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effects of acute exercise from the effects of exercise train- ing. There seems to be consistency with regard to the up-regulating effect of acute exercise on UCP3 levels. Two hours of treadmill running induced a 252% increase in UCP3 mRNA in white gastrocnemius and a 63% increase in red gastrocnemius (65). It has also been shown that the extent of increase in UCP3 depends on the duration of exercise; after only 30 minutes of exercise, UCP3 mRNA increased slightly, but significantly (66). When exercise was continued for 200 minutes, the induction in UCP3 was much more prominent, reaching levels of running (66). In this study, increased mRNA matched al- most perfectly with increased protein expression (66). In humans, 4 hours of cycling exercise induced an increase in transcriptional activity of UCP3 of almost 600% (67). The extent of increase was linked to the exercise duration, show- ing the most prominent induction after 4 hours of exercise (67). the case, one would expect exercise training to result in increased UCP3 protein levels. Strikingly, rats housed for 9 weeks in cages equipped with running wheels, permitting increased spontaneous activity, had UCP3 levels similar to their sedentary counterparts (65). When subjected to an endurance training program of stepwise incremental load for 4 weeks followed by another 4 weeks at the same level of training volume and intensity, UCP3 was significantly down-regulated in soleus and anterior tibialis muscle, with the most prominent decrease in the latter (less oxidative) muscle (68). In endurance-trained humans, UCP3 mRNA levels were significantly lower compared with physically fit but untrained controls (maximal power output, 5.6 vs. 3.9 W/kg body weight) (69). Subsequently, observations of decreased UCP3 mRNA in subjects after endurance training or in trained subjects were extended to the protein level (70,71). skeletal muscle within 72 hours after cutting the sciatic nerve (65). Comparable observations were made in skeletal muscles of tetraplegic humans, showing increased UCP3 mRNA levels, which returned to control levels after an 8-week training program of electrically stimulated cycling exercise (72). or in endurance-trained athletes indicate that it is not exer- cise per se that affects UCP3 expression. To distinguish the effects of exercise as such from the exercise-induced in- crease in fatty acid levels, we monitored UCP3 mRNA expression before and 4 hours after a 2-hour cycling exer- were given only plain water during and after exercise. This protocol resulted in substantial increases in plasma FFA levels, peaking to 1000 ercise period ( 800 to 900 body weight, in a 20% solution) before exercise and doses of 0.35 g/kg body weight, in a 10% solution, during and after exercise. Glucose ingestion successfully suppressed lipolysis as indicated by the lack of effect of exercise on plasma FFAs and the decline in fat oxidation observed in the glucose trial (73). Under both conditions, subjects were able to maintain euglycemia throughout and after exercise. We showed that, only in the fasting trial, with very high levels of fatty acids present, UCP3 mRNA was increased 4 hours after exercise, whereas in the glucose condition, with no changes in fatty acid levels but with exercise of the same duration and work load, no effect on UCP3 mRNA was detected (73). Thus, we concluded that observations of increased UCP3 mRNA after acute exercise are mediated by prolonged increased FFA levels and not by another factor intrinsically related to physical exercise. ing-induced increase in the transcriptional rate of UCP3, but not other genes related to lipid metabolism like lipoprotein lipase, long-chain acylCoA dehydrogenase, or carnitine palmitoyl transferase 1 (74). The authors suggested that fasting and exercise might trigger opposing regulatory mechanism(s) (74). This observation may indicate that it is not just FFA levels regulating UCP3 expression but that regulation of UCP3 expression is more delicate. cause of elevated plasma FFA levels. Interestingly, the study by Hildebrandt and Neufer (74) indicates that if fatty acid levels are increased at the onset of exercise, exercise may attenuate the increase in UCP3 mRNA. In this respect, it is important to note that initiation of exercise with ele- vated plasma FFA levels readily results in oxidation of fatty acids and consequently lower plasma fatty acid levels. This may indicate that the balance between fatty acid delivery to the cell and mitochondrial oxidation of fatty acids plays a crucial role in regulation of UCP3 expression. Along these lines, the decline in UCP3 content observed in trained individuals or after training can be explained by the train- ing-induced increase in fat oxidative capacity. Indeed, we previously showed that UCP3 mRNA correlated negatively with maximal aerobic capacity (69). Although we are not aware of any studies aiming to examine the decrease in UCP3 in trained subjects in relation to mitochondrial cou- pling, indirect negative associations between UCP3 mRNA and mechanical efficiency point toward improved energy |
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