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00005768-199705000-0000800005768_1997_29_635_martin_metabolism_5report< 74_0_3_3 >Medicine & Science in Sports & Exercise©1997The American College of Sports MedicineVolume 29(5)May 1997pp 635-639Effect of endurance training on fatty acid metabolism during whole body exercise[Basic Sciences: Symposium: Metabollic Adaptations to Endurance Training: Recent Advances]MARTIN, WADE H. IIISection Editor(s): Coggan, Andrew R. ChairDepartment of Medicine, Washington University School of Medicine, St. Louis, MO 63110Submitted for publication January 1996.Accepted for publication March 1996.This work was supported by National Institutes of Health Resource for Biomedical Mass Spectrometry Grant RR-00954; General Clinical Research Center Grant RR-00036; Diabetes Research and Training Center Grant AM-20579; National Institute of Aging Institutional National Research Service Award AG-00078; National Heart, Lung, and Blood Institute (NHLBI) Institutional National Research Service Award HL-07456; and NHLBI Grant HL-41290.Address for correspondence: Wade H. Martin, III, M.D., Division of Cardiology, John Cochran VA Hospital 111A-JC, 915 North Grand, St. Louis, MO 63106.ABSTRACTEndurance exercise training increases fat oxidation during large muscle mass exercise. Although the source of this fat has been thought to be plasma free fatty acids (FFA) released from adipose tissue, the training-induced decrease in lipolytic hormonal responses to exercise is not consistent with this concept. The purpose of this communication is to review findings from our laboratory indicating that, in young healthy subjects, endurance exercise training reduces plasma FFA turnover and oxidation during moderate intensity prolonged 2-leg cycling while simultaneously enhancing depletion of triglycerides from the active musculature. Evidence is presented that metabolism of intramuscular triglycerides can explain the increase in total fat oxidation observed in the trained state during large muscle mass exercise. However, these results may not be applicable to exercise involving small muscle groups, a distinction that is likely to be important in explaining the apparent conflict between our findings and those from other laboratories where experimental conditions were different. In summary, for large muscle mass exercise up to 2 h in duration, plasma FFA are a less important fuel source in the trained state, and intramuscular triglycerides supply the major portion of the increase in oxidized fatty acids.Endurance exercise training enhances the capacity of skeletal muscle to oxidize fatty acids (32). This biochemical adaptation is accompanied by an increase in the proportion of energy derived from metabolism of fat during submaximal exercise(7,21). Historically, nonesterified plasma free fatty acids (FFA) transported intravascularly from remote adipose tissue triglyceride stores have been thought to supply most of the additional fat oxidized in physically-conditioned individuals (3). However, this concept is at variance with the training-induced attenuation of neuroendocrine mechanisms that regulate plasma FFA availability during prolonged exercise (12). The primary purpose of this communication is to review our own findings supporting an alternative hypothesis that endurance exercise training increases the metabolism of intramuscular triglyceride stores and reduces the role of plasma FFA as an energy source under these conditions. Further objectives are to discuss both the physiologic basis for these alterations in substrate supply site and the differences in experimental conditions employed in other investigations that may account for the apparent conflict between these latter results and our own findings.More than 30 years ago studies with radiolabeled tracers demonstrated that plasma FFA are an important source of fat for oxidation during submaximal work(17). However, these investigations also revealed that a significant portion of the infused tracer was not immediately oxidized(19) and that even if complete oxidation did occur, the turnover rate of plasma FFA was not sufficient during a 1- to 2-h bout of moderate intensity exercise to account for the total rate of fatty acid oxidation (17). These findings have been replicated in other laboratories as well under conditions of moderate to high intensity exercise (34). Thus, alternative sources of fatty acids must be implicated to explain the discrepancy between the rates of plasma FFA and total fatty acid oxidation during prolonged strenuous exercise. Other potential sources of fatty acids include the triglycerides stored within and/or among skeletal muscle fibers and those bound to plasma lipoproteins. Both in vitro and in vivo investigations in experimental animals and humans suggest that circulating plasma triglycerides contribute less than 10% of the total fatty acids oxidized during either electrical stimulation of isolated skeletal muscle or during whole body exercise(20,26,38). In contrast, a variety of species of migratory organisms (fish, birds, insects) amass vast amounts of triglycerides within skeletal muscle fibers prior to their journey, and these deposits are absent or severely depleted following arrival(14). Several studies in mammals, including humans, have provided good evidence that triglycerides are broken down in slow-twitch and fast-twitch oxidative skeletal muscle fibers during prolonged exercise(6,9,11,33,36). Thus, these triglycerides are a likely source of fatty acids to explain the discrepancy between the rates of plasma FFA and total fatty acid oxidation during exercise.The first evidence suggesting that endurance exercise training enhances the role of fat as an energy source during prolonged work was based on measurements of the respiratory exchange ratio in expired air(7). Subsequent studies using a single leg training model confirmed these findings in blood samples obtained simultaneously from the arterial and venous circulation during exercise involving both the trained and untrained extremities (21). The latter results were also consistent with the aforementioned investigation demonstrating an increased capacity for fatty acid oxidation in endurance trained skeletal muscle(32). Despite its effect on total fat oxidation, however, physical conditioning elicits concomitant neuroendocrine adaptations that result in reduced concentrations of plasma hormones that regulate lipolysis in adipose tissue during exercise. This effect is greatest for the catecholamines(5,12,16,40) which are the most potent stimulants of lipolysis in the exercising subject(2,12). However, plasma growth hormone and glucagon responses to exercise of the same absolute intensity are also blunted after training (4,12,40). In addition, some investigators have observed that strenuous physical conditioning is associated with a slightly higher plasma insulin concentration during exercise(4,15). Because insulin is considered to be the most important inhibitor of lipolysis (2), a higher insulin concentration would tend to further decrease the rate of fatty acid release from adipose tissue below that resulting from blunted catecholamine and other lipolytic hormone responses to exercise. In conjunction with these hormonal changes, plasma FFA and glycerol concentrations at the same absolute work rate are lower after than before training (40). Based on these data and on the studies indicating that the rate of total fat oxidation is greater in the physically-conditioned state, we hypothesized that endurance exercise training would result in reduced plasma FFA turnover and oxidation during submaximal work of the same absolute intensity and that the increased fatty acids oxidized in the trained state would be supplied by triglycerides localized within skeletal muscle fibers. Investigations conducted to test these hypotheses are described below.Participants in these studies were young healthy subjects (aged 29 ± 2 yr; mean ± SE) who trained 6 d·wk-1. Each daily exercise session consisted of 40-45 min of running or cycle ergometer work. The latter included six 5-min exercise bouts performed 1-3 d·wk-1 at an intensity equivalent to 90-100% peak˙VO2, and exercise sessions on the remaining days were devoted to continuous running or cycle ergometry at 75-80% maximal or peak˙VO2, respectively. This training regimen elicited ≈25% increases in ˙VO2max and peak ˙VO2, expressed in ml·kg-1·min-1 (˙VO2max was ≈8% greater than peak ˙VO2).Metabolic investigations were carried out before and after training to characterize the rates of total fat and carbohydrate oxidation, whole body plasma FFA turnover and oxidation, and skeletal muscle triglyceride and glycogen breakdown during a 90- to 120-min bout of cycle ergometry at a constant work rate of 63 ± 2% pretraining peak ˙VO2. The pre- and post-training dietary intake was similar for the 3 d preceding the cycle ergometry protocol. During the exercise bout, total fat and carbohydrate oxidation rates were determined from the respiratory exchange ratio in expired air. Plasma FFA concentrations and kinetics were quantified using gas chromatography-mass spectrometry (GC-MS) to analyze blood samples obtained during the latter 30-60 min of the prolonged exercise protocol(13,29). These samples were drawn every 5-10 min following initiation of a primed continuous rate infusion of the[1-13C] stable isotope of palmitate, a saturated 16-carbon fatty acid that comprises ≈25% of the total plasma FFA pool. The rates of palmitate and FFA oxidation were assessed by isotope ratio mass spectrometric analyses of 13C isotopic enrichment (30) in expired air CO2 samples obtained over 2-min intervals simultaneous with the collection of blood samples. Percutaneous biopsies of the vastus lateralis muscle were performed prior to and immediately after completion of the prolonged cycle ergometry protocol. Glycogen and triglyceride concentrations were determined in freeze-dried portions of the pre- and post-exercise samples of skeletal muscle that were obtained before and after training. To quantify the breakdown of triglycerides stored within skeletal muscle fibers as opposed to those contained in adipose tissue deposits interspersed among myocytes, the triglyceride concentration was assayed in single fibers isolated by microdissection from the surrounding tissue (22). However, in these young healthy subjects, histochemical staining of OCT-mounted fragments of each biopsy demonstrated no light microscopic evidence of adipose tissue deposits among muscle fibers even before training. The activity of β-hydroxyacyl CoA dehydrogenase assessed in freeze-dried homogenates of the same muscle biposy samples increased 90% after training, indicating that the 12-wk program of running and cycle ergometer exercise markedly enhanced the capacity of the quadriceps muscle to oxidize fatty acids.During the prolonged exercise protocol, oxygen uptake was similar before and after training. However, the ventilatory RER declined progressively with increasing exercise duration on both studies and was lower in the trained state at all time points of the protocol. For the final 30-60 min of cycle ergometry, the average RER was 0.88 ± 0.01 before training and 0.82± 0.01 afterward, consistent with an increase in the role of fat as a fuel source from ≈40% of total caloric expenditure on the initial study to≈60% following completion of the physical conditioning program(Fig. 1). Despite these results, which are similar to findings reported by others (21), there was no evidence that the additional fat oxidized in the trained state was supplied by plasma FFA released from adipose tissue. Based on the stable isotope kinetics data for the final 30-60 min of the prolonged cycle ergometry protocol, the average turnover rate of palmitate, which comprised ≈26% of the total plasma FFA pool, was one-third less after versus before training. The reduced palmitate uptake was accompanied by decreases of 20-32% in average plasma concentrations of palmitate, total FFA, and glycerol on the post-training study. These findings are summarized in Table 1. Because glycerol cannot be re-esterified in adipose tissue, which has a very low activity of the enzyme glycerokinase (25), the plasma glycerol level is considered to be a more reliable indicator of the rate of whole body adipose tissue lipolysis than the plasma FFA concentration. Thus, the glycerol data provide additional supportive evidence that during exercise of the same absolute intensity, whole body adipose tissue lipolysis occurs at a slower rate in the trained state. The training-induced decrease in plasma palmitate and FFA concentrations was associated with a 24% lower rate of palmitate oxidation (Table 1). No change in the ratio of palmitate to total FFA concentrations was observed, suggesting that total FFA oxidation declined by a similar percentage. On both the pre- and post-training studies, the correlation between the plasma palmitate concentration and its rate of oxidation was ≥ 0.90, consistent with previous investigations demonstrating that plasma FFA turnover and oxidation are closely related to the plasma FFA concentration (1,10). In the face of a higher total rate of oxidation of fatty acids, the lower plasma FFA oxidation rate indicates that additional fatty acids metabolized in the trained state originate from a source other than the plasma.Figure 1-Cumulative energy derived from carbohydrate, fat, and all sources during prolonged cycle ergometer exercise before (○) and after training (•). Values are means ± SD.*P < 0.05; **P< 0.01 after vs. before training. Reproduced with permission fromreference 22. Hurley, B. F., P. M. Nemeth, W. H. Martin III, et al. Muscle triglyceride utilization during exercise: effect of training. J. Appl. Physiol. 60:562-567, 1986.TABLE 1. Effect of endurance training on plasma substrate concentrations and palmitate kinetics during prolonged cycle ergometer exercise.The vastus lateralis biopsy data were critical for direct demonstration of the extent to which intramuscular triglycerides could account for both the discrepancy between total fat and plasma FFA oxidation rates and for the extra fatty acids oxidized after physical conditioning. Prior to the prolonged exercise protocol, pooled single freezedried muscle fibers contained ≈60 mmoles triglyceride·kg-1 dry muscle mass, a concentration in the same range as that reported by other investigators(6,9,11) after adjustment for a skeletal muscle water content of ≈75% by mass. The pre-exercise triglyceride content was not altered significantly by physical conditioning. However, prolonged cycle ergometry resulted in a 41% decline in the intramuscular triglyceride concentration after training whereas beforehand the decrease was only 21%. The quantity of triglycerides depleted more than doubled from 12.7 mmoles·kg-1 dry muscle mass on the initial study to 26.1 mmoles·kg-1 in the trained state.The average molecular weight of stored triglycerides for subjects consuming a typical American diet is ≈860 g·mole-1(41). Assuming that cycle ergometer work eliciting a˙VO2 of 1.7 L·min-1 (≈8.3 kcal·min-1) activates ≈8 kg of muscle mass (2 kg dry mass equivalent) and that the energy derived from metabolism of triglycerides is 9.46 kcal·g-1 (31), then the amount of energy yielded from complete oxidation of intramuscular triglycerides (TG) was 207 kcal before training (12.7 mmoles TG·kg-1 dry muscle mass× 2 kg dry muscle mass × 860 mg·mmole-1 TG × 10-3 g·mg-1 × 9.46 kcal·g-1) and 425 kcal afterward (substitue 26.1 for 12.7 mmoles TG·kg-1 dry muscle mass). Based on a total energy expenditure of ≈1000 kcal (8.3 kcal·min-1 × 120 min) for the prolonged cycle ergometry protocol, combustion of intramuscular triglycerides accounted for slightly more than 20% of total energy expenditure in the untrained state and in excess of 40% after completion of the physical conditioning program(Fig. 2). In contrast, the percentage of energy derived from plasma FFA oxidation was slightly under 20% on the baseline study and≈15% after training. Skeletal muscle glycogen breakdown, determined from analysis of the biopsy samples, was 41% lower during the post-versus the pre-training cycle ergometry protocol in conjunction with a decrease in total energy derived from all carbohydrate fuel sources from≈60% of total caloric expenditure before training to ≈40% afterward.Figure 2-Percentage of total energy derived from carbohydrate (CHO), intramuscular triglyceride (IM TG), and plasma fatty acid (FA) fuel sources during prolonged cycle ergometer exercise before and after endurance training. Reproduced with permission from reference 29. Martin, W. H., G. P. Dalsky, B. F. Hurley, et al. Effect of endurance training on plasma free fatty acid turnover and oxidation during exercise.Am. J. Physiol. 265:E708-E714, 1993.Other investigators (6,9,11) have obtained evidence that substantial intramuscular triglyceride breakdown occurs in humans during large muscle mass exercise, particularly at work intensities in the moderate to severe range (i.e., 65-85% ˙VO2max(34) that elicit marked increases in plasma catecholamine concentrations (24). Although endurance exercise training enhances the whole body lipolytic response to catecholamines(27), intramuscular triglyceride breakdown appears to be even more sensitive to β-adrenergic stimulation than lipolysis in adipose tissue (8,36). Augmentation of exercise-induced intramuscular triglyceride utilization with training suggests that the physiologic importance of enhanced lipolytic sensitivity to catecholamines may be greater for skeletal muscle than for adipose tissue, at least during large muscle mass exercise lasting up to 2 h. Nevertheless, studies in our laboratory have demonstrated that physical conditioning does not increaseβ-adrenergic receptor density in human skeletal muscle(28). Thus, the training-induced increase in intramuscular lipolysis during exercise may be mediated by post-receptor adaptations in a manner analogous to that reported in rat adipose tissue(39). Further investigations will be necessary to characterize the mechanism of this effect in human skeletal muscle.Some exercise physiologists are skeptical that intramuscular triglycerides are an important source of fatty acids for oxidation during exercise and remain convinced that the additional fat oxidized in the trained state is supplied by plasma FFA released from adipose tissue (35). This notion is based largely on evidence obtained from cross-sectional studies(17,18), some of which employed single leg thigh exercise (37) that elicits little sympathoadrenal stimulation in comparison with the 10-fold-or-more elevation of plasma catecholamine concentrations that occurs with running or 2-leg cycling at moderate to high intensities (24). Because the sympathoadrenal system is the most potent stimulant of lipolysis during exercise (2,12), responses of plasma FFA kinetics to single leg thigh kicking may not be applicable to exercise that involves a large muscle mass. The absence of intramuscular triglyceride breakdown observed in a recent longitudinal training study using the single leg thigh extension model may also be a result of the failure of catecholamines to rise significantly above the resting level in the latter investigation(23). An increased rate of lipolysis was observed during the thigh extension protocol after 2 h of single leg kicking (15-20%˙VO2max) that was preceded by an overnight fast(37). However, in this study the higher rate of plasma FFA uptake and oxidation in trained versus untrained subjects occurred in the context of a 50% greater exercise work rate and plasma epinephrine concentration than was the case for the sedentary group(37). In contrast, our investigations were conducted during 2-leg cycling which elicits a 6-7 fold increase in plasma catecholamine concentrations at 60% peak ˙VO2 before training versus a 1-3 fold elevation at the same absolute work rate after training(40). The cycling protocol used in our studies did not exceed 2 h in duration, and the subjects ingested a light meal several hours before exercising. 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IIIBasic Sciences: Symposium: Metabollic Adaptations to Endurance Training: Recent Advances529InternalMedicine & Science in Sports & Exercise20043691602-1609SEP 2004Effects of Preexercise Carbohydrate Ingestion on Mountain Bike PerformanceCRAMP, T; BROAD, E; MARTIN, D; MEYER, BJhttp://journals.lww.com/acsm-msse/Fulltext/2004/09000/Effects_of_Preexercise_Carbohydrate_Ingestion_on.21.aspx381http://pdfs.journals.lww.com/acsm-msse/2004/09000/Effects_of_Preexercise_Carbohydrate_Ingestion_on.00021.pdf