, Department of Chemistry and Biology, Victoria University, for assistance in measuring the glucose enrichments. This study was supported by the Australian Research Council.

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