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Departments of Exercise and Sport Sciences (L.J.W., M.A.F., S.C.M.) and Radiology (H.K.), University of Florida, Gainesville, Florida 32611; Veterans Administration Medical Center (H.K.), Gainesville, Florida 32608; and Clinical Development (M.A.F.), Medtronic Sofamor Danek, Memphis, Tennessee 38132
Address all correspondence and requests for reprints to: Lesley J. White, Ph.D., Department of Exercise and Sport Sciences, University of Florida, P.O. Box 118206, Gainesville, Florida 32611-8206. E-mail: lwhite{at}hhp.ufl.edu.
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Abstract |
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O2max) and body composition were used to match subjects for aerobic fitness and body composition. Subjects performed cycle ergometry for 1 h at 65% of O2max. Expired gases were collected throughout exercise to determine caloric expenditure and substrate use. Blood samples were collected before and after exercise to evaluate markers of lipid metabolism. Pre- and postexercise proton spectra were acquired from the vastus lateralis using a 3-T whole-body imaging system. Spectra were acquired from an 18-mm3 region of interest (echo time = 45 msec; repetition time = 2000 msec) for IMCL evaluation. IMCL decreased significantly with exercise (11.5–28.5% for men and 17.1–21.7% for women) (P < 0.05); however, there were no significant differences between men and women. Although changes were found for many plasma variables [free fatty acids, glycerol, and norepinephrine (P < 0.05)], group differences were only evident for norepinephrine. In conclusion, a significant decrease in IMCL was observed during 60 min of cycling in matched men and women. |
Introduction |
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Although several investigations have evaluated total lipid oxidation and the use of plasma lipoproteins and adipose fatty acids during exercise, relatively few studies have addressed the contribution of intramyocellular lipid (IMCL) to total energy metabolism. IMCL consists predominantly of stored fatty acids (18:0, 18:1, and 16:0), are stored as fat droplets in the cytoplasm near the mitochondria (6), and provide energy for skeletal muscle during prolonged exercise (7). Further understanding of IMCL use during exercise in men and women could clarify inconsistent study findings regarding lipid metabolism between genders.
A relatively new technique, proton magnetic resonance spectroscopy (1H-MRS) has been used recently to measure IMCL (8). This technique has distinct advantages over muscle biopsy because of its low variability on repeated measurements, the ability to distinguish IMCL from extramyocellular lipid (EMCL) (inert lipid pool found within muscle fascia), and its noninvasiveness (9). Recent studies (1) using 1H-MRS have evaluated the contribution of skeletal muscle lipid to energy metabolism in males (10, 11, 12). However, only one study has been completed with women (13), and no direct comparison studies between genders have been completed. Therefore, the purpose of our study was to evaluate the contribution of IMCL to energy metabolism during exercise in men and women. Metabolic and plasma markers of lipid metabolism were acquired to further explain mechanisms associated with lipid metabolism during exercise.
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Subjects and Methods |
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Eighteen healthy, physically active men (n = 9) and premenopausal women (n = 9) between the ages of 18–38 yr were recruited for this study. Inclusion criteria included the following: 1) current participation in an aerobic exercise program (3–5 times per week, 30–60 min per session of continuous aerobic activities) for the previous 6 months; 2) being a nonuser of tobacco products; 3) being a nonuser of lipid-altering medications or oral contraceptives; 4) having normal healthy levels of body fat (men, 10–20%; women 15–25%); and 5) having dietary intake patterns similar to American Heart Association guidelines (14). Although most subjects had a competitive athletics background, none were currently training for ultraendurance activities (e.g. marathon).
To minimize the confounding effects of differences in fitness between genders, subjects were matched for maximal oxygen consumption (O2max) (±5 ml·kg fat-free mass (FFM)·min-1). All subjects had a history of weight stability at the time of the study, with no more than a 2-kg weight loss or gain over the 6 months before entry. Prestudy dietary habits were evaluated by analysis of 2-d dietary logs. Subjects with large deviations (±15%) from the traditional American Heart Association diet (carbohydrate intake, 50–60%; fat intake, <30%; protein intake, 10–15%) were excluded (14). Menstrual cycle histories were assessed with questionnaires to ensure female subjects were eumenorrheic (normal cycle for previous 6 months) and to ensure that they completed their exercise trial visit during the early to midfollicular phase (3–5 d after flow) of their menstrual cycle.
All subjects provided written informed consent, approved by The University of Florida Institutional Review Board for Human Subjects Committee before participation.
Experimental design
The experimental protocol was conducted in two parts. Initially, subjects were evaluated for aerobic fitness, body composition, and dietary habits. Subjects meeting study inclusion criteria were prescribed a standard American Heart Association diet for the 3 d before their exercise trial. Food logs were kept during this time to document nutrient intake. During visit 2, subjects performed a 60-min bout of submaximal cycle ergometry with pre- and postexercise magnetic resonance scans of the thigh to evaluate IMCL content. Blood samples were obtained before and after exercise for plasma metabolite and hormone analyses. Metabolic gas measures were made before exercise and during the exercise session.
Preliminary metabolic testing
O2max was determined using an incremental bicycle ergometer protocol, starting at 50 W and increasing by 25 W each minute (15). Test termination included a plateau in oxygen uptake with increasing work and/or a respiratory exchange ratio (RER) greater than 1.1 (16). Heart rates (HRs) were monitored using telemetry. Expired gases were monitored every 30 sec using TrueMax 2400 metabolic cart (ParvoMedics, Salt Lake City, UT). Exercise work rates were prescribed for each subject at 65% of O2max.
Anthropometric measures
Body weight and height was determined with a standard physician’s scale. Body mass index was calculated by dividing body weight (kilograms) by height (meters squared). Body density was estimated using the three skinfold site method of Jackson and Pollock (17). Body fat percentage was estimated with the formula of Brozek et al. (18).
Dietary parameters and analysis
Subjects were prescreened before entry into the exercise study to ensure compliance with the typical American Heart Association dietary intake recommendations (i.e. 50–60% carbohydrate, <30% fat, and 10–15% protein) (14). Two-day (one weekday and one weekend day) dietary recalls were used for this analysis.
Subjects were also given standard dietary instructions for nutrient intake during the 3 d before the exercise trial. Intake instructions were based on American Heart Association guidelines (14). Total kilocalorie intake range recommendations were based on body weight and from estimated resting metabolic rate [resting metabolic rate = 500 + (lean body mass x 22)] (19). Information from physical activity questionnaires (high, low, and moderate activity) was also used to aid in the calculation of total kilocalorie intake to ensure that subjects were isocaloric before the exercise trial (20). Food exchange lists with serving sizes were used for nutrient recommendations (Health Management Resources, Boston, MA). Subjects were asked to complete dietary records for all 3 d before the exercise trial. Alcohol was prohibited for 2 d before exercise, and caffeine was prohibited on the day of exercise. Nutrient intake and distribution (total kilocalorie intake and percentages of fat, carbohydrate, and protein) was completed using ESHA (Salem, OR) nutritional software, version 7.7.
Exercise protocol
The exercise protocol was conducted within 1 wk of the preliminary metabolic evaluation. Subjects reported to the Department of Radiology 8 h after their last meal. Subjects reported in a fasted state (8–10 h) before exercise. To maintain hydration during exercise, water was provided before and during exercise. Immediately before exercise, 400 ml water were ingested by each subject (21), and during exercise, water was given after min 30 and 45 [4 ml per kg/body weight at each time point (22)]. Each subject completed 60 min of cycle exercise at 65 ± 5% of O2max. The exercise protocol was continuous and included a 5-min cycle warm-up. During exercise, HRs were measured with a Polar (Woodbury, NY) HR monitor, and expired gas measurements were made at baseline and at 15-min intervals throughout exercise. Work rates were adjusted when subjects’ oxygen consumption (O2) deviated by ±5% from the prescribed intensity.
All women completed their exercise trial during the midfollicular phase (3–5 d after flow) of their menstrual cycle. Our intent was to minimize the impact of estrogens on lipid metabolism (increased fatty acid mobilization) typically observed during the luteal phase (23).
Blood collection and analysis
Immediately before and after exercise, blood samples (10 ml) were collected in EDTA tubes. Samples were stored in a cold refrigerator until centrifugation. After exercise, hematocrit and hemoglobin determination was made on whole blood. The remaining blood was centrifuged to obtain plasma, which was stored at -70 C until further analyses were completed. Plasma was frozen less than 6 months before assays were completed.
Hematocrit percentage was determined by the microcapillary tube method. Hemoglobin concentration was determined with the cyanmethemoglobin techniques as described by Drabkin and Austin (24). Estimated plasma volume changes during exercise were used to correct postexercise blood metabolite and hormone concentrations (25).
Plasma free fatty acids (FFA), glycerol, and triglyceride (TG) concentrations were measured with colorimetric reagent kits (Eagle Diagnostics, DeSoto, TX; Sigma-Aldrich, St. Louis, MO; and Wako Chemicals, Richmond, VA, respectively). Blood lactate was analyzed with an Accusport Lactate Analyzer (Roche Molecular Biochemicals, Mannheim, Germany). Plasma epinephrine and norepinephrine were measured using HPLC as described by Causon et al. (26). Cortisol was analyzed using an in-house RIA kit developed by Vanderbilt University (Hormone Assay Core, Nashville, TN). GH was determined by RIA using the Nichols Institute Diagnostics (San Juan Capistrano, CA) kit (27). Glucagon was measured with an RIA kit based on the methods of Aguilar-Parada et al. (28). All assays were performed in either duplicate or triplicate and in a single run. The average within variability of samples were as follows: TG, 5.3%; FFA, 0.4%; glycerol, 6.8%; lactate, 5.1%; epinephrine, 7.4%; norepinephrine, 4.2%; cortisol, 7.5%; GH, 10.1%; and glucagon, 4.5%.
Magnetic resonance studies
Pre- and postexercise magnetic resonance data were acquired using a 3-T whole-body imaging system (Signa, Platform 4.5; GE Medical Systems, Milwaukee, WI). Axial T1-weighted localizing images were initially acquired from the thigh. Spectra were then recorded from an 18-mm3 voxel using a quadrature coil. Localization was achieved using a PRESS sequence (echo time, 45 msec; repetition time, 2000 msec; 128 acquisitions). The subject’s right (dominant) leg was extended and aligned with the bore of the magnet.
Fitting of spectra
Quantity of each metabolite was estimated by non-linear least-square (NLLS) method, AMARES (29) in jMRUI package (Leuven, Belgium). The 2048 raw data points were fitted using prior knowledge obtained from 8–10 peaks (29). The amplitudes, phases, line widths, and frequencies were estimated by the starting values. The time domain fitting was performed using Lorentzian line shape. The water signal was analyzed by Hankel Lanczos squares singular values decomposition (30). From the water signal, only the single water peak was quantified by Lanczos algorithm. IMCL was identified as peaks resonating at 1.3 ppm and EMCL at 1.5 ppm (6). IMCL values are presented in arbitrary units as represented by the total area under the curve and as IMCL/water. Peak fitting for IMCL had a variability of 6% on repeated measures.
Data analysis
Subject descriptive comparisons were made with Student’s t tests. Blood metabolite concentration, macronutrient composition, spectral peak area, and plasma volume data were analyzed with group x time repeated-measures ANOVA. When significant time main effects were observed, post hoc analysis was completed with Student’s t tests to determine location of pairwise differences. Pearson correlations were used to examine variables of interest. An 
-level of P < 0.05 was used as the criterion for statistical significance. SPSS (Chicago, IL) was used for all statistical analyses.
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Results |
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). Women were significantly different from men in body weight and percentage of body fat (P < 0.01). Dietary analysis for the 3 d before exercise revealed group differences for average total kilocalorie intake [men, 2015, vs. women, 1775 kcal/d (average)] (P < 0.05). These differences were no longer significant when expressed as kilocalories per FFM (P > 0.05). There were also no group differences for dietary nutrient composition (percentages of fat, carbohydrate, and protein; P > 0.05; data not shown).
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O2), RER, and HR during exercise are listed in Table 2. Based on RER data, male subjects expended 695 ± 25 kcal, and female subjects expended 522 ± 41 kcal (P = 0.003) during exercise. Kilocalorie expenditure per kilogram of FFM during the 60-min exercise session was 10.0 kcal for both men and women (P > 0.05).
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Immediately after exercise, there was a 13–14% reduction in plasma volume in both men and women (P < 0.05). Plasma volume changes were used to correct for the effects of hemoconcentration in plasma metabolite and hormonal concentrations.
IMCL results are presented in Table 3. Data are expressed in arbitrary units and in arbitrary units per muscle water. Muscle water levels were similar between pre- and postexercise (P > 0.05) and were used to normalize IMCL peak area (6).
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No gender differences were observed for IMCL changes with exercise. Similar results were found when expressing IMCL changes per kilogram of FFM (P > 0.05). When correlating IMCL changes with other physiological indices, subjects with the highest baseline IMCL or the greatest percentage body fat showed the greatest decrease in IMCL after exercise (men, r = 0.78, P < 0.01; women, r = 0.64, P < 0.01; both groups collapsed, r = 0.74, P < 0.01). Figure 1 illustrates typical spectra obtained from a male subject before and after exercise.
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. There was a significant decrease in plasma TG after exercise (P < 0.01). Women decreased plasma TG by 15%, and men decreased plasma TG by 6%. Significant postexercise increases were found for glycerol, and FFA (P < 0.001). After exercise, glycerol and FFA increased 59 and 50% for men and by 121 and 74% for women, respectively (P < 0.05).
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). Changes in plasma norepinephrine immediately after exercise represented an increase of 180 and 138% from baseline for men and women. Cortisol increased by 98 and 112% in men and women, respectively, immediately after exercise compared with baseline. Group (main effect) differences were present for norepinephrine and glucagon. |
Discussion |
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Before and during exercise, RER was used to quantify total substrate use. RER decreased during exercise for both groups reflecting an increase in percentage lipid oxidation and a relative decrease in carbohydrate oxidation as exercise progressed. Percentage lipid use during exercise, as indicated by RER, was similar between men and women. RER validity was ensured during substrate estimation by maintaining exercising lactate concentration <4 mmol/liter throughout exercise (31).
Exercise studies designed to evaluate total lipid use in men and women have yielded inconsistent results. For example, Romijn et al. (3) compared lipid use in trained women and men at 25 and 65% of O2max during 60 min of cycling. No gender differences were observed for RER, fatty acid oxidation, or FFA turnover during exercise. Similarly, Roepstorff et al. (4) found no gender differences in lipid use (RER, leg respiratory quotient, FFA with tracer) in subjects who completed 90 min of cycling at 58% O2max. In contrast, others have found differences in total lipid use during exercise between genders. Davis et al. (5), Horton et al. (32), and Toth et al. (33) found gender differences for RER in studies with exercise intensities ranging from 40–60% of O2max and exercise time ranging from 30 min to 2 h in both trained and untrained subjects. RER values in these studies were significantly lower for women, suggesting a greater contribution from lipid compared with men.
Lipids may be mobilized from adipose tissue, plasma lipoproteins, and skeletal muscle sources during exercise (1), making specific lipid use patterns difficult to quantify. 1H-MRS enables two separate lipid compartments in muscle, including IMCL and EMCL (6), to be evaluated, whereas traditional biopsy techniques lack compartmental specificity (9). 1H-MRS has relatively low variability on repeated measurements at the same muscle site (6% in the current study) and has been validated for measurement of IMCL (6, 34).
We found a significant decrease in IMCL immediately after exercise for both men and women. The decreases in IMCL after exercise in our study were 11.5–28.5% and 17.1–21.7% for men and women, respectively. The time main effect decreases were present even when normalizing for muscle water fluid shifts. The difference in change between groups was not significant. There was a large degree of variability in the magnitude of IMCL decrements in both groups potentially contributing to a lack of difference between genders. Our data are consistent with a recent study by Larson-Meyer et al. (13) who had a group of well-trained women complete a 2-h treadmill run at 67% O2max. They observed a 25% reduction in IMCL in the soleus muscle immediately after exercise, but found a large variation in IMCL changes (0–40%) immediately after exercise.
Our results are consistent with other published studies that have used 1H-MRS to evaluate IMCL changes with exercise. However, the majority of studies have used well-trained subjects and prolonged (
90 min) running protocols. In a group of men distance runners, Rico-Sanz et al. (11) found significant decreases in IMCL in the tibialis anterior (32%) and soleus (19%) muscle after a 90-min treadmill run at 64% of O2max. The authors suggested that differences in oxidative capacity of the muscles accounted for the differences in lipid decrements. Brechtel et al. (35) also examined IMCL changes in a group of trained men after half- and full-marathon runs and found significantly decreased IMCL from 10–57% depending on exercise duration and muscle (tibialis anterior and soleus) examined. Recent work by White et al. (12) found a 35% decrease in IMCL of the vastus lateralis muscle in a group of moderately active men immediately after a 45-min interval cycling session.
Although there were no observed gender differences for IMCL decrements with exercise in the current study, IMCL changes after exercise were correlated with baseline levels. Thus, those subjects with the highest baseline IMCL showed the greatest decrease in IMCL after exercise. This finding is similar to that of Larson-Meyer et al. (13) who found IMCL change after exercise to be positively correlated with baseline IMCL in a group of well-trained women runners.
Mechanisms that help explain IMCL decrements during exercise are speculative. Potential regulators of IMCL mobilization and use include altered muscle hormone-sensitive lipase (HSL-M) activity and the reesterification of fatty acids in the myocyte before their uptake into the mitochondria (36). At present, limited information regarding HSL-M responses to exercise is available, although it is likely that increased HSL-M activity contributed to the availability of muscle fatty acids for oxidation in the current study.
Protein and mRNA expression of HSL-M have been identified in muscle similar to that found with adipose tissue [adipose hormone-sensitive lipase (HSL-A)] (37, 38). In adipose tissue, the activity of HSL-A (via a cAMP cascade) is regulated by sympathetic and other hormonal activity (39). Although skeletal muscle receptors are of the ß2-subtype, compared with the ß1 found in adipose tissue (40), it is speculated that the same initiators that activate HSL-A activate HSL-M. Potential initiators of this cascade include catecholamines, cortisol, and GH (41).
In the current study, several plasma hormones increased during exercise, providing a potential stimulus for increased HSL-M activity. Increases were noted for norepinephrine, epinephrine, cortisol, and GH, although gender differences were only observed for norepinephrine. To our knowledge, no studies have made gender comparisons of sympathetic activation (via hormone induction) of isolated skeletal muscle fatty acid mobilization (from IMCL sources).
Besides hormonal regulation of HSL-M, muscle contraction may activate HSL-M through an independent mechanism. Langfort et al. (42) repeatedly electrically stimulated (200-msec trains of 100 Hz; impulse duration, 0.2 msec; 25 V) rat soleus muscle for 60 min. HSL-M was increased in the first minute of stimulation. The authors suggested that contraction-induced HSL-M activation occurred through direct phosphorylation of protein kinase. If this indeed occurs during exercise, HSL-M may be activated by a dual mechanism (hormonal activation and muscle contraction) (42).
Another factor contributing to the magnitude of IMCL use during exercise is fatty acid reesterification back into IMCL storage areas. Dyck and Bohen (43) used a pulse chase palmitate labeling technique to study isolated fatty acid release and esterification in skeletal muscle TG (IMCL). Isolated soleus muscle was studied using various continuous tetanic contractions [2, 8, 20, or 40 tetani/min (30 min)]. Their results suggested that not all fatty acids mobilized from IMCL sources were oxidized, but that approximately 30–35% of fatty acids entering the cell from plasma sources were reesterified back into IMCL, regardless of contraction rate. Thus, only 65% of fatty acids entering from outside the cell were oxidized, and the remainder were reesterified and stored within the cell during exercise. The mechanism for increased TG synthesis was unclear, but the authors suggested it was related to HSL-M control (phosphorylation/dephosphorylation) and acute changes in substrate availability [i.e. increased glycerol and muscle glycerol kinase activity (44)]. Findings of FFA reesterification into IMCL during exercise are similar to what has been reported by others (45, 46, 47).
The mechanisms associated with IMCL use are not fully understood. As with most metabolic processes, multiple factors influence IMCL metabolism during exercise. Future studies should explore mechanisms affecting both IMCL deposition and use.
In conclusion, 1 h of cycle ergometry in men and women matched for fitness, physical activity, and relative body composition resulted in significant decreases in IMCL immediately after exercise, with no gender differences observed. 1H-MRS used in conjunction with other techniques (e.g. tracers) may enable a more detailed understanding of substrate use during exercise.
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Acknowledgments |
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Footnotes |
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Abbreviations: EMCL, Extramyocellular lipid; FFA, free fatty acid; FFM, fat-free mass; 1H-MRS, proton nuclear magnetic resonance spectroscopy; HR, heart rate; HSL-A, adipose hormone-sensitive lipase; HSL-M, muscle hormone-sensitive lipase; IMCL, intramyocellular lipid; RER, respiratory exchange ratio; TG, triglyceride.
Received June 10, 2003.
Accepted September 2, 2003.
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