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1 Copenhagen Muscle Research Centre, University of Copenhagen, Denmark2 The August Krogh Institute, University of Copenhagen, Denmark3 Department of Medical Physiology, The Panum Institute, University of Copenhagen, Denmark
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(Received 17 December 2003;
accepted after revision 13 January 2004;
first published online 14 January 2004)
Corresponding author F. Dela: Department of Medical Physiology, The Panum Institute, University of Copenhagen, Blegdamsvej 3, DK 2200 Copenhagen N, Denmark. Email: f.dela{at}mfi.ku.dk
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Introduction |
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In addition, we have consistently observed that the release of lactate during resting, hyperinsulinaemic conditions is significantly higher from endurance-trained compared with untrained skeletal muscle (Dela et al. 1992, 1995b). This finding is in accordance with the positive correlation to the rate of glucose disposal (Yki-Jarvinen et al. 1990), as training enhances insulin-mediated glucose uptake in skeletal muscle.
The intracellularly produced lactate leaves the cell via via simple diffusion and two monocarboxylate transporter proteins, MCT1 and MCT4 (Wilson et al. 1998). The density of MCT1 and/or MCT4 proteins in human skeletal muscle is elevated after a period of endurance training (Bonen et al. 1998; Pilegaard et al. 1999; Dubouchaud et al. 2000), although some training studies found no increase in MCT4 (Dubouchaud et al. 2000; Evertsen et al. 2001). Furthermore, lactate transport capacity is reduced in denervated (Pilegaard & Juel, 1995) and in hypokinetic (hindlimb suspension) (Dubouchaud et al. 1996) rat muscle and in humans with spinal cord injuries (Pilegaard et al. 1998). Thus, the lactate transport capacity seems to be related to the training status of the muscle.
In patients with type 2 diabetes, resting blood lactate concentrations may be elevated (Reaven et al. 1988; Chen et al. 1993; Avogaro et al. 1996) but studies on MCT1 and MCT4 content are lacking. Obese Zucker fa/fa rats with normal glucose but increased insulin plasma concentrations have increased plasma lactate concentrations and decreased fibre-type-dependent muscle MCT4 (to some extent also MCT1) content compared with control rats (Py et al. 2001). In streptozotocin (STZ)-induced diabetes (which is a model of type 1 diabetes), resting blood lactate is reported to be elevated (Py et al. 2002; Enoki et al. 2003), and STZ-induced diabetes in rats has also been found to decrease skeletal muscle lactate transport (Py et al. 2002). In these studies the STZ-induced diabetes was not associated with changes in MCT1 and MCT4 in skeletal muscle (Py et al. 2002), whereas a recent study in STZ-induced diabetic rats found a selective reduction in MCT1 and MCT4 density in some skeletal muscles and in the heart (Enoki et al. 2003). The reduction in transporter protein content was alleviated by endurance treadmill training (Enoki et al. 2003).
On the basis of this and our previous observations of increased lactate release from endurance-trained muscle during hyperinsulinaemic clamp conditions, we expected that lactate release would also be increased in strength-trained muscle. We hypothesized that strength training would increase the protein contents of MCT1 and MCT4 in human skeletal muscle – in line with the known effects of training on GLUT4 protein content (Dela et al. 1993, 1994; Holten et al. 2004). We used a one-legged training protocol, a model which is robust against biological variation and which has previously been used to demonstrate the effect of endurance training on skeletal muscle insulin sensitivity (Dela et al. 1995b). Secondly, we obtained muscle biopsies from both legs and analysed the MCT1 and MCT4 protein content.
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Methods |
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Ten male Caucasian patients with type 2 diabetes (Type 2) and seven male Caucasian healthy control subjects (Control) without a family history of type 2 diabetes participated in the study, which was approved by the ethical committee of Copenhagen and Frederiksberg (KF 01-204/99). All of the subjects gave written, informed consent.
The time since diagnosis of type 2 diabetes ranged from 2 to 11 years. All the patients were treated with diet recommendations and in addition some patients were treated with 1000 mg day–1 tolbutamide (n=2), 7 mg day–1 glibenclamide (n=1), 1700 mg day–1 metformin (n=1), 5mg day–1 amlodipin (n=1), and 200µg day–1 cerivastatin (n=1). On the experimental day no medication was taken. None of the control subjects took any medication. The patients were similar to the control subjects with respect to age (62±2 versus 61±2 years), body weight (85±5 versus 78±3 kg), but the height (172±1 versus 178±2 cm (P<0.05)) was lower in Type 2 compared with Control. Thus, body mass index (BMI) was different (P<0.05) between Type 2 (28.3±1.2 kg m–2) and Control (24.5±0.8 kg m–2). Resting arterial blood pressure was 157±10 mmHg (systolic) and 82±6 mmHg (diastolic), and 147±6 and 74±3 mmHg, in Type 2 and Control, respectively). Other characteristics of the subjects are given in Table 1.
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Training programme
All subjects participated in a 6 week strength-training programme. The focus of the programme was to have one leg performing strength-training exercises, while the other leg remained sedentary. The leg to be trained was chosen by drawing lots.
Training sessions were all supervised and took place three times a week, with each training session lasting no more than 30min. This included time for a warm-up, which involved light exercises for the upper body plus 10–12 repetitions with a light load on each leg followed by a 2min rest period. During the first and the last training session the subject's three-repetition maximum (3RM) was measured. One RM was calculated as 106% of the measured 3RM for each leg exercise (leg press, knee extension, hamstring curl). During the first 2 weeks of the training, the subjects performed 3 sets of 10 repetitions, utilizing a load equivalent to 50% of one RM. During weeks 3–6 the subjects performed 4 sets of 8–12 repetitions utilizing 70–80% of one RM. For the last 2 weeks of the 6 week period the load was adjusted so that all sets were exhaustive within 8–12 repetitions. The subjects rested for >90 s between sets, and for >2 min between lifting stations (different exercise equipment).
Experimental procedure
On the day after the last training session (i.e. in the trained state, ‘between’ sessions) an isoglycaemic, hyperinsulinaemic clamp, combined with arterio-venous catheterization of both legs, was performed. Having fasted since midnight (only water allowed thereafter), the subjects arrived in the laboratory in the morning. Leg volume (by water displacement) and thigh circumference (20 cm proximal to the patella) were measured. The subjects were weighed, their height was measured and then they were placed in a bed. Electrocardiogram (ECG) and heart rate were monitored by precordial electrodes. A catheter was inserted into a medial cubital vein for infusions of insulin and glucose (20%), and an arterial cannula was inserted into the radial or brachial artery for the sampling of blood and continuous monitoring of blood pressure. Teflon catheters were inserted into both femoral veins for the sampling of blood and measurement of leg blood flow (thermodilution technique) as previously described (Dela et al. 1995a).
After basal measurements, a two-step, sequential isoglycaemic, hyperinsulinaemic clamp was started. For each subject an 50 ml insulin infusate was prepared for each clamp step (clamp steps I and II) from insulin (Actrapid, Novo, Copenhagen, Denmark, 100IU ml–1), saline, and 2.5 ml of the subject's own plasma. At each clamp step insulin was given as a 2 ml bolus followed by constant infusion (rates of 28 and 480 mU min–1 m–2) for 120min each. Plasma glucose was maintained at isoglycaemia, i.e. the glucose concentration was kept at individual fasting plasma glucose concentrations throughout the clamp by frequent arterial blood samples analysed on an automatic glucose analyser (YSI 2300, Yellow Springs Instruments, USA), with subsequent adjustment of the glucose infusion rate. Arterial and femoral venous blood samples were drawn and blood flow measurements were made (3–5 single measurements in each leg at each time point) at 30 and 15min before start, and then after 90, 105 and 120min from the start of each clamp step. In the basal state – before initiation of the clamp – muscle biopsies were obtained from both legs.
Calculations and analytical procedures
Whole body glucose clearance rates during the final 30min of each clamp step were calculated as the glucose infusion rate divided by the glucose concentration in plasma. Leg balance of lactate was calculated as arterio-venous concentrations in whole blood difference multiplied by blood flow. Leg balance data are expressed relative to leg mass, assuming that the volume of one litre corresponds to one kilogram of leg. All samples were stored at –20°C until analysis, except for C-peptide and muscle biopsies which were stored at –80°C.
Blood lactate was measured on an automatic glucose/lactate analyser (YSI 2300, Yellow Springs International) with Triton-X added to the analysing buffer solution (Foxdal et al. 1992).
After excision the muscle biopsies were quickly cleaned from visible blood and fat and frozen immediately in liquid nitrogen. Biopsies were stored at –80°C until analysed. Before measurement of lactate dehydrogenase (LDH) activity (Roche/Hitachi 912 analyser) and lactate concentrations (Olsen, 1971), biopsies were freeze-dried, and connective tissue and fat tissue removed. Lactate concentrations in muscle are given as mmol (kg dry weight)–1, and thus contain both intracellular lactate and lactate molecules in the evaporated extracellular water.
MCT1 and MCT4 detection in total crude membranes (Western blotting)
The 30mg of each muscle sample was homogenized in sucrose buffer (250mM sucrose, 30mM Hepes, 2mM EGTA, 40mM NaCl, 2mM phenylmethylsulphonyl fluoride (PMSF), pH 7.4) using a Polytron 2100 and centrifuged at 1000 g for 5 min. The supernatant was spun at 190 000 g for 90min at 4°C in a high-speed centrifuge equipped with a swing-out bucket rotor. The resulting pellet (corresponding to the membrane fraction) was re-suspended in Tris-SDS (10mM Tris, 4% SDS, 1mM EDTA, 2mM PMSF, pH 7.4) and protein content determined with a bovine serum albumin (BSA) standard (DC protein assay, Bio-Rad). Samples were mixed 1 : 1 with sample buffer containing 10% SDS, 5% glycerol, 10mM Tris-HCl, 1mM EDTA, 10mM dithiothreitol, and subjected to SDS–PAGE (ExcelGel 8–18% gradient gel). The amount of protein per lane was 6µg. The separated proteins were electro-blotted onto a Millipore Immobilon-P polyvinylidene difluoride membrane. This membrane was blocked by 1% BSA, 0.5% low fat dry milk, 0.1% Tween-20, and incubated with the primary antibody diluted in a BSA-containing buffer. After treatment with the horseradish peroxidase (HRP)-coupled secondary antibody, it was repeatedly washed with distilled water, 0.05% Tween-20 and 1 M NaCl. The membrane was then incubated with ECL or ECL + reagents (Amersham) and visualized on film. Scanning the film and analysing band intensities with SigmaGel software yielded quantities of protein. Membranes were used for more than one primary antibody taking advantage of the different protein molecular weights. Some membranes were re-used after treatment with Re-Blot Plus (Chemicon Int.). The antibodies to the human lactate–H+ cotransporter isoforms MCT1 and MCT4 were provided by Professor A. P. Halestrap (Bristol, UK; Price et al. 1998).
Statistics
Results are presented as mean±S.E.M. Analysis of variance for repeated measures was used to detect differences in lactate balances across the trained and the untrained legs in the two groups. When a significant main effect was observed, the Student-Newman-Keuls test was used post hoc. Other comparisons were tested with Student's t tests, paired and unpaired as appropriate. The SigmaStat version 2.03 software package was used for all statistical calculations. P<0.05 was considered significant in two-tailed testing.
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Results |
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After the strength-training programme, leg volumes and sizes were similar for Control and Type 2, with slightly higher values in T versus UT legs (Table 2). Muscle strength and the training-induced improvements were similar in the two groups (Table 2).
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Insulin infusion elevated plasma insulin concentrations to 377±26 and 270±20 pmol l–1, in Type 2 and Control, respectively (P<0.05), in clamp step I, while at clamp step II plasma insulin concentrations were 12 453±856 and 11 066±874 pmol l–1 (P > 0.05), in Type 2 and Control, respectively.
Whole body glucose clearance rates were lower in Type 2 compared with Control (2.5±0.6 and 8.9±0.7 versus 5.7±0.9 and 14.4±0.7 ml min–1 (kg body weight)–1 in the two clamp steps, respectively; both P<0.05).
Lactate concentrations and release from trained and untrained legs
Arterial concentrations of lactate were similar between Control and Type 2 before insulin infusion began and the concentrations also increased (P<0.05) similarly in the two groups with insulin infusion (Fig. 1).
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Insulin infusion increased leg blood flow in both groups, and leg blood flow was higher in Control compared with Type 2 (main effect: P=0.034) (Table 3).
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Biopsy data
MCT1. MCT1 content in the skeletal muscle was significantly lower in Type 2 compared with Control (P = 0.04; values from trained and untrained muscle pooled within each group; Fig. 2). Training resulted in +48% and +75% higher MCT1 content in Control and Type 2, respectively (both P<0.05; Fig. 2).
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Lactate. Lactate concentration in the untrained muscle was significantly lower in Control compared with Type 2 (P<0.05), but with training the intramuscular lactate concentration increased (P<0.05) to levels seen in Type 2 (Fig. 3). No effect of training was seen in Type 2 (Fig. 3).
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Discussion |
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The difference in MCT1 content in the untrained skeletal muscle between the patients with type 2 diabetes and the healthy controls was substantial, 35%. MCT1 is considered to be the major monocarboxylate transporter in the oxidative slow-twitch muscle fibres, while the MCT4 isoform is found mainly in the glycolytic fast-twitch fibres (Wilson et al. 1998). However, this preferential location of the transporters cannot explain the difference in MCT1 content between Type 2 and Control in the present study, because – as reported elsewhere – the ratio of slow versus fast-twitch fibre types was similar in these subjects (and between trained and untrained muscle) (Holten et al. 2004). The lower MCT1 content in Type 2 versus Control also cannot be explained by differences in leg muscle strength between the two groups. Furthermore, the MCT1 content in the muscles (Fig. 2) does not seem to vary in parallel with the intracellular lactate concentrations (Fig. 3) or with blood lactate concentrations (Table 1). Although the diminished MCT1 content in untrained muscle in Type 2 versus Control might fit well with the increased intracellular lactate concentration in the former versus the latter, the training-induced increase in MCT1 content in Control (Fig. 2) was not accompanied by a decrease in intracellular lactate concentration (Fig. 3). The present findings in humans are not in agreement with data from known animal studies. Thus, in the insulin-resistant obese Zucker fa/fa rat the densities of muscle MCT1 and MCT4 are both decreased in the red tibialis anterior muscle, and MCT4 also in the extensor digitorum longus and soleus muscles (Py et al. 2001). In animals with STZ-induced diabetes both unchanged (Py et al. 2002) and decreased (Enoki et al. 2003) MCT1 and MCT4 content is found in skeletal muscle. However, the animal model used does not perfectly mimic human type 2 diabetes. For example in the obese Zucker fa/fa rats hyperglycaemia was not present (Py et al. 2001) and in the STZ-treated rats circulating glucose concentration was elevated by a factor of 3–4 while body weights were less than control animals (Py et al. 2002; Enoki et al. 2003). Altogether, we are unable to explain the difference in MCT1 content between Type 2 and Control subjects and this finding warrants further (human) studies.
It is known that high intensity endurance training increases MCT1 content in healthy, untrained people. Thus, Dubouchaud et al. used bicycle ergometer training for 1 h day–1, 6 days week–1 at 75% of 
for nine weeks + interval training and obtained a 
90% increase (Dubouchaud et al. 2000), Bonen et al. also used bicycle ergometers but for 2 h day–1 at 60% of 
for 7–8 days and obtained an 18% increase (Bonen et al. 1998), and Pilegaard et al. used 3–5 sets of intermittent one-legged knee extensor exercise training for 3–5 days week–1 and obtained a 70% increase (Pilegaard et al. 1999). However, in already highly trained athletes no effect of moderate or high-intensity training was found on MCT1 content (Evertsen et al. 2001). With the present study, it can now be concluded that the type of training is not of importance for the increase in MCT1 content in skeletal muscle.
Apart from the type of training, it is remarkable that the quite low training effort used in the present study (3 sessions week–1 for 6 weeks, with each session lasting no more than 30 min), elicited increases in MCT1 content comparable to those using high intensity endurance training increase (Bonen et al. 1998; Pilegaard et al. 1999; Dubouchaud et al. 2000). In fact, the present strength-training programme was moderate in intensity, using low weights but a high number of repetitions. This was done in order to avoid exercises which would substantially increase blood pressures.
What is then the signal behind the training-induced adaptation of MCT1 content? Due to the model used in the present study, humoral blood-borne factors can be excluded. The adaptation of MCT1 content must be based upon local, contraction-induced factors. One such factor could be the local formation of lactate during the actual training bouts. Although we did not measure blood lactate concentrations during the training sessions in the present study, it is reasonable to believe that blood lactate concentrations did not reach the 5–6 mmol l–1 seen in the study by Pilegaard et al. (1999) or which must have been present in the previously used high intensity endurance training/interval training programmes (Bonen et al. 1998; Dubouchaud et al. 2000). However, substantial lactate accumulations in the trained muscle may not be necessary for mediating increases in MCT gene transcription and protein expression, but the signal basically remains unknown – as with the training-induced increase in GLUT4.
In this study we have confirmed our previous findings of increased lactate release from trained muscle during insulin stimulation (Dela et al. 1992, 1995b) (Fig. 1). The increased release was not dependent on the observed larger blood flow rates in the trained leg, as the difference between the trained and the untrained leg in arterial–femoral venous differences attained statistical significance. The reason for the enhanced lactate release from trained muscle is most likely a consequence of increased glucose uptake rates in trained muscle and subsequent enhancement of glycolysis, in agreement with earlier reports (Yki-Jarvinen et al. 1990), and further supported by the positive correlation between lactate release and glucose uptake rates found the present study (Fig. 4). The MCT1 and MCT4 densities did not correlate with leg lactate balances before or during insulin stimulation.
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In summary, in this study we report that MCT1 content is reduced in skeletal muscle from patients with type 2 diabetes, but strength training normalizes the reduction. In healthy people, but not in patients with type 2 diabetes, MCT4 increases in response to strength training. Lactate release from trained muscle is increased during hyperinsulinaemia, and lactate release rates from muscle are positively correlated with glucose uptake rates.
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References |
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Significant difference (P<0.05) from previous value. B, venous–arterial differences in blood lactate across trained (hatched columns) and untrained (open columns) legs.*Main effect of training in both Control (P=0.014) and Type 2 (P<0.001). C, lactate balance across the legs. Positive value=release.*Main effect of training in both Control and Type 2 (both P<0.05).
