Skeletal muscle is the major producer of lactic acid in the body, but its oxidative fibres also use lactic acid as a respiratory fuel. The stereoselective transport of L‐lactic acid across the plasma membrane of muscle fibres has been shown to involve a proton‐linked monocarboxylate transporter (MCT) similar to that described in erythrocytes and other cells. This transporter plays an important role in the pH regulation of skeletal muscle. A family of eight MCTs has now been cloned and sequenced, and the tissue distribution of each isoform varies. Skeletal muscle contains both MCT1 (the only isoform found in erythrocytes but also present in most other cells) and MCT4. The latter is found in all fibre types, although least in more oxidative red muscles such as soleus, whereas expression of MCT1 is highest in the more oxidative muscles and very low in white muscles that are almost entirely glycolytic. The properties of MCT1 and MCT2 have been described in some detail and the latter shown to have a higher affinity for substrates. MCT4 has been less well characterized but has a lower affinity for L‐lactate (i.e. a higher Km of 20 mM) than does MCT1 (Km of 5 mM). MCT1 expression is increased in response to chronic stimulation and either endurance or explosive exercise training in rats and humans, whereas denervation decreases expression of both MCT1 and MCT4. The mechanism of regulation is not established, but does not appear to be accompanied by changes in mRNA concentrations. However, in other cells MCT1 and MCT4 are intimately associated with an ancillary protein OX‐47 (also known as CD147). This protein is a member of the immunoglobulin superfamily with a single transmembrane helix, whose expression is known to be increased in a range of cells when their metabolic activity is increased.

Strength training represents an alternative to endurance training for patients with type 2 diabetes. Little is known about the effect on insulin action and key proteins in skeletal muscle, and the necessary volume of strength training is unknown. A total of 10 type 2 diabetic subjects and 7 healthy men (control subjects) strength-trained one leg three times per week for 6 weeks while the other leg remained untrained. Each session lasted no more than 30 min. After strength training, muscle biopsies were obtained, and an isoglycemic-hyperinsulinemic clamp combined with arteriofemoral venous catheterization of both legs was carried out. In general, qualitatively similar responses were obtained in both groups. During the clamp, leg blood flow was higher (P < 0.05) in trained versus untrained legs, but despite this, arterio-venous extraction glucose did not decrease in trained legs. Thus, leg glucose clearance was increased in trained legs (P < 0.05) and more than explained by increases in muscle mass. Strength training increased protein content of GLUT4, insulin receptor, protein kinase B-␣/␤, glycogen synthase (GS), and GS total activity. In conclusion, we found that strength training for 30 min three times per week increases insulin action in skeletal muscle in both groups. The adaptation is attributable to local contraction-mediated mechanisms involving key proteins in the insulin signaling cascade. Diabetes 53: 294 -305, 2004 I t is an established finding that aerobic endurance training increases insulin action in patients with type 2 diabetes (1-9), and also that the effect of training is predominantly located to the skeletal muscle (10). Glycemic control also improves along with training (11). Furthermore, with the increased insulin action, the need for insulin to mediate the clearance of a given amount of glucose is lessened. Thus, the need for exogenous insulin or oral hypoglycemic agents is decreased (12). Apart from the beneficial effects on glucose metabolism, physical training also exerts marked improvement on most of the components of the metabolic syndrome (13).Despite the scientific evidence of the therapeutic effect of exercise training, it is a well-known clinical experience that it is often very difficult to engage the patients into taking exercise on a regular basis, and even if one succeeds, the adherence is disappointing. The majority of patients with type 2 diabetes are overweight and have usually been sedentary for the major part of their lives. For many reasons, both psychological and sociological, they are not likely to take up endurance training. Obesity may even be a physical problem in the performance of exercise, especially endurance-type exercises.For patients with type 2 diabetes, resistance training probably represents an attractive exercise modality, but little is known about the overall effect, and the effect in muscle has not been studied. Furthermore, dose-response studies on resistance training effects have not been carried out. To provide support for the recommendations about...

The newly cloned proton-linked monocarboxylate transporter MCT3 was shown by Western blotting and immunofluorescence confocal microscopy to be expressed in all muscle fibers. In contrast, MCT1 is expressed most abundantly in oxidative fibers but is almost totally absent in fast-twitch glycolytic fibers. Thus MCT3 appears to be the major MCT isoform responsible for efflux of glycolytically derived lactic acid from white skeletal muscle. MCT3 is also expressed in several other tissues requiring rapid lactic acid efflux. The expression of both MCT3 and MCT1 was decreased by 40 -60% 3 weeks after denervation of rat hind limb muscles, whereas chronic stimulation of the muscles for 7 days increased expression of MCT1 2-3-fold but had no effect on MCT3 expression. The kinetics and substrate and inhibitor specificities of monocarboxylate transport into cell lines expressing only MCT3 or MCT1 have been determined. Differences in the properties of MCT1 and MCT3 are relatively modest, suggesting that the significance of the two isoforms may be related to their regulation rather than their intrinsic properties.Lactic acid is both a major fuel for skeletal muscle ("red" oxidative fibers) and a major metabolic end product ("white" glycolytic muscles). Even oxidative fibers become net lactic acid exporters when oxygen supply cannot meet demand, and glycolysis is stimulated to maintain ATP supplies. Fatigue occurs when lactic acid builds up within the myocyte. This causes intracellular pH (pH i ) to drop, inhibiting both glycolysis and contractile activity (1, 2). In the extreme case further muscle activity is totally prevented, a phenomenon used to advantage by anglers "playing" their fish to exhaustion. The transport of lactic acid out of skeletal muscle fibers is essential if such intracellular accumulation of lactic acid is to be prevented.Better removal of lactic acid from the muscle fibers might improve athletic performance during intense exercise and enable better muscle function and subsequent recovery under pathological conditions such as inherited mitochondrial diseases, hypoxia, and reperfusion following a period of ischemia.Transport of lactic acid into skeletal muscle fibers for oxidation is thought to be mediated by the proton-linked monocarboxylate transporter (MCT) 1 isoform MCT1 whose expression correlates with the oxidative capacity of muscle fibers and is increased following chronic muscle stimulation (3, 4). However, sarcolemmal membranes of muscle fibers that are primarily glycolytic do not contain significant amounts of MCT1 yet transport lactic acid by means of a saturable carrier that is inhibited by known inhibitors of MCT1 (3,5,6). These data imply the presence of another MCT isoform in such glycolytic fibers. MCT kinetics in heart (7-9) and liver (10) cells also imply the existence of other MCT isoforms, and this conclusion has been confirmed by cloning and sequencing studies.The first MCT isoform (MCT1) was cloned from Chinese hamster ovary cells (11) and has since been cloned and sequenced from huma...

Skeletal muscle and most other tissues possess a membrane transport system mediating a coupled lactate and H+ translocation. Muscle possesses several lactate-proton transporter isoforms of which two have been cloned; however, the main isoform remains to be identified. The isoforms may have different properties and functional roles, but these have not been specifically characterized. The distribution of lactate-proton transport capacity in skeletal muscle is fiber type dependent, with a higher capacity in slow-twitch fibers compared with fast-twitch fibers. During intense muscle activity and in the recovery period, the lactate and H+ effluxes are mainly mediated by the lactate-proton transporter, which reduces the accumulation of lactate in muscle as well as the drop in internal pH suggested to be involved in muscle fatigue. Thus the lactate-proton transporter is of functional importance for pH regulation in association with muscle activity. This carrier is also important for lactate uptake into resting muscle and other tissues; therefore, the carrier distribution is important for the fate of lactate in the body. In addition, the capacity of the lactate-proton transporter can be increased by intense training and is reduced by inactivity; thus the lactate-proton transporter can undergo adaptive changes.

SUMMARY1. Eight subjects performed one-legged, dynamic, knee-extensor exercise, first at 10 W followed by 10 min rest, then at an intense, exhaustive exercise load (65 W) lasting 3-2 min. After 60 min recovery, exercise was performed for 8-10 min each at 20, 30, 40 and 50 W. Measurements of pulmonary oxygen uptake, heart rate, blood pressure, leg blood flow, and femoral arterial-venous differences of oxygen content and lactate were performed as well as determination of ATP, creatine phosphate (CP) inosine monophosphate (IMP) and lactate concentrations on biopsy material from the quadriceps muscle before and immediately after the intense exercise, and at 3, 10 and 60 min into recovery.2. Individual linear relations (r = 0-95-1-00) between the power outputs for submaximal exercise and oxygen uptakes (leg and pulmonary) were used to estimate the energy demand during intense exercise. Pulmonary and leg oxygen deficits determined as the difference between energy demand and oxygen uptake were 0-46 and 0-48 1 (kg active muscle)-', respectively. Limb and pulmonary oxygen debts (oxygen uptake during 60 min of recovery -pre-exercise oxygen uptake) were 0-55 and 1P65 1 (kg active muscle)-', respectively. J. BANGSBO AND OTHERS for less than 10 % of the leg oxygen debt, and lactate elimination including resynthesis of glycogen for another 25 %. 5. The anaerobic energy contribution during the first half-minute of intense exercise accounted for 80 % of the total energy turnover and this decreased to 30 % during the last phase of the exercise. The mean anaerobic energy contribution was 45 % for the 3-2 min of exhaustive exercise.6. The maximal anaerobic capacity of human muscle amounted to the equivalent of close to 051 02 kg-1. An extrapolation to whole-body anaerobic capacity cannot be made, as the magnitude of neither [ATP] and [CP] reduction nor lactate release from the muscle is likely to be comparable in all muscles when the human performs whole-body exercise.7. When exercising with a small muscle group the measurements of (i) oxygen deficit and (ii) energy yield, based on metabolic alterations of the active muscle, give similar values for the anaerobic energy release. The dominant fraction of the elevation in recovery oxygen uptake (i.e. oxygen debt) is not accounted for, as normalization of nucleotides, CP, muscle and blood lactate only amounted to about 3 of the debt measurement. Elevation in hormones such as adrenaline and noradrenaline as well as temperature do not appear to play a role in the high recovery oxygen uptake in the present study.