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1 Copenhagen Muscle Research Centre, National University Hospital, Denmark2 Department of Physiology, Medical University of Bialystok, Bialystok, Poland
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(Received 4 June 2003;
accepted after revision 4 November 2003)
Corresponding author J. W. Helge: Copenhagen Muscle Research Centre, Department of Medical Physiology, The Panum Institute, University of Copenhagen, Blegdamsvej 3, DK-2102 Copenhagen N, Denmark. Email: Jhelge{at}mfi.ku.dk
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(TNF) and interleukin 1 (IL-1), 1,25-dihydroxyvitamin D3, dexametasone and UV light (Peraldi et al. 1996; Mathias et al. 1998). In addition, ceramide can also be synthesized de novo from fatty acids and serine (Schmitz-Peiffer et al. 1999) and by conversion of sphingosine to ceramide (Mathias et al. 1998) (Fig. 1). There is only limited information available on the content of ceramide in skeletal muscle cells. A recent study demonstrated that ceramide content in the fast-twitch white muscle was lower than in the fast-twitch red and the slow-twitch red rat muscle (Dobrzyn & Gorski, 2002b). Only limited information is available on the effect of acute exercise on muscle ceramide content and the effect of training on muscle ceramide content is not known. In rat skeletal muscle Turinsky et al. (1990) did not find any effect of in vivo electrical stimulation (25 min, one contraction per second). However, when prolonged exercise of moderate intensity was used a reduced ceramide content was observed in both fast-twitch red and slow-twitch red rat muscle (Dobrzyn & Gorski, 2002b). The reduction in ceramide content was accompanied by a reduction in the activity of neutral, Mg2+-dependent sphingomyelinase activity (Dobrzyn & Gorski, 2002b). The role of ceramide during exercise is not well described. In myocytes increased ceramide content led to a reduction in glucose uptake (Schmitz-Peiffer et al. 1999) and in rat muscle an inverse relation between 2-deoxyglucose uptake and ceramide content was present after prolonged exercise (Dobrzyn & Gorski, 2002b) and it is therefore possible that ceramide content contributes to the regulation of muscle glucose uptake during and after exercise. There is, to our knowledge, no available information on the ceramide content and the activity of neutral Mg2+-dependent sphingomyelinase in human skeletal muscle. The present study aimed to investigate ceramide- and sphingomyelin fatty acid content and composition and neutral, Mg2+-dependent sphingomyelinase activity in an untrained and a trained group of young volunteers at rest and after prolonged whole body exercise. Training affects lipid metabolism in skeletal muscles (Van der Wusse & Reneman, 1996), but its affect on metabolism of ceramide has not been studied. The underlying hypothesis of the study was that the expected exercise induced changes in ceramide content and neutral sphingomyelinase activity would be attenuated after exercise in a trained versus an untrained group.
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Sixteen healthy young male subjects (age 27 ± 1 years, height 181 ± 2 cm, weight 77 ± 2 kg) participated in the study. Subjects were fully informed of the nature and the possible risks associated with the experimental part of the study before they volunteered to participate. The study was approved by the ethical committee of Copenhagen municipality and adhered to the Principles of the Helsinki Declaration. All of the eight trained subjects were heavily engaged in endurance training, whereas none of the eight untrained subjects participated in any organized endurance type of training.
Experimental protocol
Subjects reported to the laboratory on two days over a 2-week period. On the first day a graded incremental exercise protocol was used to establish maximal oxygen uptake (VO2,max) and VO2–work relationship. On the second occasion the subjects performed a 3-h exercise bout at 58%VO2,max.
On day one, the subjects performed two consecutive 10–12-min submaximal bicycle exercise bouts (Monark 839E, Monark Exercise AB, Sweden; or Lode, Lode, Gronningen, The Netherlands) to establish a workload–VO2 relation. After a break of 5–10 min following the second submaximal exercise bout a standard progressive maximal oxygen uptake test was performed with increments of 45 W min–1 until exhaustion. Two days prior to the second experimental day the subjects were asked to include carbohydrate-rich foods in their dietary intake to ensure full restoration of the muscle glycogen content and on the last day the subjects were asked to refrain from vigorous physical activity. The subjects fasted overnight prior to the experiment and came to the laboratory in the morning. After an initial 15-min rest period a needle biopsy from the vastus lateralis muscle was obtained with suction (Bergström, 1962). Prior to exercise, the body weight and height were measured. Subjects then started bicycle exercise at a workload estimated to elicit a load of 58% of VO2,peak. This workload was elected such that the subjects were able to continue exercise for 3 h and yet still be close to fatigue at termination of exercise. Exercise was performed on one of two bicycle ergometers (Monark 839E or Lode), but for each subject the same bicycle was used on the two experimental days. The pulmonary VO2 and carbon dioxide excretion (VCO2) were measured during the initial 10–12 min of exercise and during the last 7–8 min at 30-min intervals through the remainder of the exercise. The heart rate was recorded continuously. The subjects were asked to exercise for 180 min. They had free access to water, and were encouraged to drink regularly during exercise to avoid dehydration. After termination of exercise subjects were immediately placed on a bed and a second muscle biopsy from the vastus lateralis was obtained.
Analytical procedures
Heart rate was recorded continuously with a PE 3000 Sports Tester (Polar Electro, Finland). Pulmonary VO2 and VCO2 were measured by an automated on-line system (CPX, Medical Graphics, Spiropharma, Denmark). Gases of known composition were used to calibrate the system regularly.
The biopsies were frozen in liquid nitrogen within 10–15 s after sampling and they were stored at –80°C until further analysis. Before biochemical analysis for enzyme activity the muscle biopsy samples were freeze-dried and dissected free of connective tissue, visible fat and blood using a stereomicroscope. The maximal activity of ß-hydroxy-acyl-coenzyme A (CoA)-dehydrogenase (HAD), citrate synthase (CS), phospho-fructo-kinase (PFK) and lactate dehydrogenase (LDH) were determined fluorometrically (Lowry & Passonneau, 1972).
Ceramide- and sphingomyelin fatty acid content was measured as previously described (Dobrzyn & Gorski, 2002b). The muscle samples were pulverized in an aluminium mortar with a stainless steel pestle precooled in liquid nitrogen. The powder was then transferred to clean glass tubes, containing methanol at a temperature of –20°C. Methanol contained butylated hydroxytoluene (Sigma) (30 mg per 100 ml) as an antioxidant. Lipids were extracted by the method of Folch et al. (1957). Sphingomyelin was isolated on silica plates (Kieselgel 60, 0.22 mm, Merck) using a developing solvent composed of chloroform–methanol–acetic acid–water (50: 37.5: 3.5: 2 v/v/v/v). Ceramide was isolated using plates as above. First, the plates were developed to one-third of the total length of the plate in chloroform–methanol–25% NH3 (20: 5: 0.2, v/v/v). Next, they were dried and chromatographed in heptane-isopropyl ether-acetic acid (60: 40: 3, v/v/v). Standards of sphingomyelin (sphingomyelin from bovine brain, Sigma) and ceramide (non-hydroxy fatty acid ceramide, Sigma) were run along with the samples. The retention factor (Rf) values are 0.31 for ceramide and 0.40 for diacylglycerol. The plates were allowed to dry at room temperature and lipid bands were visualized under UV light after spraying with a 0.5% solution of 3'5'-dihydrofluorescein prepared in absolute methanol. The gel bands corresponding to the standards of ceramide and sphingomyelin were scraped off the plate into screw tubes containing methylpentadecanoic acid (Sigma) as an internal standard. Fatty acids were transmethylated along with the gel in the presence of 1 ml of 14% boron fluoride in methanol at 100°C for 90 min (Morrison et al. 1965). The resulting fatty acid methyl esters were identified and quantified by means of gas liquid chromatography. A Hewlett-Packard 5890 Series II chromatograph and a fused Hp-INNOWax (50 m) capillary column were used. The chromatograph was equipped with a double flame ionization detector. Injector and detector temperatures were set at 250°C each. The oven temperature was increased linearly from 160 to 230°C at a rate of 5°C min–1. Individual fatty acid methyl esters were quantified using area corresponding to internal standards. The fatty acid standards were obtained from Sigma.
Activity of neutral, Mg2+-dependent sphingomyelinase was determined according to Tomiuk et al. (2000). Briefly, the muscle samples were homogenized in a buffer composed of 0.05 M Tris-HCl (pH 7.4), 0.23 M saccharose, 10 mM EDTA, 10 mM EGTA and 5 mM DTT and the tubes were centrifuged. Three hundred microlitres of the supernatant was added to a solution containing 10 nmol of N-[14CH3]-sphingomyelin (specific activity (SA) 52 mCi mmol–1; Du Pont) dissolved in 100 µl of incubation buffer composed of 0.1 M Tris-HCl (pH 7.4), 5 mM DTT, 0.05% Triton X-100 and 5 mM MgCl2. The mixture was incubated for 30 min at 37°C. The reaction was terminated with chloroform/methanol (2: 1). The solution was shaken, water was added, centrifuged and radioactivity of the upper water phase containing N-[14CH3]-phosphorylcholine was counted using a Packard TRI-CARB 1900 TR scintillation counter and the Ultima Gold scintillation cocktail (Packard). The total protein content was measured according to Lowry et al. (1951).
Statistics
Results are given as mean ±S.E.M., if not otherwise stated. One-way and two-way analysis of variance (ANOVA) with repeated measures (RM) for the time factor was performed to test for changes resulting from training and/or time. In the case of significant main effects or interactions a Student–Newman–Keuls post hoc test was performed to discern statistical differences. In all cases, P P 0.05 was taken as the level of significance in two-tailed tests.
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At rest, the total content of ceramide fatty acids and the composition of ceramide fatty acids was similar in both groups (Fig. 3A, Table 2). After exercise, the total ceramide fatty acid content was elevated (P P 0.05) in both groups. This increase in ceramide content was accounted for by an elevation in the content of ceramides containing oleic, linoleic and eicosapentaenoic acid residue in the untrained group, and ceramides containing palmitic, stearic, oleic, linoleic and eicosapentaenoic acid residue in the trained group (P P 0.05 in each case, Table 2). The ratio of the total content of ceramide containing saturated fatty acids to the total content of ceramide containing unsaturated fatty acids did not differ between the groups (Table 2).
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At rest, the total sphingomyelin fatty acid content in the trained group was lower (P P 0.05) than in the untrained group (Fig. 3B). This was due to a reduced content of sphingomyelin containing stearic and oleic acids (P P 0.05) whereas the content of sphingomyelin containing arachidonic acid was increased (P P 0.05) in the trained group (Table 3). Consequently, the ratio of the content of sphingomyelin saturated fatty acids to the content of sphingomyelin unsaturated fatty acids was lower (P P 0.05) in the trained than in the untrained group (Table 3)). Exercise increased (P P 0.05) the sphingomyelin fatty acid content only in the trained group. As a result, the post-exercise content of the compound was similar in both groups (Fig. 3B).
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Exercise reduced the enzyme activity in each group (P P 0.05). The activity of neutral Mg2+-dependent sphingomyelinase was similar in the two groups, both at rest and after exercise (Fig. 3C).
The ratio of the total content of ceramide fatty acids to the total content of sphingomyelin fatty acids
The ratio of the total content of ceramide fatty acids to the total content of sphingomyelin fatty acids was similar in the two groups and it was increased (P P 0.05) after exercise (Fig. 3D). No correlation was present between the activity of neutral Mg2+-dependent sphingomyelinase and the total content of ceramide fatty acids and the total content of sphingomyelin fatty acids in either group at rest or after exercise.
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The present study reports, for the first time, data on the content of ceramide fatty acids in human skeletal muscle. In a study by Itani et al. (2002) the content of ceramide in human muscle was measured, but the data were not presented. The total content of ceramide in human skeletal muscle in the present study is higher by 
39% (on average) than previously reported total ceramide fatty acid content in the rat skeletal muscle (Turinsky et al. 1990; Dobrzyn & Gorski, 2002b). The ratio of the total content of saturated fatty acids to the total content of unsaturated fatty acids is similar to that in the rat muscle (Dobrzyn & Gorski, 2002b). However, there are notable differences in individual fatty acid content between human and rat (red gastrocnemius) muscle. First, in human skeletal muscle ceramide contains arachidic acid (20: 0), which is not present in the rat skeletal muscle. Moreover, human muscle lacks ceramide-containing linolenic (18: 3) and docosahexaenoic (22: 6) acids, which are present in the rat muscle. Furthermore, the percentage content of ceramide containing palmitic (16: 0) and eicosapentaenoic (20: 5) acids is higher, whereas ceramide containing stearic (18: 0), oleic (18: 1) and arachidonic (20: 4) acids is lower in human muscle compared with rat muscle (Dobrzyn & Gorski, 2002b). A relationship between ceramide fatty acid composition and its biological effects has not been recognized so far. It would be premature to discuss the biological meaning of the difference in the content of individual ceramides between human and rat muscle at present.
Acute prolonged exercise elevated the content of ceramide in human skeletal muscle. This is in sharp contrast to results from rat skeletal muscles (soleus and the red part of the gastrocnemius), in which a reduction in the content of ceramide after prolonged exercise was described (Dobrzyn & Gorski, 2002b). An explanation for this apparent discrepancy between the data obtained in the rat and the results of the present study may at least in part be explained by a difference in exercise intensity and mode and/or be due to a species difference. However, prolonged whole body exercise is normally considered to be a definite stress to the human body and the finding of an increased muscle ceramide content after exercise is therefore in line with the observation of increased ceramide content after cell stress seen in different muscle cell lines (Begum et al. 1996; Begum & Ragolia, 1996; Basu & Kolesnick, 1998). The content and composition of ceramide at rest were similar in the untrained and trained subjects. In addition, the acute exercise increased the total content of ceramide in the untrained and trained subjects to a similar degree. After exercise the muscle water content was slightly (1.1 ± 0.3%) higher in both trained and untrained muscle (our unpublished data), and water content was identical between trained and untrained subjects. Therefore, the observed changes are not due to a water shift induced by exercise. There are no available data on the effect of training on ceramide content in skeletal muscle.
Sphingomyelin is claimed to be the major source of ceramide in the sphingomyelin-signalling pathway. As already mentioned, the plasma membrane bound sphingomyelin is hydrolysed to ceramide and phosphocholine in a reaction catalysed by the enzyme-neutral, Mg2+-dependent sphingomyelinase. Certain amounts of the compound can be formed also from sphingomyelin localized in the membrane of lysosomes and endosomes by the action of the enzyme acidic sphingomyelinase (Monney et al. 1998; Garcia-Ruiz et al. 2002). Therefore, we also measured the content of sphingomyelin fatty acids and the activity of neutral, Mg2+-dependent sphingomyelinase. The data published so far on the content of sphingomyelin fatty acids in human muscle are not uniform: the content of unsaturated fatty acids was reported to be in the range of 15–50% of the total fatty acids (Svennerholm et al. 1972; Kunze et al. 1975; Pearce et al. 1981). In the present study this value was 32% and lies in the middle of the values reported in the studies mentioned above. Training moderately (by 12%; P P 0.05) reduced the total content of sphingomyelin fatty acid. In the present study acute exercise did not affect the total content of sphingomyelin fatty acids in the untrained group and elevated it moderately in the trained group. If activation of the sphingomyelin signalling pathway was a reason for the elevation in the total content of ceramide fatty acids, one should expect a concomitant reduction in the content of sphingomyelin fatty acids, which is not the case. Consistent with this, the activity of neutral, Mg2+-dependent sphingomyelinase was reduced after exercise in both groups. Sphingomyelin can be synthesized from ceramide using phosphatidylcholine as a phosphocholine donor (Riboni et al. 1997) and this may help to explain the concomitant increase in ceramide and sphingomyelin in the trained group. During exercise there is a very limited uptake of very low-density lipoprotein (VLDL)-chylomicrons in the overnight fasted state (Kiens et al. 1993), and it is therefore unlikely that there is a significant contribution of sphingomyelin from the plasma lipoproteins. These data are in line with the results of a prior study in rats, which demonstrated that exhaustive exercise decreased the neutral Mg2+-dependent sphingomyelinase activity (Dobrzyn & Gorski, 2002b). It should be added that the data on the activity of the enzyme in human muscle are reported here for the first time. In the heart, the activity of acidic sphingomyelinase is much higher than the neutral, Mg2+-dependent one (Chatterjee, 1998). There are no data on the acidic isoform of the enzyme in skeletal muscles. However, taking into account that the content of sphingomyelin fatty acids after exercise remained either stable or even slightly increased, sphingomyelin can probably be excluded as a major source of ceramide in human muscle during exercise. In the rat, prolonged exercise has been shown to increase the content of sphingosine (the product of ceramide hydrolysis) in skeletal muscles (Dobrzyn & Gorski, 2002a). This strongly indicates that contractile activity increases catabolism of ceramide in active skeletal muscle. Ceramide is synthesized de novo from serine and long-chain fatty acids (Fig. 1), but this pathway is probably rather slow (Schmitz-Peiffer et al. 1999). However, our subjects exercised for 3 h and the type of exercise performed is well known to increase the concentration of plasma free fatty acids considerably. This creates favourable conditions for an elevation in the rate of ceramide synthesis. In turn, this could contribute to the elevation in the content of ceramide observed in the muscle after exercise.
In conclusion, this study shows the presence of 11 ceramide fatty acids in the human muscle. It further demonstrates that prolonged exercise elevated the total content of ceramide fatty acids and reduced the activity of neutral, Mg2+-neutral sphingomyelinase both in untrained and in endurance-trained young men. Ceramide is involved, as a second messenger, in regulation of a number of different cell functions and the exercise-induced increase in ceramide content could influence muscle cell adaptation after exercise. One potential role of ceramide and sphingolipid metabolites could be an effect on glucose uptake. Further studies should include measurement of the pathways that lead to ceramide/sphingomyelin formation and the targeted ceramide second messenger effects to elucidate the specific effects of exercise on changes in ceramide fatty acids and their effects on muscle cell metabolism and adaptation.
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P P 0.05 versus last sample; 
:P P 0.05 versus previous level.