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Am J Physiol Regul Integr Comp Physiol 281: R760-R769, 2001;
0363-6119/01 $5.00
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Vol. 281, Issue 3, R760-R769, September 2001

Postexercise fat intake repletes intramyocellular lipids but no faster in trained than in sedentary subjects

Jacques Décombaz1, Beat Schmitt2, Michael Ith3, Bernard Decarli1, Peter Diem4, Roland Kreis3, Hans Hoppeler2, and Chris Boesch3

1 Nestlé Research Center, Nestec Ltd., CH-1000 Lausanne 26, Switzerland; 2 Department of Anatomy, University of Bern, 3 Department of Clinical Research (Magnetic Resonance Spectroscopy and Methodology), University of Bern and Inselspital of Bern, and 4 Division of Endocrinology and Diabetology, Inselspital of Bern, CH-3010 Bern, Switzerland


    ABSTRACT
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

The hypotheses that postexercise replenishment of intramyocellular lipids (IMCL) is enhanced by endurance training and that it depends on fat intake were tested. Trained and untrained subjects exercised on a treadmill for 2 h at 50% peak oxygen consumption, reducing IMCL by 26-22%. During recovery, they were fed 55% (high fat) or 15% (low fat) lipid energy diets. Muscle substrate stores were estimated by 1H (IMCL)- and 13C (glycogen)-magnetic resonance spectroscopy in tibialis anterior muscle before and after exercise. Resting IMCL content was 71% higher in trained than untrained subjects and correlated significantly with glycogen content. Both correlated positively with indexes of insulin sensitivity. After 30 h on the high-fat diet, IMCL concentration was 30-45% higher than preexercise, whereas it remained 5-17% lower on the low-fat diet. Training status had no significant influence on IMCL replenishment. Glycogen was restored within a day with both diets. We conclude that fat intake postexercise strongly promotes IMCL repletion independently of training status. Furthermore, replenishment of IMCL can be completed within a day when fat intake is sufficient.

muscle; triacylglycerol; glycogen; insulin sensitivity; proton magnetic resonance spectroscopy


    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

FAT AND CARBOHYDRATE ARE THE major fuels of skeletal muscle during work and rest. Past research has established that muscle glycogen concentration is a major determinant of endurance capacity. Accordingly, it is important for an endurance athlete to ingest optimal amounts of carbohydrate after training and before competition. Less is known about muscle triacylglycerol (TAG) use during exercise, and there is little information about the role of fat intake in fat storage in muscle during recovery. Therefore, the objective of this work was to compare the acute effects of a moderately high-fat (HF; 55% energy from lipids) diet and a low-fat (LF; 15% energy from lipids) diet on IMCL concentration during recovery from exercise in endurance-trained (T) and sedentary [untrained (UT)] subjects using noninvasive 1H-magnetic resonance (MR) spectroscopy (1H-MRS).

Circulating fatty acids (FA) and muscle TAG supply the lipid fuel required by muscle. Muscle tissue contains two TAG compartments: the first is made of adipocytes interspersed between muscle fibers [extramyocellular lipids (EMCL)], which are probably accessed in a similar way as lipids of adipocytes in adipose tissue. The second compartment represents lipid droplets that are in contact with mitochondria within the cytoplasm of muscle cells [intramyocellular lipids (IMCL)], which can be identified by ultrastructural stereology in muscle biopsy samples (50). However, the majority of studies in past years have used chemical analysis of biopsy samples to quantify muscle TAG content, a method that does not allow to differentiate between the two lipid compartments and is fraught with a large variability (52). Others have estimated muscle TAG consumption by evaluating the difference between total fat oxidation (by indirect calorimetry) and muscle uptake of plasma FA. This was based on the uncertain assumption that FA disappearance equals FA oxidation. Studies using these techniques have indicated that muscle TAG decreases 15-50% during prolonged exercise; see references in Ref. 25. Despite these findings, some controversy still exists as to whether they are a major energy source for exercise (29). Recently, a noninvasive technique to estimate IMCL has been introduced. The IMCL compartment can be determined specifically and noninvasively by 1H-MRS (4, 5, 42, 47). Use of this direct way of IMCL determination should help to resolve the above-mentioned disagreement (44).

One of the major physiological adaptations to endurance training is the enhanced capacity for fat metabolism at submaximal exercise intensity. The following factors are known to be increased: the FA extraction by muscle, the transport protein capacity, the activities of carnitine palmitoyltransferase I as well as the oxidative enzymes (see references in Ref. 26), and the peroxisome proliferator-activated receptor-alpha -related nuclear transcription factor (19). Additionally, muscle stores of IMCL are enlarged (18, 21, 33, 45). Globally, these adaptations to endurance training increase the availability of fat during exercise, which spares muscle glycogen and contributes to performance. It would make sense that other training adaptations would occur that facilitate IMCL replenishment at rest. Indeed, there are indications that this might be the case: resting basal lipid kinetics are markedly increased in athletes involved in strenuous endurance training (39); lipoprotein lipase (LPL) activity (34), FA transport proteins (28), hormone-sensitive lipase (HSL) (35), and clearance of circulating TAG-rich lipoproteins (40) are enhanced. We therefore hypothesized that IMCL repletion rate would be faster in endurance-trained than in sedentary subjects.

In line with the stimulation of whole body lipid oxidation that is observed after exercise (49), a decrease in muscle TAG concentration after the end of exercise (29) and a stagnation at low levels (46) have been reported. In these studies, feeding of LF diets during recovery and using the biopsy technique for assessing muscle TAG leave it unclear whether the observations depend on fat in the diet and whether they are applicable to IMCL per se. Feeding of an HF diet chronically (24, 27), or acutely for 24 h after exercise (44), indeed leads to elevated TAG concentrations in quadriceps femoris muscle. In recent case studies based on MRS (3, 10), in a total of two subjects our laboratory has observed complete IMCL replenishment with high fat intake during postexercise recovery. Our second, confirmatory hypothesis, therefore, was that the IMCL repletion rate is influenced by lipid intake.


    MATERIALS AND METHODS
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

Subjects. Six T and six UT male subjects were selected to participate in the study. Exclusion criteria at entry were a history of diabetes, cardiovascular disease, hemophilia, hyperlipidemia, and hypertension; liver, renal, and inflammatory disease; chronic use of drugs; inability to exercise; and contraindications to exposure to a 1.5-T magnetic field (ferromagnetic implants or ornaments). Physical capacity tests were carried out at selection. Peak oxygen consumption (VO2 peak) was determined through an incremental treadmill exercise. Initial speed was 10 km/h (T) or 8 km/h (UT), 5% uphill, with steps of 2 km/h every 3 min until volitional exhaustion. Oxygen consumption (VO2) over a 15-s period was taken as end point when the respiratory exchange ratio exceeded 1.05 (Metabolic cart, Sensormedics, Anaheim, CA). The 4 mmol/l lactate anaerobic threshold was measured 30 min later using the same exercise up to submaximal intensity. Ear lobe blood lactate was determined (model LP20, Lange, Berlin, Germany) at the end of each plateau, and the threshold value (km/h) was obtained by curvilinear interpolation. Selection criteria required running aerobic power and speed at the 4 mmol/l lactate threshold to be higher in T than in UT (by >5 ml O2 · min-1 · kg-1 and by >1.5 km/h, respectively) with no individual overlap. Running, which is usually associated with a high oxidative capacity of the tibialis anterior (TA) muscles, contributed substantially to the exercise routine of the T subjects. Fasting venous blood plasma glucose and insulin were obtained in the morning of a different day. Several alternative indexes of insulin sensitivity or resistance (7) were evaluated: insulin, 1/insulin, homeostasis model assessment [HOMA = (glucose × insulin)/22.5], 1/HOMA, ln HOMA, glucose/insulin, insulin/glucose. Hemoglobin A1c was normal. The protocol was approved by the Ethics Committee of the Nestlé Research Center, and the subjects confirmed their consent in writing. The characteristics of the subjects are given in Table 1.

                              
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  		Table 1.   Subjects

Experimental design. The subjects were submitted to 2 h of exercise at ~50% VO2 peak [an intensity where endogenous muscle TAG utilization is expected to be maximal (38)] on two occasions at intervals of 2-6 wk (Table 2). The exercise consisted of jogging (T) or fast walking (UT) uphill (5% incline) on a treadmill (Mercury, LMT, Wallisellen, Switzerland). To augment the use of TA muscle, subjects had steel weights fastened to the shoelaces of each foot for the duration of the exercise (T 70 g, UT 50 g). Intensity was monitored by continuous heart rate recording (Polar, Kempele, Finland) and checked after 30 min by indirect calorimetry (Jaeger, Würzburg, Germany) on the first occasion. The speed was then set identically on the second occasion. The drinking of water during and at the end of exercise was encouraged. After exercise, the subjects were fed either a moderately HF diet (55% fat energy) or an LF diet (15% fat energy) for 1.66 days. The chronological order of dietary treatments was balanced within training groups. Muscle glycogen and IMCL stores were assessed in the TA muscle by MRS at four time points: at baseline (preexercise) and 1, 9 (after 2 meals), and 30 h (after 3 more meals) after the end of exercise. During recovery, physical activity was restricted to a minimum.

                              
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  		Table 2.   Two-hour test exercise

Baseline period. For 4 days before the first exercise each subject kept a food diary. He was asked to replicate his intake before the second exercise. UT subjects followed their usual sedentary lifestyle. T subjects were allowed to train according to their usual exercise routine up to 2 days before the test exercise. The last training was identical (individually) at both occasions and separated from the baseline MR measurement by at least five meals and 33 h. The preexercise measurement took place in the late afternoon of the day preceding exercise. It was followed by a maintenance snack (a standard sandwich and an apple) in the evening. The next morning before the test exercise, a 90-g white bread snack was eaten on awakening.

Postexercise diets. The recovery diets (HF or LF) covered one full day plus breakfast and lunch the next day (i.e., 1.66 days, total 5 meals). They were composed of normal foods and an experimental liquid formula, one for each diet, contributing one-third of the energy (Table 3). Diet composition was calculated from standard food tables and manufacturers' label information. Dietary protein was balanced by inclusion of a whey protein concentrate (Lacprodan DI-8090, MD Foods Ingredients, Viby J, Denmark) in "müsli"-type yogurts. Quantitative energy intake was set to correspond to that of athletes in training (52 kcal · kg-1 · 24 h-1). Meals were prepared in advance. Subjects were instructed to eat all that was offered and nothing else except water.

                              
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  		Table 3.   Composition of postexercise recovery diets

The experimental liquid formulas were based on skim milk powder, maltodextrin (Glucidex C19, Roquette, Lestrem, France), water, and, for the HF formula only, Sanolio oil. They were prepared as 200-g aseptic tetrapack servings of 1.50 kcal/g. The LF formula contained (%energy) 0% fat, 11% protein, and 89% carbohydrate. The HF formula contained (%energy) 36% fat, 11% protein, and 53% carbohydrate. Eight servings of the liquid foods contributed 37% of total dietary energy.

FA class distribution was determined on 92% (HF diet) and 81% (LF diet) of total fat intake. The proportions of total fat energy obtained from saturated FA, monounsaturated FA, and polyunsaturated FA were 37, 37, and 18%, respectively, for the HF diet, and 49, 26, and 6%, respectively, for the LF diet. The detailed FA profile was known for 64% (HF) and 81% (LF) of the dietary fat. On this incomplete basis the n-6/n-3 ratio was equal to 5.4 (HF) and 5.0 (LF).

MR measurements. Muscle glycogen (1) and IMCL (5) stores were measured sequentially (total time for 1 measurement ~90 min) in the right TA muscle by 13C- and 1H-MRS, respectively. This muscle was chosen because the orientation of the fibers nearly parallel to the magnetic field gives an optimal separation of the IMCL resonance, because in UT subjects significant IMCL depletion in quadriceps muscles can easily be limited by systemic (cardiovascular) factors and because TA seems to respond to running exercise much like thigh muscles, at least qualitatively (3). MR examinations were done on a clinical 1.5-T whole body scanner (SIGNA, General Electric, Milwaukee WI) equipped with a 13C/1H double-tuned flexible coil (1H: Helmholtz design, 13C: single turn 11.5 × 11.5 cm2, Medical Advance) and a partially home-built second channel for decoupling and nuclear Overhauser effect buildup. The right leg of the subjects was placed in a specially designed cast to guarantee a reproducible position and shape of TA muscle for all eight sessions (2 diets with examinations before and 1, 9, and 30 h after exercise). Repositioning of TA muscle, fixation of the surface coil, and placement of the 1H-voxel were monitored by two series of localizer images. IMCL and EMCL levels were measured in a 11 × 12 × 18-mm3 voxel in the TA muscle using an optimized PRESS sequence (repetition time = 3 s, echo time = 20 ms, 128 acquisitions, water presaturation, outer volume suppression) and quantified using the unsuppressed fully relaxed MR signal as internal standard.

Because signal contamination by EMCL is strongly dependent on inclusion of patches of lipid infiltration, the EMCL signal was used to monitor the reproducibility of voxel content. With regard to reproducibility of position, whereas the voxel position was determined on MR images relative to the tibia within <1 mm, the absolute position (relative to magnet) varied by 2.8 mm (standard deviation from individual average position) in inferior-superior, by 1.4 mm in anterior-posterior, and 3.0 mm in right-left direction. The EMCL signal varied by 18% (coefficient of variation, 4-74%) and the creatine signal by 19% (8-31%) between different sessions on the same subject. Whereas IMCL showed significant effects (P < 0.05) between sessions, no systematic variations of EMCL and creatine were found. Absolute quantitation of IMCL levels in millimoles per kilogram muscle wet weight (ww) was carried out as reported earlier (3). Because the size of the EMCL signal in a specific spectrum is not representative for a specific muscle, the size of the EMCL signal cannot be evaluated in terms of depletion and recovery.

Glycogen was measured by 13C-MRS using a pulse-and-acquire sequence (repetition time = 300 ms) with an adiabatic 90° excitation pulse, decoupling during data acquisition, and nuclear Overhauser effect buildup in the recovery periods (6,000 averages per time point). Glycogen was quantified in arbitrary units relative to the creatine signal.

Fat oxidation. Total fat oxidation during exercise was estimated from indirect calorimetry according to Weir's classic work (51), assuming 5% contribution from protein to VO2. A rough estimate of the contribution of IMCL use to total fat oxidation was obtained on the assumption that 10 kg of muscle were involved in the exercise with a metabolic load comparable to that of the TA muscle.

Statistics. Values are means ± SE. Student's t-test with assumption of equal variance was first used to compare characteristics of T and UT populations. If Levene statistics indicated unequal variance in the two groups, t-testing with unequal variance was applied (weight, 2-h VO2, glycogen at rest and glycogen 1 h after exercise, and IMCL depletion and IMCL 1 h after exercise). In four instances (age, lactate threshold, glycogen depletion, and relative IMCL depletion), where a Kolmogorov-Smirnov test with Lilliefors correction hinted at nonnormal distributions, groups were compared with a Mann-Whitney U-test. None of the significance values indicated in the tables was altered when the more general tests were used.

Changes in IMCL and glycogen were tested using ANOVA with the following factors: order of treatments, diet, training status, and diet-training interaction (43). Comparisons between diet treatments at specific time points were made using t-tests or Mann-Whitney U-tests as stated above. Linear regressions were used to estimate the degree of association between individual preexercise IMCL concentration (averages of 2 independent measurements) and the insulin sensitivity indexes, the percent body fat, and the preexercise glycogen. Linear regression was also used to estimate the time required for complete repletion of IMCL to initial values. P values >0.05 were taken as nonsignificant (NS).


    RESULTS
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

Subjects and exercise. T subjects were lighter and leaner than UT subjects, but the body mass index was well in the normal range (<25 kg/m2) for both groups. Subjects in the T group were training heavily for endurance with running as a major discipline. Their aerobic capacity was 44% higher than that of the UT subjects. At their 4 mmol/l lactate threshold, they ran 74% faster (Table 1). Fasting plasma glucose and insulin were normal. All of the indexes of insulin sensitivity with insulin in the denominator (for example, 1/HOMA) showed significantly higher values for the T subjects (P = 0.05). As described below, the insulin sensitivity indexes were significantly correlated with resting IMCL and glycogen levels.

Body weight at the onset of the 2-h exercise was equal before both treatment diets (Delta  0.2 ± 0.3 kg). Initially planned at one-half aerobic capacity, the exercise was effectively run a little higher in T (54% peak oxygen consumption) than in UT (48%; Table 2). The T subjects achieved an absolute energy expenditure and distance run that were both ~30% higher than the UT subjects, and their weight loss was threefold greater (T 1.6 ± 0.2 kg and UT 0.4 ± 0.2 kg). The weight regain of all subjects over the 30-h recovery was greater with the LF (i.e., high carbohydrate) diet than with the HF (i.e., low carbohydrate, isoenergetic) diet (1.28 ± 0.17 and 0.83 ± 0.15 kg, respectively; P < 0.01).

IMCL. The average concentration of IMCL in the initial resting conditions of both exercise trials was 71% higher in T (although more variable) than in UT (P < 0.05; Table 4). These average resting IMCL levels correlated significantly with most of the alternative measures of insulin sensitivity, in particular 1/HOMA, when T and UT subjects are considered as one group (|r| = 0.49-0.74, P = 0.1-0.006, respectively). This correlation was significant also within the T group alone (|r| = 0.76-0.84, P = 0.08-0.04) but not within the UT group. (Positive correlation occurred with those indexes that feature insulin in the denominator.) This relationship is illustrated in Fig. 1A for 1/HOMA.

                              
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  		Table 4.   Intramyocellular lipids and glycogen in tibialis anterior muscle



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  		Fig. 1.   Correlation of resting intramyocellular lipid (IMCL; A) and glycogen (B) levels of tibialis anterior muscle (mean of both preexercise values) with 1/homeostasis model assessment (HOMA), an index of insulin sensitivity. T, trained; UT untrained; ww, muscle wet weight; a.u., arbitrary units. The plotted correlations are significant overall (IMCL: r = 0.74, P < 0.01; glycogen: r = 0.77, P < 0.01) and tend to account for even more of the variation within the T group alone (IMCL: r = 0.76, P = 0.08; glycogen: r = 0.82, P < 0.05).

Collectively, T subjects had more IMCL (Table 4) and less total body fat (Table 1) than UT subjects. However, within the T group initial IMCL concentrations tended to be positively correlated with body fat (T, r = 0.78 and P = 0.07; UT, r = 0.38 and P = 0.46). Finally, preexercise IMCL levels were not significantly different between the two diets in either group.

During exercise, the IMCL concentrations diminished equally in relative terms (by 22-26%) in both training groups, whereas in absolute terms the IMCL usage was almost twice as high in the T compared with the UT subjects (P = 0.06). Whole body fat oxidation was in the range 22-34% of nonprotein energy expenditure, and it was estimated that IMCL contributed 15% (T) and 17% (UT) of the whole body fat utilization. Between 1 and 30 h of recovery, the changes in IMCL were influenced by diet (P = 0.0001) but not by training status. Recovery on the HF diet led to a steady increase in IMCL to reach higher (P < 0.001) final concentrations than before exercise (T 130 ± 8% and UT 145 ± 15%; Fig. 3A). Final values at 30 h with this diet were 4.3 ± 0.8 mmol/kg ww (T) and 2.5 ± 0.2 mmol/kg ww (UT; Fig. 2A). Net rates of replenishment on the HF diet were similar in T and UT subjects, either from 1 to 30 h (T 59 ± 9 vs. UT 40 ± 9 µmol · kg ww-1 · h-1; NS) or over the late phase (9-30 h) of postexercise recovery (T 55 ± 7 µmol · kg ww-1 · h-1 vs. UT 48 ± 6, µmol · kg ww-1 · h-1; NS). The time required for the IMCL concentration to return to preexercise level on the HF diet, estimated from a three-point regression (ranges for r: T 0.90-1.00 and UT 0.65-1.00), did not depend on training (T 15 ± 4 h vs. UT 15 ± 3 h after the termination of exercise) with a 95% confidence interval for all subjects of 10.7-19.9 h.


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  		Fig. 2.   IMCL concentration in tibialis anterior muscle of T and UT men before and after 2-h treadmill exercise (arrows). The high-fat (HF; 55% lipid energy; closed symbols; A) or low-fat (LF; 15% lipid energy; open symbols; B) diets were given during 30 h of recovery. Values are means ± SE.

During recovery from exercise on the LF diet, IMCL remained unchanged (T) or continued to decrease slightly during the first 9 h (UT). At 30 h postexercise, IMCL content had not recovered, reaching concentrations lower (P < 0.05) than before exercise (T 83 ± 7% and UT 95 ± 20% of initial; Fig. 3A). Final values at 30 h with this diet were 2.7 ± 0.5 mmol/kg ww (T) and 1.8 ± 0.2 mmol/kg ww (UT; Fig. 2A). Expressed as net linear rates, IMCL replenishment from 1 to 30 h postexercise was not different from zero (T 7 ± 4 µmol · kg ww-1 · h-1 and UT 4 ± 9 µmol · kg ww-1 · h-1) on the LF diet.


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  		Fig. 3.   Postexercise IMCL (A) and glycogen (B) concentrations relative to preexercise (pre-ex = 100%) in tibialis anterior muscle of T and UT men fed an HF (55% lipid energy) or a LF (15% lipid energy) diet during 30 h of recovery. Values are means ± SE. Arrows = 2-h treadmill exercise.

Muscle glycogen. The average glycogen concentration in the initial resting conditions of both exercise trials was 60% higher in T than in UT (P = 0.03; Table 4). Preexercise glycogen was correlated with IMCL (r = 0.78, P < 0.01). Hence, like for IMCL, the average resting glycogen levels were correlated significantly with most of the indexes of insulin sensitivity, in particular 1/HOMA, when T and UT subjects are considered as one group (|r| = 0.51 to 0.78, P = 0.09 to 0.003). This correlation was highly significant also within the T group alone (|r| = 0.82 to 0.95, P = 0.05 to 0.004) but again failed to reach significance within the UT group (as for IMCL, positive correlation occurred with those indexes that feature insulin in the denominator). This relationship is illustrated in Fig. 1B for 1/HOMA.

Preexercise glycogen levels were not significantly different between the two diets. Relative glycogen usage during exercise (35-43%) did not differ between training groups. The changes in muscle glycogen between 1 and 30 h of recovery were not influenced either by diet or by training. However, the changes in the early recovery phase (1-9 h) were different between diets (P < 0.05), with a training effect at the limit of significance at 9 h (P = 0.06). Recovery on the HF diet led to glycogen concentrations at 30 h similar to baseline values (T 96 ± 9% and UT 108 ± 9%; Fig. 3B). During recovery from exercise on the LF (i.e., high carbohydrate) diet, glycogen apparently increased faster during the first 9 h than afterward, to reach glycogen concentrations at 30 h (T 97 ± 14% and UT 155 ± 30%) that were not significantly different from baseline. Figure 3 illustrates the contrasting effect of the HF and LF diets on the relative replenishment of IMCL and glycogen.


    DISCUSSION
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

IMCL and glycogen stores. The TAG content of human skeletal muscle is reported to vary between 5 and 15 mmol/kg ww (41), where the molecular mass that is taken is that of the whole TAG molecule. These values are from measurements made on biopsy samples free from visible fat, but the possibility remains that part of this fat is localized in the extrafiber space. 1H-MRS in situ specifically identifies intracellular lipid droplets as a major contributor to the MR spectrum, whereby IMCL content can be measured with a typical error of 6% on repeated samples (3, 5, 42, 47). The mean resting values of 2-4 mmol/kg ww found in the T and UT subjects of this study using the MRS technique are consistent with the concept that fluorometric determinations on biopsies overestimate IMCL. However, the extent of this overestimation is uncertain, because prior 1H-MRS work indicates that IMCL concentrations are lower (up to a factor of 2- to 3-fold) in TA muscle than in soleus and gastrocnemius muscles (37) or than in vastus muscles (3). The majority of measurements in humans stems from the latter muscles. Hence, individual muscles appear to have distinct IMCL levels. This can, in part, be attributed to different fiber-type composition, with slow-twitch muscle fibers containing more TAG than fast-twitch fibers (21, 41).

Supporting previous knowledge (18, 33, 45), the T subjects had greater resting IMCL concentrations than the UT subjects. Similarly, that they had greater muscle glycogen concentrations is also a confirmation of earlier observations (17). These two adaptations to training are useful in reducing the reliance on exogenous substrates during endurance exercise. Resting IMCL concentrations were not only larger in T subjects but also they were more variable than in the UT, again a finding also made by others (22). This suggests that run-in periods controlling for diet and physical activity may need to exceed 4 days, especially for subjects in training, whose stores are likely to oscillate within a larger range.

Recently, several studies, including some with 1H-MRS (23, 30), have associated a high IMCL content with insulin resistance. In contrast, in the present study, higher IMCL levels were significantly associated with increased insulin sensitivity, as judged from alternative indexes (Ref. 7 and references therein) calculated from fasting glucose and insulin plasma contents. Because the glucose levels were fairly homogeneous over the whole study population, the correlation of IMCL with the indexes is primarily due to the direct relation with the insulin level, and no statement can be made as to which index would be most appropriate to describe this effect in a population of sedentary subjects and athletes (7). The correlations were found within the group of T subjects, but also as a group effect, because both insulin sensitivity and IMCL content are higher in T compared with UT subjects. This is consistent with the evidence that insulin sensitivity is generally improved with exercise training (9). The higher IMCL of trained subjects was also associated with less total body fat, in contrast to reports that claim that intramuscular lipid content is increased in obesity (14). These observations underscore the different physiological significance that the regional IMCL compartment may have in different subject cohorts, like trained vs. sedentary subjects or healthy vs. glucose-intolerant individuals. There is a clear need to gain a better understanding of the factors involved in the regulation and function of IMCL. The present findings also show that IMCL levels depend on many factors and definitely cannot be regarded monofactorially as an indicator of insulin sensitivity. In addition, one should keep in mind that a significant correlation does by no means prove a causal relationship. This is illustrated quite clearly by the correlation found between insulin sensitivity and resting glycogen levels, which happens to be even stronger than the one found with respect to IMCL levels. As suggested by Bergman and Ader (2), an association of insulin resistance and muscle glycogen levels might be found for individuals with Type 2 diabetes, which would by no means prove that low glycogen causes insulin resistance. In the present study, a positive correlation of glycogen with insulin sensitivity was established, but similarly, the muscular glycogen increase cannot be taken as the cause of enhanced insulin sensitivity.

IMCL depletion during exercise. Both carbohydrate and fat fuels are used during exercise, with a peak value for total fat and muscle TAG utilization at an intensity of ~50% VO2 max (38). The present study provides direct evidence that IMCL decreases during prolonged exercise at such intensity and brings support to the few existing 1H-MRS data in TA and quadriceps muscles [case studies (3, 5, 10)] as well as soleus muscle (31). The rough estimate of the magnitude of the IMCL contribution (15-17%) to the oxidation of total fat fell within the range of 11-26% estimated earlier for marathon running (3). These numbers are lower estimates because TA muscle has much lower IMCL concentration than thigh muscles. Now that it is possible, one should determine more precisely the relative contributions of IMCL and peripheral fat to total fat oxidation in muscle at different exercise intensities.

It has long been recognized that endurance training increases the reliance on fat as a source of energy during submaximal exercise, hence resulting in a reduced reliance on carbohydrates. Although this clearly occurs at identical absolute work intensity after, compared with before, training, and sometimes also at identical relative intensity (26), in our conditions glycogen was not spared during exercise. Its use even appeared to be larger in the T subjects but this was not significant (P > 0.1). This may be explained by one or several of the following. First, as an alternative to glycogen sparing, training reduces the production and utilization of plasma-borne glucose during exercise performed at the same absolute or relative intensity (8). Second, when exercise is performed with higher initial glycogen concentration in the muscle, as was the case in the T subjects, glycogen may be used at a higher rate (16). And last, T subjects actually exercised at a slightly but significantly higher (+11%) relative intensity than UT subjects.

Recovery with the LF diet. During recovery from exercise on the LF diet, IMCL concentrations remained low for at least 30 h. IMCL concentrations in muscle of the UT subjects seemed to continue to decrease until 9 h after exercise, although this was not significant. This is consistent with other studies (29, 46) where diet during recovery provided only 20-25% energy from fat. These data support the concept that there is no net deposition of cellular lipids postexercise (during an undetermined period of time), when fat intake is limited. They are also in line with the fact that whole body fat oxidation remains elevated above resting levels after exercise (20, 49). Kiens and Richter (29) suggested that muscle glycogen resynthesis has such high metabolic priority during recovery that utilization of lipids is necessary to cover energy expenditure in muscle and that muscle TAG accounts for a substantial part of it. From this perspective, deeper (29) or longer lasting (46) postexercise depressions in muscle TAG could be explained by a greater depletion of muscle glycogen in these protocols compared with ours.

The mechanism by which continued utilization of IMCL occurs postexercise is as yet unexplained. A muscle-specific HSL appears to be implicated in muscle TAG lipolysis (35). If this enzyme is regulated as adipose tissue HSL, it should be inhibited by insulin. Because the LF diet contained a high proportion (70% energy) of carbohydrate, circulating insulin must have been raised during much of the recovery period on this diet, ruling out a role for continued HSL-mediated lipolysis, unless the sensitivity of muscle-specific HSL to insulin is very different to that of adipose tissue HSL. Another mechanism suggested to play a role in the regulation of FA oxidation is through malonyl-CoA, the first intermediate in the formation of long-chain FA. Carnitine acyltransferase I, the rate-limiting step for long-chain fatty acyl-CoA transport into the mitochondria, is inhibited by malonyl-CoA. Muscle malonyl-CoA, which is decreased during exercise, remains depressed, whereas fat oxidation is elevated for relatively prolonged periods after a single bout of exercise (36). Thus the inhibition of carnitine acyltransferase I by malonyl-CoA may be decreased and FA oxidation increased, allowing IMCL to contribute more to muscle energy and leaving more glucose for the replenishment of muscle glycogen. Overall, our data support the view that IMCL are used during exercise, as well as in the postexercise period, provided that fat intake is restricted during recovery.

Recovery with the HF diet. During recovery on the HF diet, there was a fast increase in IMCL, resulting in a significant supercompensation at 30 h relative to preexercise concentrations. Fat-rich meals are followed by an elevation of plasma TAG lasting 3-5 h, the clearance of which is improved by prior exercise (15). In the capillary endothelium, LPL, a key enzyme regulating the disposal of lipid fuels in the body (12), undergoes a tissue-specific regulation that is broadly correlated with tissue requirement for FA. On fasting and presumably postexercise, muscle LPL is upregulated, with suppression of adipose tissue LPL activity; for references see Ref. 12. Therefore, it is reasonable to assume that much of the accumulated IMCL was derived from circulating TAG-rich particles. Combination of rest with sufficient fat intake resulted in restoring IMCL levels within 20 h, a process that appears to be linear as far as this can be judged from the present data. It has been supposed for some time that variations of the dietary lipid content could be a major factor contributing to the fluctuation of TAG stores in skeletal muscle (41). Now it is recognized how metabolically dynamic this lipid compartment is and how fast it can respond to proper stimuli. How much fat intake is necessary to fill up IMCL stores efficiently remains unanswered. Although not very high in relative fat content, the 55% lipid energy diet was associated with a fairly high fat intake (3.2 g/kg), equivalent to the fat intake from a 70% lipid energy diet by a sedentary individual. Preliminary experiments had indicated an efficient IMCL replenishment with 2.4 g fat · kg-1 · day-1 (10). More work is needed to determine the threshold fat intake for a prompt replenishment of IMCL and also its relationship to the concurrent insulin level (6).

A major concern of athletes is to ensure that glycogen replenishment is boosted before competition. No exercise test has yet been devised to demonstrate in which exercise conditions IMCL may become limiting for endurance performance. However, the evidence strongly suggests that IMCL play an important, although permissive, role by sparing muscle glycogen. Therefore, it would be wise to try and optimize IMCL storage before competition, at the same time ensuring that glycogen storage is not compromised. Because glycogen storage postexercise is a biphasic phenomenon (13), for which carbohydrate may be particularly important in the early phase, a strategy involving a high-carbohydrate followed by a normal to HF diet during recovery could be an interesting option to optimally load both fat and carbohydrate substrates in muscle within the shortest time.

Training and postexercise IMCL replenishment. We expected to observe a faster rate of IMCL replenishment in T vs. UT subjects on the basis of the overall improvement in the capacity of athletes for fat metabolism and, more particularly, on the following observations: 1) LPL activity is related to capillary density, which itself increases with endurance training; and 2) there is evidence (in the rat) that muscles with predominant red fibers, those with specifically improved microcirculation and enlarged TAG stores after training, are characterized by higher LPL activity and faster incorporation of chylomicron-derived FA (48). We found no difference in the rate of replenishment of IMCL in the T compared with the UT subjects. One reason may lie in the choice of the muscle. A muscle such as the soleus, with a larger proportion of slow oxidative fibers, might be more susceptible than TA muscle to training adaptations of the lipid storage pathways. Another possible explanation relates to the experimental design. T subjects exercised at much higher absolute intensity, and also at a slightly higher relative rate than UT subjects (54 vs. 48% VO2 peak), hence expending ~60% more energy during the test exercise. A higher rate of IMCL replenishment may thus have been masked by a faster lipolytic rate, preventing faster net IMCL deposition.

On the other hand, many of the adaptations to physical exercise that have been thought to be acquired by training are in fact associated with the stress of the most recent bout and are reversed within a few days. As reviewed by Hardman and Herd (15), the low lipemic response of athletes to a fatty meal and enhanced LPL activity may, in part, be one of those relatively short-lasting effects. If the acute effect of exercise on IMCL storage was important relative to an effect due to training, our protocol including acute exercise did not permit us to observe a training effect specific to the T group. Furthermore, there are aspects of lipid metabolism, such as adipose tissue lipolysis and FA extraction from plasma, that do not seem to increase after training (see Ref. 26). In addition, the primary drive for the metabolic adaptations to physical training, namely muscle contraction with its inherent metabolic demands, may perhaps more efficiently stimulate biochemical pathways involved in the efficiency of energy utilization than those involved in energy restoration, a process that may take place at rest and over longer time periods. It is possible that the higher IMCL stores of trained individuals should be explained not by the rate of the biochemical processes engaged in the sequence of cell entry, transport and reesterification but by the lasting training-induced increases in ultrastructural capacity (mitochondrial, cytoskeletal) necessary to accommodate more numerous and larger functional intrafibrillar lipid bodies.

In conclusion, this study supports the notion that IMCL deposits are a dynamic fuel compartment that provides readily available energy for muscle contraction. We demonstrate that IMCL storage during the day after prolonged moderate exercise strongly depends on fat intake and appears to be similar in sedentary men and well-trained endurance athletes. With appropriate fat intake, IMCL can be restored within a day. In addition, in T subjects resting IMCL levels are positively correlated with indexes of insulin sensitivity.

Perspectives

IMCL are a plastic and dynamic fuel reserve for the muscle just like glycogen. Both stores have approximately the same size (0.1-0.3 MJ/kg), are lowered by exercise, and are replenished (even supercompensated) within a day when an appropriate diet is fed. Obviously, IMCL and glycogen require diets with an opposite fat-to-carbohydrate ratio. The controversial issue of whether HF diets can improve endurance performance should now be studied on the assumption that higher muscle IMCL content before exercise may be beneficial to performance, provided that glycogen is also maintained at optimal levels. Dietary protocols and models of exercise performance can be developed around this physiological target. Suitable dietary manipulations of the lipid intake may become part of the dietetic management of endurance events with a defined profile.

The clinically more relevant evidence of a positive association between muscle triglyceride levels and insulin resistance (with the notable exception of athletes as shown in this work) is now confronted with the fact that IMCL levels are not static within each person but are strongly dependent on the recent history of diet and muscular work. This variability should be examined in populations with various degree of metabolic abnormalities. Modulating IMCL with repeated measurements by MRS should help to experimentally disconnect this marker of insulin resistance from recognized determinants such as circulating FA concentration. In addition, IMCL levels could be a marker of intracellular diacylglycerol, itself a potential molecular link between an increased availability of saturated FA and the induction of insulin resistance (32), suggesting a potential role for the FA profile and other lipid components of the diet.


    ACKNOWLEDGEMENTS

We are grateful to the Nestlé Product Technology Center, Konolfingen, Switzerland (A. Clément), for manufacturing the liquid formulas; to the Institutè fuer Sport und Sportwissenschaft, Bernè University, Bernè, Switzerland (J. Hegner and K. Egger), for allowing us access to their facility; and to M. Baumgartner (Nestlé Research Center, Nestec Ltd., Lausanne, Switzerland) for statistical assistance.


    FOOTNOTES

This work was supported by Swiss National Science Foundation Grant 31-53788.98.

Some of these results have been published in abstract form (11).

Address for reprint requests and other correspondence: J. Décombaz, Nestlé Research Center, Nestec Ltd., PO Box 44, CH-1000 Lausanne 26, Switzerland (E-mail: jacques.decombaz{at}rdls.nestle.com).

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 2 November 2000; accepted in final form 24 April 2001.


    REFERENCES
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
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