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1 Department of Medicine, University of California, San Diego, La Jolla, CA 92093-0623, USA 2 Department of Health and Human Performance, Auburn University, Auburn, AL 36849, USA 3 Department of Biomedical Sciences and Technology, University of Milan, Italy
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Abstract |
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60% of initial value); and (2) following CAF administration. Resting muscle ATP, PCr and lactate contents were 25.2 ± 0.4, 76.9 ± 3.3 and 14.4 ± 3.3 mmol (kg dry weight)–1, respectively. At fatigue, generated tetanic tension was 61.1 ± 6.9% of initial contractions. There was a small but statistically significant recovery of tetanic tension (64.9 ± 6.6% of initial value) with CAF infusion, after which the muscle showed incomplete relaxation. At fatigue, muscle ATP and PCr contents had fallen significantly (P < 0.05) to 18.1 ± 1.1 and 18.9 ± 2.1 mmol (kg dry weight)–1, respectively, and lactate content had increased significantly to 27.7 ± 5.4 mmol (kg dry weight)–1. Following CAF, skeletal muscle ATP and PCr contents were significantly lower than corresponding fatigue values (15.0 ± 1.3 and 10.9 ± 2.2 mmol (kg dry weight)–1, respectively), while lactate was unchanged (22.2 ± 3.9 mmol (kg dry weight)–1). These results demonstrate that caffeine can result in a small, but statistically significant, recovery of isometric tension in fatigued canine hindlimb muscle in situ, although not nearly to the same degree as seen in isolated single muscle fibres. This suggests that, in this in situ isolated whole muscle model, alteration of Ca2+ metabolism is probably only one cause of fatigue.
(Received 13 July 2005;
accepted after revision 17 August 2005; first published online 23 August 2005)
Corresponding author R. A. Howlett: Department of Medicine, MC0623A, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0623, USA. Email: rhowlett{at}ucsd.edu
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Introduction |
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Some of the direct ergogenic effects of caffeine are mediated through the central and peripheral nervous actions. Caffeine is a non-selective adenosine receptor antagonist (Fredholm, 1995; Greer et al. 2001) and has been demonstrated to increase most neurotransmitters, especially dopamine (Nehlig et al. 1992), and it has also been shown to affect neural transmission and sensitivity (Wilson, 1973). Subjects can be more alert or stimulated, and there is often a decrease in the reported perception of effort (MacIntosh & Wright, 1995; Trice & Haymes, 1995) or an increase in work done at a given perceived effort (Cole et al. 1996).
Apart from adenosine receptor antagonism, other likely cellular mechanisms include alterations in Na+–K+ ATPase activity (Lindinger et al. 1993; Hawke et al. 1999), phosphodiesterase inhibition (Fredholm, 1995) and alterations in intracellular Ca2+ release. However, high concentrations (i.e. >1 mM), are required for caffeine to influence Ca2+ release/reuptake and sensitivity. Since this concentration of caffeine is normally toxic to humans (Fredholm, 1995), research on these phenomena is usually confined to in vitro tissue preparations. Caffeine exerts an effect on muscle contractility via the release of Ca2+ from the sarcoplasmic reticulum. This occurs via the direct activation of calcium release channels and not through depolarization of the cell membrane. In intact, living single fibres (Westerblad & Lannergren, 1987; Westerblad & Allen, 1991; Allen & Westerblad, 1995; Stary & Hogan, 2000) and superfused in vitro whole muscle preparations (Connett et al. 1983; James et al. 2004; Reading et al. 2004), caffeine is often used to facilitate the bulk release of Ca2+ from the sarcoplasmic reticulum. By doing this, investigators can briefly restore tetanic tension to levels near initial prefatigue values in fatigued single fibres (Westerblad & Allen, 1991; Allen & Westerblad, 1995). This observation has reinforced the idea that one cause of fatigue, among many (Fitts, 1994), is a failure in Ca2+ release mechanisms, and that the contractile sites are unimpaired if adequate intracellular Ca2+ levels are restored.
The present study was undertaken to determine whether delivery of pharmacological doses of caffeine in an intact, fatigued whole muscle in situ would lead to a rapid recovery of tension generation during contractions, as previously observed in isolated single muscle fibres (Westerblad & Lannergren, 1987; Allen & Westerblad, 1995; Stary & Hogan, 2000). Our hypothesis was that, similar to its effects in single isolated fibres, caffeine would cause a large efflux of sarcoplasmic reticulum (SR) Ca2+ into the muscle cytosol and cause a rapid, albeit transient, recovery of tension in contracting fatigued muscle.
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Methods |
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Adult mongrel dogs (n = 8) were used for this study. All procedures were approved by the Auburn University IACUC and conformed to NIH and American Physiological Society guidelines.
Surgical procedures
The surgical preparation utilized was the isolated canine gastrocnemius–plantaris–flexor digitorum superficialis in situ model (GP) described in detail elsewhere (Stainsby & Welch, 1966; Hogan et al. 1998). Briefly, animals were anaesthetized with pentobarbitone sodium (30 mg kg–1), with maintenance doses given as required. The dogs were intubated and ventilated on room air with a respirator (model 613, Harvard Apparatus, Holliston, MA, USA) to maintain normal arterial partial pressures of O2 and CO2. The gastrocnemius complex was isolated as previously described. The skin of the left hindlimb was cut from mid-thigh to the ankle, and the muscles overlying the GP were severed at their insertions and reflected. All the vessels draining into the popliteal vein, except those from the GP, were ligated, and the popliteal vein was cannulated. Venous outflow was returned to the animal via a reservoir attached to a cannula in the left jugular vein. The arterial circulation to the GP was isolated by ligating all vessels from the femoral and popliteal artery that did not enter the gastrocnemius. The right femoral artery was also isolated and cannulated. Blood from this artery was passed through cannulae into the contralateral, isolated popliteal artery supplying the left GP. This arrangement allowed infusion of caffeine into the arterial supply of the GP.
A portion of the calcaneus, with the two tendons from the gastrocnemius attached, was cut away at the heel and clamped around a metal rod for connection to an isometric myograph via a load cell (SM-250 Interface Inc., Scottsdale, AZ, USA) and a universal joint coupler. The other end of the muscle was left attached to its origin; both the femur and the tibia were fixed to the base of the myograph by bone nails. A turnbuckle strut was placed parallel to the muscle between the tibial bone nail and the arm of the myograph to minimize flexing of the myograph.
The sciatic nerve was exposed and isolated near the gastrocnemius. The distal stump of the nerve, 1.5–3.0 cm in length, was pulled through a small epoxy electrode containing two wire loops for stimulation. The muscle was covered with saline-soaked gauze and a thin plastic sheet to prevent drying and cooling.
Outputs from the load cell were fed through a strain gauge coupler into a computerized (PowerComputing PowerBase 240 Macintosh clone) data acquisition system (GW Instruments Inc., SuperScope II and instruNet Model 100B D–A input–output system). The tension signal was sampled at a rate of 100 Hz by the computerized data acquisition system. The load cell was calibrated with known weights prior to each experiment.
Experimental protocol
To evoke muscle contractions, the nerve was stimulated by supramaximal square pulses of 4–6 V amplitude and 0.2 ms duration (Grass S48 stimulator), isolated from earth by a stimulus isolator (Grass SIU8TB). Before each experiment, the muscle was set at optimal length (L0) by progressively lengthening the muscle as it was stimulated at a rate of 0.2 Hz, until a peak in developed tension (total tension minus resting tension) was obtained. For the experiments, isometric tetanic contractions were triggered by stimulation with trains of stimuli (4–6 V, 200 ms duration, 50 Hz frequency) at a rate of one contraction every second for 3 min, at which time significant fatigue (isometric tension 60% of initial values) was reached.
For each animal, following a resting baseline, the experiment consisted of a single contraction period to fatigue (Fig. 1). When severe fatigue had been induced, after 3 min of electrically stimulated contractions, the contractions were maintained at the same frequency and caffeine was infused into the arterial inflow just upstream from the muscle. A quantity (2.0 ml) of a stock solution of 100 mM caffeine (dissolved in saline) was infused over 20 s, during a constant bloodflow of 100 ml (100 g)–1 min–1, resulting in an arterial concentration of 5 mM for that period. Ten seconds after the initial bolus, a second larger bolus (4 ml) of caffeine was infused over 20 s in all animals to raise the arterial concentration to 10 mM. Muscle biopsies were obtained by superficial excision of muscle samples with a scalpel at rest, at fatigue and approximately 30 s after caffeine administration (coinciding with peak tension recovery). Biopsy samples were immediately frozen in liquid nitrogen and were subsequently freeze dried for analysis. The experimental gastrocnemius was excised and weighed, and the weight was used to normalize tension per unit of muscle.
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Frozen biopsy samples were freeze dried, and the dried samples were dissected free from any blood and/or connective tissue and ground to a fine powder. This freeze-dried muscle (4–8 mg) was weighed into tubes and extracted with 0.5 M HClO4 (containing 1 mM EDTA) and neutralized with 2.2 M KHCO3. This extract was used for determination of creatine, phosphocreatine (PCr), adenosine-5'-triphosphate (ATP) and lactate by enzymatic spectrophotometric (Beckman DU 640B) assays (Bergmeyer, 1974).
Statistics
All results are presented as means ± S.E.M. All data (muscle tension and muscle metabolite contents) were analysed for statistical differences using a one-way ANOVA with repeated measures. To further test for differences only between the Fatigue and CAF time points, developed tension was also analysed by Student's paired t test. When significant differences were found, a Tukey LSD post hoc test was used. Significance was set at P < 0.05 for all tests.
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Results |
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Figure 1 is a raw tension tracing from a representative muscle showing the reduction in development of tension over the stimulation period. The period of CAF administration is indicated by a filled bar. Following CAF, there is a highly reproducible, albeit modest, increase in developed tension, but the muscle soon displays incomplete relaxation.
Mean (±
S.E.M.) muscle tensions for critical periods of the experiment (Initial, Fatigue and Post-CAF) are shown in Fig. 2. Tetanic tension at the start of contractions (Initial) was 352.3 ± 25.5 kg (kg wet weight)–1 of muscle. Following 3 min of the electrical stimulation protocol, tetanic tension had fallen significantly (P < 0.05) to approximately 61% (209.8 ± 19.9 kg (kg wet weight)–1) of the initial value. After the administration of CAF, developed tetanic tension during electrical stimulation rose (223.2 ± 19.5 kg (kg wet weight)–1; 65% Initial) from the fatigue level, a statistically significant increase of approximately 6% from Fatigue to CAF.
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Table 1 contains the data for the skeletal muscle metabolite contents during the experimental protocol. Gastrocnemius ATP content fell significantly from resting values during the stimulation protocol and was further significantly decreased from fatigue levels approximately 30 s after CAF injection. Skeletal muscle PCr was significantly decreased from resting values at fatigue and was further significantly lowered following CAF administration. Lactate content of the skeletal muscle increased significantly at fatigue compared to resting values but did not change further following CAF.
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Discussion |
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6%) following the administration of pharmacological concentrations (5–10 mM) of caffeine. While this increase in tension development is considerably lower than that often seen in isolated single skeletal muscle cells, which can generate tetanic tension levels approaching prefatigue tension levels immediately when caffeine is applied to the perfusate, this modest increase in tension is likely to be biologically significant and is certainly large enough to be ergogenic when compared to previous studies.
Several studies in humans that used caffeine in an attempt to increase performance during very high-intensity (i.e. sprint-type) exercise, analogous to the severe electrical stimulation protocol of the present study, have also shown small but significant ergogenic effects (Anselme et al. 1992; Wiles et al. 1992; Anderson et al. 2000; Bruce et al. 2000; Doherty et al. 2002, 2004), while others have shown no effect or have been equivocal (Williams et al. 1988; Collomp et al. 1992; Greer et al. 1998; Bell et al. 2001). In the present study, we observed an increase in developed tension of 6% (13 kg (kg wet weight)–1) following CAF administration. While the present study did not demonstrate the magnitude of tension recovery expected based on previous single fibre studies, the significant rise in tension is still provocative in terms of enhancing performance. Certainly at high levels of competition, increases of 6% in muscle performance would be highly beneficial and are in line with the magnitude of effects reported in many studies on short-term high-intensity exercise (see Doherty & Smith, 2005).
In contrast to endurance exercise, the direct mechanism(s) of the ergogenicity of caffeine during short-term intense contractions is still poorly understood. For instance, there is evidence that K+ and/or Na+ handling can be modulated by caffeine. Caffeine has been shown to affect both resting (MacIntosh & Wright, 1995) and exercise (Lindinger et al. 1993; Doherty et al. 2002) plasma K+ concentrations, although this has not been seen in every study (Greer et al. 1998). Likewise, paraxanthine, a caffeine metabolite, has been shown to increase Na+–K+ ATPase activity in the perfused rat hindlimb (Hawke et al. 1999).
While it is possible that oral caffeine ingestion can affect plasma potassium levels, previously it was thought that the doses of caffeine required to affect SR Ca2+ release are above those that can be safely ingested by human subjects (Fredholm, 1995). However, this has been challenged recently, since at least two papers (Tarnopolsky & Cupido, 2000; Plaskett & Cafarelli, 2001) have shown that muscle contractility can be affected during short-term exercise by tolerable doses of caffeine. Tarnopolsky & Cupido (2000) demonstrated that caffeine ingestion inhibited the decline in tetanic tension production in response to 20, but not 40 Hz, stimulation, over a 2 min period and they suggest that this was due to direct effects on Ca2+ metabolism. Similarly, Plaskett & Cafarelli (2001) showed that time to exhaustion during isometric contractions at 50% MVC was increased significantly following caffeine ingestion.
These authors (Plaskett & Cafarelli, 2001) suggested that this increase in endurance is neurally mediated, since tension sensation was attenuated at the beginning of exercise. This is in agreement with other studies (see Doherty & Smith, 2005) that have shown decreased ratings of perceived exertion following caffeine ingestion (MacIntosh & Wright, 1995; Trice & Haymes, 1995; Doherty et al. 2002, 2004) or the analgesic effects of caffeine during exercise (Motl et al. 2003).
Although a significant rise in tension was seen following caffeine administration in the present study, it is unclear why there was not a greater increase in developed tension, given the relative efficacy of higher caffeine doses in modulating tension production via Ca2+ release mechanisms in other models (Frank, 1987; Westerblad & Lannergren, 1987; Allen & Westerblad, 1995; Chin & Allen, 1998). However, several possible explanations for the modest effect of caffeine administration on tension development in the present study must be considered: (1) the caffeine was not taken up into the working muscle or did not reach the target effector(s); (2) this dosage of caffeine was not effective in causing the release of Ca2+ by the SR in this muscle; and/or (3) the cause of fatigue was not strictly related to Ca2+ handling in this model.
When caffeine is applied to single skeletal muscle fibres during an experiment, the entire myocyte is exposed to the full caffeine dose because the cell is bathed in a perfusion medium and therefore effects are seen in <3 s (Allen & Westerblad, 1995; Stary & Hogan, 2000). While the exact concentration of intramuscular caffeine is unknown in the present study, it is likely that the administered caffeine rapidly entered the working muscle at a sufficient concentration. The dose was delivered to the muscle via arterial perfusion during a period of high blood flow to the whole muscle. To our knowledge, however, no one has ever directly perfused contracting fatigued muscle with pharmacological concentrations of caffeine before. In horses, intravenous injection of caffeine resulted in complete equilibration with skeletal muscle within the first sampling period of 5 min, when measured by microdialysis (Chou et al. 2001). Direct evidence that high levels of caffeine did reach the contracting skeletal muscle in the present study is provided by the fact that the fatigued muscle quickly began to show incomplete relaxation following caffeine administration (see Fig. 1), as is often noted in the isolated muscle preparations. Likewise, there was an apparent utilization of both ATP and PCr immediately following caffeine (Table 1).
The effective caffeine concentration during stimulation should have been sufficient to induce SR Ca2+ release. Although the dose of caffeine that will cause contractures and SR Ca2+ release in resting muscle is comparatively high, in the millimolar range (Connett et al. 1983), the initial concentration (5 mM) of caffeine used in the present study was delivered rapidly and directly into the circulation perfusing the working muscle, and was increased rapidly with a subsequent addition to 10 mM.
Connett et al. (1983) showed that the optimal dose for contractures was 20 mM in whole rat soleus, but that twitch potentiation was highest at a caffeine concentration of only 0.5 mM. In the present study, the muscle was continually stimulated during administration of caffeine, so full contractures were not required. Caffeine concentrations of 5 mM will cause significant potentiation in mouse single fibres (Allen & Westerblad, 1995) and strong recovery of tetanic tension following fatigue (Chin & Allen, 1998). Therefore, despite similar doses of caffeine, the level of tension recovery observed in the present study was much less than that seen in other preparations.
The Ca2+-modulating effects of caffeine are not restricted only to amphibians, nor do they occur only in single fibres. However, there is evidence that the mechanism of fatigue is different between fatigue induced by low- and high-frequency stimulation and also between skeletal muscle fibre types. Chin & Allen (1998) showed that tension production recovered with caffeine less after very rapid fatigue than with longer fatiguing runs. A similar observation was made in humans; caffeine ingestion improved endurance during 20 but not 40 Hz stimulation (Tarnopolsky & Cupido, 2000). These authors suggest that the fatigue at 20 Hz is caused by impairment of excitation–contraction coupling and is therefore reactive to caffeine, while higher frequency-induced fatigue is due to other mechanisms. Similarly, caffeine has been shown in single fibres to have no effect on the early stages of fatigue, but is effective during long-term fatiguing contractions (Westerblad & Allen, 1991). This further illustrates that there are likely fatigue processes that are Ca2+ sensitive versus others that are not caused by alterations in Ca2+ handling.
Given that fatigue rate may play a role in the locus of fatigue and response to caffeine, there may also be some differences in the response to caffeine between fibre types (Reading et al. 2004). Single mice fibres are often taken from a muscle (flexor brevis) that contains a very high proportion of fast-twitch fibres (Allen & Westerblad, 1995; Chin & Allen, 1998). In Xenopus single fibres (Westerblad & Lannergren, 1987) both oxidative (type 3) and glycolytic (type 1) fibres showed similar responses to 15 mM caffeine following fatiguing stimulation, but the oxidative fibres required a much more severe contraction protocol to elicit fatigue. The canine gastrocnemius used in the present study is a very oxidative slow-twitch, slow-fatiguing muscle. The preparations in the present study required stimulation of 1 tetanus s–1 over several minutes to elicit fatigue to 60% of initial tension. In response to this intense stimulation, large-scale changes in homeostasis, as evidenced by decreases in muscle ATP and PCr contents, were observed. The resulting rise in free Pi may have either inhibited cross-bridge cycling and subsequent tension generation or decreased Ca2+ release to inhibit tension. The binding of Ca2+ in the SR by free Pi has been strongly implicated in the development of fatigue (Westerblad et al. 2002). It is possible that the canine model in the present study has increased Ca2+ binding with inorganic phosphate or that sensitivity of the myofibrils to released Ca2+ is decreased in this model.
It is well documented that the causes of fatigue in skeletal muscle are multifactorial (Fitts, 1994), and failure of calcium release/resequestration is only one possible cause of reduced tension production. Skeletal muscle fatigue can be caused by accumulation of metabolites such as hydrogen ions or inorganic phosphate (see above). Also, since this in situ preparation, unlike single fibres, relies on electrical stimulation of the sciatic nerve for muscle activation, failure at the neuromuscular junction cannot be excluded.
In summary, while the present data do not completely support our hypothesis that high doses of caffeine administered during contractions to an intact fatigued skeletal muscle would cause increased tension development by muscle in situ similar to that in isolated single muscle fibres, we did observe a small but consistent and statistically significant increase in tension in fatigued muscle. This suggests that, while caffeine may have a direct ergogenic effect on skeletal muscle during fatiguing contractions, processes other than the failure of calcium release and resequestration may be more responsible for the decrease in tension production seen in this model during the present fatigue protocol.
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significantly different from Fatigue (Student's paired t test; P < 0.005).