Terry E. Graham

Caffeine and exercise: metabolism, endurance and performance.

AbstractCaffeine is a common substance in the diets of most athletes and it is now appearing in many new products, including energy drinks, sport gels, alcoholic beverages and diet aids. It can be a powerful ergogenic aid at levels that are considerably lower than the acceptable limit of the International Olympic Committee and could be beneficial in training and in competition. Caffeine does not improve maximal oxygen capacity directly, but could permit the athlete to train at a greater power output and/or to train longer. It has also ben shown to increase speed and/or power output in simulated race conditions. These effects have been found in activities that last as little as 60 seconds or as long as 2 hours. There is less information about the effects of caffeine on strength; however, recent work suggests no effect on maximal ability, but enhanced endurance or resistance to fatigue. There is no evidence that caffeine ingestion before exercise leads to dehydration, ion imbalance, or any other adverse effects.The ingestion of caffeine as coffee appears to be ineffective compared to doping with pure caffeine. Related compounds such as theophylline are also potent ergogenic aids. Caffeine may act synergistically with other drugs including ephedrine and anti-inflammatory agents. It appears that male and female athletes have similar caffeine pharmacokinetics, i.e., for a given dose of caffeine, the time course and absolute plasma concentrations of caffeine and its metabolites are the same. In addition, exercise or dehydration does not affect caffeine pharmacokinetics. The limited information available suggests that caffeine non-users and users respond similarly and that withdrawal from caffeine may not be important. The mechanism(s) by which caffeine elicits its ergogenic effects are unknown, but the popular theory that it enhances fat oxidation and spares muscle glycogen has very little support and is an incomplete explanation at best. Caffeine may work, in part, by creating a more favourable intracellular ionic environment in active muscle. This could facilitate force production by each motor unit.

Caffeine ingestion does not alter carbohydrate or fat metabolism in human skeletal muscle during exercise

1 This study examined the effect of ingesting caffeine (6 mg kg−1) on muscle carbohydrate and fat metabolism during steady‐state exercise in humans. Young male subjects (n= 10) performed 1 h of exercise (70 % maximal oxygen consumption (V̇O2,max)) on two occasions (after ingestion of placebo and caffeine) and leg metabolism was quantified by the combination of direct Fick measures and muscle biopsies. 2 Following caffeine ingestion serum fatty acid and glycerol concentration increased (P≤ 0.05) at rest, suggesting enhanced adipose tissue lipolysis. 3 In addition circulating adrenaline concentration was increased (P≤ 0.05) at rest following caffeine ingestion and this, as well as leg noradrenaline spillover, was elevated (P≤ 0.05) above placebo values during exercise. 4 Caffeine resulted in a modest increase (P≤ 0.05) in leg vascular resistance, but no difference was found in leg blood flow. 5 Arterial lactate and glucose concentrations were increased (P≤ 0.05) by caffeine, while the rise in plasma potassium was dampened (P≤ 0.05). 6 There were no differences in respiratory exchange ratio or in leg glucose uptake, net muscle glycogenolysis, leg lactate release or muscle lactate, or glucose 6‐phosphate concentration. Similarly there were no differences between treatments in leg fatty acid uptake, glycerol release or muscle acetyl CoA concentration. 7 These findings indicate that caffeine ingestion stimulated the sympathetic nervous system but did not alter the carbohydrate or fat metabolism in the monitored leg. Other tissues must have been involved in the changes in circulating potassium, fatty acids, glucose and lactate.

Modest PGC-1α Overexpression in Muscle in Vivo Is Sufficient to Increase Insulin Sensitivity and Palmitate Oxidation in Subsarcolemmal, Not Intermyofibrillar, Mitochondria

PGC-1α overexpression in skeletal muscle, in vivo, has yielded disappointing and unexpected effects, including disrupted cellular integrity and insulin resistance. These unanticipated results may stem from an excessive PGC-1α overexpression in transgenic animals. Therefore, we examined the effects of a modest PGC-1α overexpression in a single rat muscle, in vivo, on fuel-handling proteins and insulin sensitivity. We also examined whether modest PGC-1α overexpression selectively targeted subsarcolemmal (SS) mitochondrial proteins and fatty acid oxidation, because SS mitochondria are metabolically more plastic than intermyofibrillar (IMF) mitochondria. Among metabolically heterogeneous rat hindlimb muscles, PGC-1α was highly correlated with their oxidative fiber content and with substrate transport proteins (GLUT4, FABPpm, and FAT/CD36) and mitochondrial proteins (COXIV and mTFA) but not with insulin-signaling proteins (phosphatidylinositol 3-kinase, IRS-1, and Akt2), nor with 5′-AMP-activated protein kinase, α2 subunit, and HSL. Transfection of PGC-1α into the red (RTA) and white tibialis anterior (WTA) compartments of the tibialis anterior muscle increased PGC-1α protein by 23-25%. This also induced the up-regulation of transport proteins (FAT/CD36, 35-195%; GLUT4, 20-32%) and 5′-AMP-activated protein kinase, α2 subunit (37-48%), but not other proteins (FABPpm, IRS-1, phosphatidylinositol 3-kinase, Akt2, and HSL). SS and IMF mitochondrial proteins were also up-regulated, including COXIV (15-75%), FAT/CD36 (17-30%), and mTFA (15-85%). PGC-1α overexpression also increased palmitate oxidation in SS (RTA, +116%; WTA, +40%) but not in IMF mitochondria, and increased insulin-stimulated phosphorylation of AKT2 (28-43%) and rates of glucose transport (RTA, +20%; WTA, +38%). Thus, in skeletal muscle in vivo, a modest PGC-1α overexpression up-regulated selected plasmalemmal and mitochondrial fuel-handling proteins, increased SS (not IMF) mitochondrial fatty acid oxidation, and improved insulin sensitivity.

Caffeine ingestion elevates plasma insulin response in humans during an oral glucose tolerance test

We tested the hypothesis that caffeine ingestion results in an exaggerated response in blood glucose and (or) insulin during an oral glucose tolerance test (OGTT). Young, fit adult males (n = 18) underwent 2 OGTT. The subjects ingested caffeine (5 mg/kg) or placebo (double blind) and 1 h later ingested 75 g of dextrose. There were no differences between the fasted levels of serum insulin, C peptide, blood glucose, or lactate and there were no differences within or between trials in these measures prior to the OGTT. Following the OGTT, all of these parameters increased (P < or = 0.05) for the duration of the OGTT. Caffeine ingestion resulted in an increase (P < or = 0.05) in serum fatty acids, glycerol, and plasma epinephrine prior to the OGTT. During the OGTT, these parameters decreased to match those of the placebo trial. In the caffeine trial the serum insulin and C peptide concentrations were significantly greater (P < or = 0.001) than for placebo for the last 90 min of the OGTT and the area under the curve (AUC) for both measures were 60 and 37% greater (P < or = 0.001), respectively. This prolonged, increased elevation in insulin did not result in a lower blood glucose level; in fact, the AUC for blood glucose was 24% greater (P = 0.20) in the caffeine treatment group. The data support our hypothesis that caffeine ingestion results in a greater increase in insulin concentration during an OGTT. This, together with a trend towards a greater rather than a more modest response in blood glucose, suggests that caffeine ingestion may have resulted in insulin resistance.

Tricarboxylic acid cycle intermediate pool size and estimated cycle flux in human muscle during exercise

We examined the relationship between tricarboxylic acid (TCA) cycle intermediate (TCAI) pool size, TCA cycle flux (calculated from leg O2 uptake), and pyruvate dehydrogenase activity (PDHa) in human skeletal muscle. Six males performed moderate leg extensor exercise for 10 min, followed immediately by intense exercise until exhaustion (3.8 +/- 0.5 min). The sum of seven measured TCAI (SigmaTCAI) increased (P </= 0.05) from 1.39 +/- 0.11 at rest to 2. 88 +/- 0.31 after 10 min and to 5.38 +/- 0.31 mmol/kg dry wt at exhaustion. TCA cycle flux increased approximately 70-fold during submaximal exercise and was approximately 100-fold higher than rest at exhaustion. PDHa corresponded to 77 and 90% of TCA cycle flux during submaximal and maximal exercise, respectively. The present data demonstrate that a tremendous increase in TCA cycle flux can occur in skeletal muscle despite a relatively small change in TCAI pool size. It is suggested that the increase in SigmaTCAI during exercise may primarily reflect an imbalance between the rate of pyruvate production and its rate of oxidation in the TCA cycle.We examined the relationship between tricarboxylic acid (TCA) cycle intermediate (TCAI) pool size, TCA cycle flux (calculated from leg O2uptake), and pyruvate dehydrogenase activity (PDHa) in human skeletal muscle. Six males performed moderate leg extensor exercise for 10 min, followed immediately by intense exercise until exhaustion (3.8 ± 0.5 min). The sum of seven measured TCAI (ΣTCAI) increased ( P ≤ 0.05) from 1.39 ± 0.11 at rest to 2.88 ± 0.31 after 10 min and to 5.38 ± 0.31 mmol/kg dry wt at exhaustion. TCA cycle flux increased ∼70-fold during submaximal exercise and was ∼100-fold higher than rest at exhaustion. PDHa corresponded to 77 and 90% of TCA cycle flux during submaximal and maximal exercise, respectively. The present data demonstrate that a tremendous increase in TCA cycle flux can occur in skeletal muscle despite a relatively small change in TCAI pool size. It is suggested that the increase in ΣTCAI during exercise may primarily reflect an imbalance between the rate of pyruvate production and its rate of oxidation in the TCA cycle.

Rapid exercise-induced changes in PGC-1α mRNA and protein in human skeletal muscle

The mRNA of the nuclear coactivator peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) increases during prolonged exercise and is influenced by carbohydrate availability. It is unknown if the increases in mRNA reflect the PGC-1alpha protein or if glycogen stores are an important regulator. Seven male subjects [23 +/- 1.3 yr old, maximum oxygen uptake (Vo(2 max)) 48.4 +/- 0.8 ml.kg(-1).min(-1)] exercised to exhaustion ( approximately 2 h) at 65% Vo(2 max) followed by ingestion of either a high-carbohydrate (HC) or low-carbohydrate (LC) diet (7 or 2.9 g.kg(-1).day(-1), respectively) for 52 h of recovery. Glycogen remained depressed in LC (P < 0.05) while returning to resting levels by 24 h in HC. PGC-1alpha mRNA increased both at exhaustion (3-fold) and 2 h later (6.2-fold) (P < 0.05) but returned to rest levels by 24 h. PGC-1alpha protein increased (P < 0.05) 23% at exhaustion and remained elevated for at least 24 h (P < 0.05). While there was no direct treatment effect (HC vs. LC) for PGC-1alpha mRNA or protein, there was a linear relationship between the changes in glycogen and those in PGC-1alpha protein during exercise and recovery (r = -0.68, P < 0.05). In contrast, PGC-1beta did not increase with exercise but rather decreased (P < 0.05) below rest level at 24 and 52 h, and the decrease was greater (P < 0.05) in LC. PGC-1alpha protein content increased in prolonged exercise and remained upregulated for 24 h, but this could not have been predicted by the changes in mRNA. The beta-isoform declined rather than increasing, and this was greater when glycogen was not resynthesized to rest levels.

Dietary carbohydrate and postexercise synthesis of proglycogen and macroglycogen in human skeletal muscle

This study examined the role of carbohydrate (CHO) ingestion on the resynthesis of two pools of glycogen, proglycogen (PG) and macroglycogen (MG), in human skeletal muscle. Nine males completed an exhaustive glycogen depletion exercise bout at 70% maximal O2 consumption on two occasions. Subsequent 48-h dietary interventions consisted of either high (HC, 75% of energy intake) or low (LC, 32% of energy intake) CHO diets. Muscle biopsies were taken at exhaustion (EXH) and 4, 24, and 48 h later. The total muscle glycogen (Gt) at EXH for the HC and LC conditions was not significantly different, and the MG represented ∼12% of the Gt. From EXH to 4 h, there was an increase in the PG only for HC and no change in MG in either diet ( P < 0.05). From 4 to 24 h, the concentration of PG increased in both conditions ( P < 0.05). Between 24 and 48 h, in HC the majority of the increase in Gt was due to the MG pool ( P < 0.05). The MG and PG concentrations for HC were significantly greater than for LC at 24 and 48 h ( P < 0.05). At 48 h the MG represented 40% of the Gt for the HC diet and only 21% for the LC diet. There was no change in the net rates of synthesis of PG or MG over 48 h for LC ( P < 0.05). The net rate of PG synthesis from 0 to 4 h for HC was 16 ± 1.68 mmol glucosyl units ⋅ kg dry wt-1 ⋅ h-1, which was threefold greater than for LC ( P < 0.05). The net rate of PG synthesis decreased significantly from 4 to 24 h for HC, whereas the net rate of MG synthesis was not different over 48 h but was significantly greater than in LC ( P< 0.05). The two pools are synthesized at very different rates; both are sensitive to CHO, and the supercompensation associated with HC is due to a greater synthesis in the MG pool.This study examined the role of carbohydrate (CHO) ingestion on the resynthesis of two pools of glycogen, proglycogen (PG) and macroglycogen (MG), in human skeletal muscle. Nine males completed an exhaustive glycogen depletion exercise bout at 70% maximal O2 consumption on two occasions. Subsequent 48-h dietary interventions consisted of either high (HC, 75% of energy intake) or low (LC, 32% of energy intake) CHO diets. Muscle biopsies were taken at exhaustion (EXH) and 4, 24, and 48 h later. The total muscle glycogen (Gt) at EXH for the HC and LC conditions was not significantly different, and the MG represented approximately 12% of the Gt. From EXH to 4 h, there was an increase in the PG only for HC and no change in MG in either diet (P < 0.05). From 4 to 24 h, the concentration of PG increased in both conditions (P < 0.05). Between 24 and 48 h, in HC the majority of the increase in Gt was due to the MG pool (P < 0.05). The MG and PG concentrations for HC were significantly greater than for LC at 24 and 48 h (P < 0.05). At 48 h the MG represented 40% of the Gt for the HC diet and only 21% for the LC diet. There was no change in the net rates of synthesis of PG or MG over 48 h for LC (P < 0.05). The net rate of PG synthesis from 0 to 4 h for HC was 16 +/- 1.68 mmol glucosyl units . kg dry wt-1 . h-1, which was threefold greater than for LC (P < 0. 05). The net rate of PG synthesis decreased significantly from 4 to 24 h for HC, whereas the net rate of MG synthesis was not different over 48 h but was significantly greater than in LC (P < 0.05). The two pools are synthesized at very different rates; both are sensitive to CHO, and the supercompensation associated with HC is due to a greater synthesis in the MG pool.

Anaplerotic processes in human skeletal muscle during brief dynamic exercise.

1 This study examined changes in tricarboxylic acid cycle intermediates (TCAIs) in human skeletal muscle during 5min of dynamic knee extensor exercise (∼80% of maximum workload) and following 2 min of recovery. 2 The sum of the seven measured TCAIs (ΣTCAIs) increased from 1.10 ± 0.08mmol (kg dry weight)−1 at rest to 3.12 ± 0.24, 3.86 ± 0.35 and 4.33 ± 0.30 mmol (kg dry weight)−1after 1, 3 and 5 min of exercise, respectively (P≤ 0.05). The ΣTCAIs after 2 min of recovery (3.74 ± 0.43 mmol (kg dry weight)−1) was not different compared with 5 min of exercise. 3 The rapid increase in ΣTCAIs during exercise was primarily mediated by large changes in succinate, malate and fumarate. These three intermediates accounted for > 90 % of the net increase in ΣTCAIs during the first minute of contraction. 4 Intramuscular alanine increased after 1 min of exercise by an amount similar to the increase in the ΣTCAIs (2.33 mmol (kg dry weight)−1) (P≤ 0.05). Intramuscular pyruvate was also higher (P≤0.05) during exercise, while intramuscular glutamate decreased by ∼50% within 1 min and remained low despite an uptake from the circulation (P≤ 0.05). 5 The calculated net release plus estimated muscle accumulation of ammonia after 1 min of exercise (∼60 μmol (kg wet weight)−1) indicated that only a minor portion of the increase in ΣTCAIs could have been mediated through the purine nucleotide cycle and/or glutamate dehydrogenase reaction. 6 It is concluded that the close temporal relationship between the increase in ΣTCAIs and changes in glutamate, alanine and pyruvate metabolism suggests that the alanine amino‐transferase reaction is the most important anaplerotic process during the initial minutes of contraction in human skeletal muscle.

Stimulation of muscle ammonia production during exercise following branched-chain amino acid supplementation in humans.

1. This study examined the effects of a large (308 mg kg‐1) oral dose of branched‐chain amino acids (BCAAs) on muscle amino acid and ammonia (NH3) metabolism during 90 min of dynamic knee extensor exercise (64 +/‐ 2% of maximum workload). 2. BCAA supplementation resulted in a 4‐fold increase in the arterial BCAA level (from 373 to 1537 microM, P < 0.05) and a 1.5‐fold increase in the intramuscular BCAA level (from 3.4 +/‐ 0.2 to 5.2 +/‐ 0.5 mmol (kg dry weight)‐1, P < 0.05) by the onset of exercise. Over the 90 min exercise period, the exercising muscle removed a total of 7104 +/‐ 2572 mumol kg‐1 of BCAAs. In contrast, in the control trial, there was a total release of 588 +/‐ 86 mumol kg‐1 (P < 0.05) of BCAAs. 3. The total release of NH3 over the 90 min exercise period was 2889 +/‐ 317 mumol kg‐1 (P < 0.05) in the control trial and 4223 +/‐ 552 mumol kg‐1 (P < 0.05) in the BCAA trial. Similarly, the total release of alanine and glutamine was 1557 +/‐ 153 and 2213 +/‐ 270 mumol kg‐1, respectively, for the control trial and 2771 +/‐ 178 and 3476 +/‐ 217 mumol kg‐1, respectively, for the BCAA trial. 4. The lactate release and arterial lactate values were all consistently lower in the BCAA trial than in the control trial. The net production of lactate (intramuscular shifts + total release) was lower (P < 0.05) in the BCAA trial (49.9 +/‐ 11.4 mmol kg‐1) than in the control trial (64.0 +/‐ 11.7 mmol kg‐1). 5. It is concluded that: (1) the administration of BCAAs can greatly increase their concentration in plasma and subsequently their uptake by muscle during exercise, and (2) long‐term exercise following BCAA administration results in significantly greater muscle NH3, alanine and glutamine production, as well as lower lactate production, than is observed during exercise without BCAA supplementation. These data strongly suggest that BCAAs are an important source of NH3 during submaximal exercise and that their contribution to NH3, alanine and glutamine production can be significantly altered by changes in BCAA availability.

Novel aspects of skeletal muscle glycogen and its regulation during rest and exercise.

SHEARER, J., and T. E. GRAHAM. Novel aspects of skeletal muscle glycogen and its regulation during rest and exercise. Exerc. Sport Sci. Rev., Vol. 32, No. 3, pp. 120–126, 2004. Although it is often viewed as a homogenous substrate, glycogen is comprised of individual granules or ‘glycosomes’ that vary in their composition, subcellular localization, and metabolism. These differences result in additional levels of regulation allowing granules to be regulated individually or regionally within the cell during both rest and exercise.