To investigate whether this could be due to sex-specific regulation of hormone-sensitive lipase (HSL) and to use sex comparison as a model to gain further insight into HSL regulation, nine women and eight men performed bicycle exercise (90 min, 60% V O2 peak), and skeletal muscle HSL expression, phosphorylation, and activity were determined. Supporting previous findings, basal IMTG content (P Ͻ 0.001) and net IMTG decrease during exercise (P Ͻ 0.01) were higher in women than in men and correlated significantly (r ϭ 0.72, P ϭ 0.001). Muscle HSL mRNA (80%, P ϭ 0.11) and protein content (50%, P Ͻ 0.05) were higher in women than in men. HSL total activity increased during exercise (47%, P Ͻ 0.05) but did not differ between sexes. Accordingly, HSL specific activity (HSL activity per HSL protein content) increased during exercise (62%, P Ͻ 0.05) and was generally higher in men than in women (82%, P Ͻ 0.05). A similar pattern was observed for HSL Ser 659 phosphorylation, suggesting a role in regulation of HSL activity. Likewise, plasma epinephrine increased during exercise (P Ͻ 0.05) and was higher in men than in women during the end of the exercise bout (P Ͻ 0.05). We conclude that, although HSL expression and Ser 659 phosphorylation in skeletal muscle during exercise is sex specific, total muscle HSL activity measured in vitro was similar between sexes. The higher basal IMTG content in women compared with men is therefore the best candidate to explain the higher IMTG net hydrolysis during exercise in women. intramuscular triacylglycerol; epinephrine; extracellular signal-regulated kinase TRIACYLGLYCEROL STORED IN skeletal muscle fibers (intramuscular triacylglycerol, IMTG) represents a large source of energy that may be used for muscle contraction during exercise. In men, it is still controversial to what extent IMTG is utilized during exercise (18,29,40). This is probably so because methodological limitations in measuring IMTG content have made it difficult to detect the relatively small net hydrolysis of IMTG that appears to occur during submaximal exercise in men (13,29,40,46). On the other hand, in women it has been shown that IMTG content is reduced by ϳ25% during 90-min bicycle exercise at 60% peak oxygen uptake (V O 2 peak ) (33), and it can be estimated that IMTG covers a large fraction (ϳ25%) of oxidative energy production in such an exercise bout in women (27). Therefore, the degree of IMTG hydrolysis during submaximal exercise appears to depend on sex, being higher in women than in men. It is presently unknown what may be the cause underlying this sex difference in IMTG hydrolysis during exercise.Hormone-sensitive lipase (HSL) is thought to catalyze the hydrolysis of IMTG in skeletal muscle as it does in adipose tissue (14,21). In rodent as well as in human skeletal muscle, neutral lipase activity increases during contraction (22,28,41), and it has been shown that the increase in neutral lipase activity elicited by contraction is completely accounted for by HSL activation both in rats and in man (22,28,45)...
Hormone-sensitive lipase (HSL) catalyses the hydrolysis of myocellular triacylglycerol (MCTG), which is a potential energy source during exercise. Therefore, it is important to elucidate the regulation of HSL activity in human skeletal muscle during exercise. The main purpose of the present study was to investigate the role of 5 AMP-activated protein kinase (AMPK) in the regulation of muscle HSL activity and Ser 565 phosphorylation (the presumed AMPK target site) in healthy, moderately trained men during 60 min bicycling (65%V O 2 peak ). α 2 AMPK activity during exercise was manipulated by studying subjects with either low (LG) or high (HG) muscle glycogen content. HSL activity was distinguished from the activity of other neutral lipases by immunoinhibition of HSL using an anti-HSL antibody. During exercise a 62% higher (P < 0.01) α 2 AMPK activity in LG than in HG was paralleled by a similar difference (61%, P < 0.01) in HSL Ser 565 phosphorylation but without any difference between trials in HSL activity or MCTG hydrolysis. HSL activity was increased (117%, P < 0.05) at 30 min of exercise but not at 60 min of exercise. In both trials, HSL phosphorylation on Ser 563 (a presumed PKA target site) was not increased by exercise despite a fourfold increase (P < 0.001) in plasma adrenaline. ERK1/2 phosphorylation was increased by exercise in both trials (P < 0.001) and was higher in LG than in HG both at rest and during exercise (P = 0.06). In conclusion, the present study suggests that AMPK phosphorylates HSL on Ser 565 in human skeletal muscle during exercise with reduced muscle glycogen. Apparently, HSL Ser 565 phosphorylation by AMPK during exercise had no effect on HSL activity. Alternatively, other factors including ERK may have counterbalanced any effect of AMPK on HSL activity.
Objective: In obese subjects, chronically elevated plasma concentrations of non-esterified fatty acids (NEFAs) exert a marked risk to contract insulin resistance and subsequently type 2 diabetes. When NEFA is acutely increased due to i.v. infusion of lipid, glucose disposal during a hyperinsulinemiceuglycemic clamp is reduced. This effect has been explained by a NEFA-induced decrease in skeletal muscle insulin sensitivity caused by accumulation of the lipid intermediates such as ceramide and diacylglycerol in the myocytes. However, neither the lipid-induced reduction of glucose disposal nor the intramyocellular lipid deposition has been compared directly in obese females and males. Design: We studied eight obese females and eight obese males (body mass index (BMI): 32.6G1.4 and 32.8G0.8 respectively, non significant (NS)) matched for cardiorespiratory fitness relative to lean body mass (43.7G1.6 and 47.6G1.3 ml/kg min respectively, NS). Methods: Each subject underwent two hyperinsulinemic-euglycemic clamps with infusion of lipid or saline respectively. Furthermore, the subjects exercised during the last half an hour of each clamp. Results: The lipid-induced reduction in glucose disposal during the clamp was similar in females and males (46G10 and 60G4% respectively, NS). However, whole-body insulin sensitivity as well as nonoxidative glucose disposal was higher in obese females compared with obese males both during lipid and saline infusion (P!0.001 and PZ0.01 respectively). Muscle ceramide, triacylglycerol (TAG), diacylglycerol (DAG), and glycogen content were similar between sexes and remained unchanged during the clamp and when exercise was superimposed. Conclusions: The lipid-induced inhibition of glucose disposal is similar in obese females and males. However, obese females are more insulin sensitive compared with obese males (both during saline and lipid infusion), which is not due to differences in the concentration of the muscle lipid intermediates such as ceramide and DAG.European Journal of Endocrinology 158 61-68
FAT/CD36 is a transmembrane protein that is thought to facilitate cellular long-chain fatty acid uptake. However, surprisingly little is known about the localization of FAT/CD36 in human skeletal muscle. By confocal immunofluorescence microscopy, we demonstrate high FAT/CD36 expression in endothelial cells and weaker but significant FAT/CD36 expression in sarcolemma in human skeletal muscle. No apparent intracellular staining was observed in the muscle cells. There are indications in the literature that caveolae may be involved in the uptake of fatty acids, possibly as regulators of FAT/CD36 or other fatty acid transporters. We show that in sarcolemma, FAT/CD36 colocalizes with the muscle-specific caveolae marker protein caveolin-3, suggesting that caveolae may regulate cellular fatty acid uptake by FAT/CD36. Furthermore, we provide evidence that FAT/ CD36 expression is significantly higher in type 1 compared with type 2 fibers, whereas caveolin-3 expression is significantly higher in type 2 fibers than in type 1 fibers. -Vistisen, B., K. Roepstorff, C. Roepstorff, A. Bonen, B. van Deurs, and B. Kiens. Sarcolemmal FAT/CD36 in human skeletal muscle colocalizes with caveolin-3 and is more abundant in type 1 than in type 2 fibers. J. Lipid Res. 2004. 45: 603-609.
In the present study, we investigated possible sites of regulation of long-chain fatty acid (LCFA) oxidation in contracting human skeletal muscle. Leg plasma LCFA kinetics were determined in eight healthy men during bicycling (60 min, 65% peak oxygen uptake) with either high (H-FOX) or low (L-FOX) leg fat oxidation (H-FOX: 1,098 +/- 140; L-FOX: 494 +/- 84 micromol FA/min, P < 0.001), which was achieved by manipulating preexercise muscle glycogen (H-FOX: 197 +/- 21; L-FOX: 504 +/- 25 mmol/kg dry wt, P < 0.001). Several blood metabolites and hormones were kept nearly similar between trials by allocating a preexercise meal and infusing glucose intravenously during exercise. During exercise, leg plasma LCFA fractional extraction was identical between trials (H-FOX: 17.8 +/- 1.6; L-FOX: 18.2 +/- 1.8%, not significant), suggesting similar LCFA transport capacity in muscle. On the contrary, leg plasma LCFA oxidation was 99% higher in H-FOX than in L-FOX (421 +/- 47 vs. 212 +/- 37 micromol/min, P< 0.001). Probably due to the slightly higher (P < 0.01) plasma LCFA concentration in H-FOX than in L-FOX, leg plasma LCFA uptake was nonsignificantly (P = 0.17) higher (25%) in H-FOX than in L-FOX, yet the fraction of plasma LCFA uptake oxidized was 61% higher (P < 0.05) in H-FOX than in L-FOX. Accordingly, the muscle content of several lipid-binding proteins did not differ significantly between trials, although fatty acid translocase/CD36 and caveolin-1 were elevated (P < 0.05) by the high-intensity exercise and dietary manipulation allocated on the day before the experimental trial. The present data suggest that, in contracting human skeletal muscle with different fat oxidation rates achieved by manipulating preexercise glycogen content, transsarcolemmal transport is not limiting plasma LCFA oxidation. Rather, the latter seems to be limited by intracellular regulatory mechanisms.
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