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1Department of Human Biology and Nutritional Sciences, University of Guelph, Guelph, Ontario N1G 2W1; and 2Department of Medicine, McMaster University, Hamilton, Ontario, Canada L8N 3Z5
Submitted 20 December 2002 ; accepted in final form 13 February 2003
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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20-fold greater than that at rest by 120 min. Epinephrine was increased above rest (P < 0.05) at 60 (1.47 ± 0.15 nM) and 120 min (4.87 ± 0.76 nM) of exercise. Insulin concentrations decreased rapidly and were lower than resting levels by 10 min and continued to decrease throughout exercise. In summary, HSL activity was increased from resting levels by 10 min, increased further by 60 min, and decreased to near-resting values by 120 min. The increased HSL activity at 60 min was associated with the stimulating effect of increased epinephrine and decreased insulin levels. After 120 min, the decreased HSL activity was associated with the proposed inhibitory effects of increased free AMP. The accumulation of LCFA CoA in the 2nd h of exercise may also have reduced the flux through HSL and accounted for the reduction in IMTG utilization previously observed late in prolonged exercise. fat oxidation; lipolysis; epinephrine; insulin; free AMP
Similar to the regulation of adipose tissue lipolysis, hormone-sensitive lipase (HSL) is thought to be the rate-limiting enzyme for skeletal muscle IMTG hydrolysis, because the enzyme exhibits an 10-fold higher specific activity for diacylglycerol than for triacylglycerol. HSL is regulated acutely via reversible phosphorylation (20). Experiments conducted in isolated rat skeletal muscle demonstrated increased HSL activity with epinephrine infusion and contractions (25, 26). A study in adrenalectomized epinephrine-deficient humans suggested that epinephrine is essential for increased HSL activity (24), although recent work in healthy men does not support these findings (41). Instead, the increased HSL activity at the onset of exercise was largely independent of exercise intensity and plasma epinephrine concentrations (41), suggesting that factors other than 
-adrenergic stimulation enhance HSL activity. Aside from epinephrine, evidence from adipose tissue preparations indicate that calcium, 5'-AMP-activated protein kinase (AMPK), long-chain fatty acyl-CoA (LCFA CoA), and insulin are regulators of HSL activity (20). Data relating to the control of HSL activity in skeletal muscle are limited.
LCFA CoA represent the activated form of fatty acids and are important intermediates in numerous cellular processes, including lipid biosynthesis and oxidation. The LCFA CoA pool is labile and increases when lipid availability is augmented by high-fat feeding and fasting in rat skeletal muscle (6, 12). In light of these acute responses, it seems reasonable that LCFA CoA may accumulate late in prolonged exercise given the marked increase in plasma FFA availability and uptake (33). Thus the decreased IMTG utilization observed with prolonged exercise (40) may be explained by cytosolic accumulation of LCFA CoA, an allosteric inhibitor of HSL activity in adipose tissue (22).
Hence, the primary purpose of this study was to measure HSL activity and selected putative regulators of HSL, including LCFA CoA, during 2 h of moderate-intensity exercise. We tested the hypothesis that HSL activity would decrease late in exercise in association with LCFA CoA accumulation.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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O
2) were as follows: 21 ± 1 yr, 77 ± 3 kg, and 49.9 ± 1.8 ml · kg-1 · min-1, respectively. The Human Ethics Committees from both institutions approved all experimental procedures.
Preexperimental procedures. Subjects visited the laboratory on one occasion and completed an incremental cycling (Excalibur, Quinton Instrument, Seattle, WA) test to volitional exhaustion for the determination of peak O2
(O2 peak). Expired gases were collected, and O2
was determined on-line using a metabolic cart (Q-plex 1, Quinton Instruments). Subjects visited the laboratory on a second occasion to perform a familiarization trial, which consisted of 120 min of cycling at a power output corresponding to 60% O2 peak. Before this visit, subjects were asked to consume a high-carbohydrate meal (70% carbohydrate) 4 h before commencement of exercise and to replicate this meal before the experimental trial. For the 24 h before the experimental trial, subjects were asked to abstain from heavy exercise and consumption of caffeine and alcohol.
Experimental procedures. Subjects arrived at the laboratory and rested quietly on a bed, and a Teflon catheter was introduced into an antecubital vein for subsequent blood sampling. The catheter was kept patent by flushing with 0.9% saline. Each leg was prepared for percutaneous needle biopsy of the vastus lateralis muscle by making two incisions in the skin and deep fascia under local anesthesia (2% lidocaine without epinephrine). Immediately before exercise, a muscle and blood (5 ml) sample was obtained while subjects remained on the bed. All muscle samples were rapidly frozen in liquid nitrogen for later analysis.
Subjects then moved to the ergometer and commenced cycling at their predetermined power output, which averaged 155 ± 4 W. Expired gases were collected from 5 to 10 min, with the last 2 min being recorded. The subjects maintained a constant workload and pedal frequency during the collection of all expired gas measurements. A blood sample was obtained at 9 min while subjects continued to cycle. Subjects temporarily stopped cycling at 10 min, and a second biopsy was immediately (<20 s) obtained from the same leg used for the resting biopsy while subjects remained on the ergometer. This leg was bandaged, and subjects commenced cycling within 2 min of exercise cessation. Muscle samples were obtained from the contralateral leg at 60 and 120 min of exercise. Venous blood samples and expired gases were obtained at 30, 60, 90, and 120 min.
Analysis. One portion of heparinized whole blood was immediately deproteinized 1:5 with 0.6% (wt/vol) HClO4 and centrifuged. The extract was stored at -80°C and subsequently analyzed for blood glucose, lactate, and glycerol (4). A second portion of whole blood was centrifuged, and the plasma was removed for the determination of FFA by an enzymatic colorometic method (NEFA C test kit, Wako Chemicals) and insulin by radioimmunoassay (Coat-a-Count insulin test kit, Diagnostic Products). A final portion of blood (1.5 ml) was added to 30 µl of EGTA-glutathione, mixed thoroughly, and centrifuged. The supernatant was stored at -80°C and subsequently analyzed for plasma epinephrine by radioimmunoassay (Adrenaline RIA, Labor Diagnostika Nord).
Skeletal muscle was freeze-dried, dissected free of connective tissue, blood, and fat under magnification, and powdered. One aliquot (6–8 mg) of powdered muscle was used for the determination of HSL activity according to the methods of Langfort et al. (26) as modified by Watt et al. (41). Briefly, the powdered muscle was homogenized on ice in 20 vol of homogenizing buffer using a rotating Teflon pestle on glass. After centrifugation, the supernatant was removed and stored on ice for immediate analysis of HSL activity. A substrate consisting of 5 mM triolein, 14 x 106 disintegrations/min [9,10-3H]triolein, 0.6 mg phospholipid [3:1 (wt/wt) phosphatidylcholine-phosphatidylinositol], 0.1 M potassium phosphate, and 20% BSA was emulsified by sonication (14, 29). The muscle homogenate supernatant (14 µl) was incubated at 37°C with enzyme dilution buffer (86 µl) and 100 µl of triolein substrate. The reaction was stopped after 20 min by the addition of 3.25 ml of 10:9:7 (vol/vol/vol) methanol-chloroform-heptane, and 1.1 ml of 0.1 M potassium carbonate-0.1 M boric acid were added to facilitate the separation of the organic and aqueous phases. The mixture was vortexed and centrifuged at 1,100 g for 20 min, and 1 ml of the upper phase containing the released fatty acids was removed for determination of radioactivity on a beta spectrometer (Beckman LS 5000TA). All measurements were made in triplicate, and the mean of these values is reported. This assay measures covalent effects and does not allow for the observation of allosteric effects.
A second aliquot of freeze-dried muscle (10 mg) was extracted in 0.5 M HClO4 (1 mM EDTA) and neutralized with 2.2 M KHCO3. The supernatant and acid-insoluble pellet were separated and stored at -80°C. The supernatant was used for the determination of ATP, phosphocreatine (PCr), creatine, and lactate by spectrophotometric assays (4, 19) and acetyl-CoA, acetylcarnitine, and carnitine by radiometric methods (5). The acid-insoluble pellet was homogenized and extracted as previously described (2), and the supernatant was removed for radiometric measurement of LCFA CoA and LCFA carnitine (5). The free CoA and carnitine were first cleaved from the LCFAs as described above. All enzyme and metabolite measurements were normalized to the highest total creatine content from the nine samples obtained for each subject to correct for nonmuscle contamination.
Calculations. Free ADP and AMP concentrations were calculated with the assumption of equilibrium of the adenylate kinase and creatine kinase reactions (11). Free ADP was calculated using the measured ATP, creatine, and PCr values, an estimated H+ concentration (34), and the creatine kinase equilibrium constant of 1.66 x 109. Free AMP concentration was calculated from the estimated free ADP and measured ATP with the adenylate kinase constant of 1.05. Whole body carbohydrate and fat oxidation rates were estimated using the following equations
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CO2 is CO2 output. Statistical analysis. Values are means ± SE. Statistical analysis was performed by one-way analysis of variance with repeated measures, and specific differences were located using a Student-Newman-Keuls post hoc test. Statistical significance was set at P < 0.05.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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O2 averaged 29.6 ± 0.6 ml · kg-1 · min-1 at 10 min and remained constant until 120 min, when a small increase occurred (Table 1). O2 throughout the trial averaged 61 ± 2% O2 peak. Respiratory exchange ratio at 10 min averaged 0.97 ± 0.01 and progressively decreased (P < 0.05) throughout exercise, reaching a nadir of 0.86 ± 0.01 at 120 min (Table 1). Accordingly, the calculated carbohydrate oxidation rate was greatest early (10 min) in exercise, decreased (P < 0.05) by 30 min, and decreased further at 120 min (Fig. 1). Fat oxidation increased (P < 0.05) throughout exercise from 4.6 ± 1.1 kJ/min at 10 min to 22.6 ± 1.5 kJ/min at 120 min.
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HSL activity at rest and during exercise. HSL activity at rest averaged 2.09 ± 0.19 mmol · min-1 · kg dry mass-1 and increased (P < 0.05) to 2.56 ± 0.22 mmol · min-1 · kg dry mass-1 at 10 min. HSL activity increased (P < 0.05) further at 60 min but decreased (P < 0.05) to near-resting values by 120 min (Fig. 2).
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Muscle metabolites at rest and during exercise. LCFA CoA averaged 15.9 ± 3.0 µmol/kg dry mass at rest and increased in a linear manner throughout exercise, reaching significance (P < 0.05) at 60 and 120 min (Fig. 3). LCFA carnitine was unchanged from resting values at 10 min of exercise, increased by 74% from resting values by 60 min, and increased further (P < 0.05) at 120 min (Fig. 3).
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Muscle contents of ATP were maintained throughout exercise (Table 2). PCr was decreased (P < 0.05) at 10 min of exercise and remained lower than resting values throughout exercise (Table 2). Muscle lactate contents were higher (P < 0.05) than resting values throughout exercise (Table 2). Acetyl-CoA and acetylcarnitine were increased (P < 0.05) from resting levels at 10 and 60 min of exercise. Acetyl-CoA was greater at 120 min than at rest but decreased from previous exercise levels. No such decrease in acetylcarnitine was observed (Table 2). Consistent with the increase in acetylcarnitine, free carnitine was decreased (P < 0.05) at 10 min and remained lower than resting values throughout exercise (Table 2).
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Free AMP at rest averaged 0.32 ± 0.12 µmol/kg dry mass, was increased (P < 0.05) at 60 min, and was further increased at 120 min (Table 2). Free ADP was increased (P < 0.05) from resting concentrations at all exercise time points. The increase at 120 min was greater than that observed at 10 and 60 min (Table 2).
Plasma hormones at rest and during exercise. Plasma epinephrine averaged 0.28 ± 0.11 nM at rest (Fig. 4). No increase in plasma epinephrine was observed at 10 min, and concentrations increased (P < 0.05) significantly at 60 min (1.47 ± 0.15 nM). Plasma epinephrine increased (P < 0.05) with exercise duration and was greater (P < 0.05) than all time points by 120 min (4.87 ± 0.76 nM; Fig. 4). Plasma insulin averaged 58.8 ± 14.3 pM at rest, decreased (P < 0.05) at 10 min, and remained low throughout exercise [i.e., was significantly reduced (P < 0.05) from 10 min by 90 and 120 min (Fig. 5)].
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Blood metabolites at rest and during exercise. Plasma FFA averaged 0.19 ± 0.08 mM at rest, increased (P < 0.05) by 60 min (0.84 ± 0.13 mM), and continued to increase in the 2nd h of exercise, reaching 1.34 ± 0.11 mM by 120 min (Table 3). Blood glucose was maintained within narrow limits throughout exercise, and a small decrease (P < 0.05) was observed at 120 min (Table 3). Blood lactate increased (P < 0.05) from resting values at 10 min and remained elevated throughout exercise (Table 3).
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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Regulation of skeletal muscle HSL activity during exercise. The present understanding of skeletal muscle HSL activity is not well defined. HSL is primarily regulated by reversible phosphorylation and is phosphorylated and activated by kinases and dephosphorylated and inactivated by phosphatases. It is known from studies conducted in purified adipose HSL and recombinant HSL mutants that this enzyme contains at least five phosphorylation sites (3, 16, 17). Protein kinase A (PKA) phosphorylates and activates HSL at Ser563, Ser659, and Ser660 (3). Accordingly, agents that stimulate PKA (e.g., epinephrine) increase HSL activity (26), whereas those that ultimately decrease PKA (e.g., insulin) should inhibit HSL activity. Recent work has demonstrated that HSL is also a substrate of extracellular signal-regulated kinase, which phosphorylates HSL at Ser600 and increases adipocyte lipolysis (17). In contrast, phosphorylation at Ser565 by Ca2+/calmodulin-dependent kinase II, AMPK, and glycogen synthase kinase-IV (20) has been shown to inhibit phosphorylation at Ser563 in adipose tissue and has been termed the "inactive site" (16). Therefore, factors such as increased calcium and AMPK may be expected to decrease HSL activity and lipolysis in skeletal muscle, as has been demonstrated in adipose tissue (38, 45). Thus there exists at least five known kinases that stimulate or inhibit HSL activity. Additionally, HSL activity is also thought to be allosterically inhibited by LCFA CoAs (22). Although the mechanism(s) underlying the activation of HSL is poorly understood, we measured HSL activity and the putative regulators of HSL, muscle LCFA CoA and free AMP (possible AMPK effect), and plasma epinephrine and insulin.
Regulation of HSL activity from 10 to 60 min of exercise. The increased HSL activity early in exercise (25%) was consistent with previous values obtained in human skeletal muscle (41). In the present study, we extended our previous findings obtained during 10 min of exercise and report that HSL activity was increased further from 10 to 60 min.
Epinephrine exerts profound effects on skeletal muscle metabolism by a well-defined pathway that increases cAMP content and, ultimately, PKA activity. Previous studies in the isolated rat soleus (26) and adrenalectomized epinephrine-deficient humans (24) suggest that -adrenergic stimulation is essential for increased HSL activity. Data from our laboratory that demonstrate near-maximal increases in HSL activity in resting human skeletal muscle with epinephrine infusion (41) support these findings. In contrast, we have also observed HSL activation early (≤10 min) during low- to moderate-intensity exercise (30 and 60% O2 peak), where no changes in plasma epinephrine were observed (41). However, the increased plasma epinephrine observed between 10 and 60 min of exercise (Fig. 4) in the present study may have been sufficient to stimulate HSL activity.
Insulin is the key antilipolytic hormone in adipose tissue and may exert an inhibitory role on skeletal muscle HSL. In adipose tissue, insulin decreases HSL activity by initiating a signaling cascade that results in phosphorylation and activation of phosphodiesterase (PDE) 3B, a subsequent reduction in cAMP, and, ultimately, reduced PKA activity (9). A similar mechanism is likely to exist in skeletal muscle, although the precise regulatory PDE isoform is unknown (13). There is no evidence on the regulation of skeletal muscle HSL activity by insulin. Enoksson et al. (13) demonstrated a 33% reduction in skeletal muscle interstitial glycerol during a euglycemic, hyperinsulinemic clamp that was completely abolished by the addition of the nonselective PDE inhibitor theophylline. We observed a rapid reduction in plasma insulin during moderate-intensity exercise that declined further with exercise duration (Fig. 5). Combined with the increase in plasma epinephrine and modest changes in the putative intramuscular regulators, the drop in insulin may be important for stimulating HSL activity during moderate-intensity exercise.
AMPK is proposed to be an important energy sensing/signaling protein, because the protein targets of AMPK (e.g., GLUT-4, acetyl-CoA carboxylase, malonyl-CoA decarboxylase) are intimately linked to the control of fuel metabolism (42). AMPK is activated in response to a decrease in energy charge, such that increased free AMP and decreased ATP and PCr (32) result in allosteric activation of AMPK during contraction (18). During exercise in humans, the 
2-isoform of AMPK is activated during moderate (>64% O2 peak)to intense exercise (7, 37, 44) but not during prolonged low-intensity (50% O2 peak) exercise (44). We have measured two of the allosteric effectors of AMPK (free AMP and PCr) and report no differences in the contents of these substrates between 10 and 60 min. Although there is no reason to suggest that AMPK would be further elevated at 60 min, these conclusions must be tempered until direct measurements of AMPK activity determine the precise effects of AMPK on HSL activity in human skeletal muscle in vitro and during prolonged exercise.
In the present study, LCFA CoA was unchanged from rest at 10 min and increased 3.2-fold from resting values by 1 h. The allosteric effect of LCFA CoA on HSL activity cannot be distinguished using the in vitro assay employed in this study. However, given the proposed inhibitory effect of LCFA CoA on HSL activity, the possibility exists that LCFA CoA reduced the actual in vivo flux through HSL at 60 min.
Taken together, these data suggest that increased epinephrine and decreased insulin stimulate HSL activity at 60 min. Nonetheless, some other unknown intra- or extramuscular factor may also contribute to the increased HSL activity at 60 min.
Regulation of HSL activity from 60 to 120 min of exercise. The increased HSL activity at 60 min was completely reversed by 120 min of exercise. The decreased HSL activity coincided with an accumulation of LCFA CoA (75% from 60 min) and a twofold increase in free AMP and occurred despite a marked increase in plasma epinephrine and low insulin levels.
The plasma hormone responses at 120 min would have been expected to further increase HSL activity from 60 min. Plasma epinephrine concentrations were 3.5-fold greater at 120 min than at 60 min of exercise. However, the increased HSL activity observed during the previous exercise time points (10 and 60 min) was attenuated, and HSL activity returned to near-resting values. Thus the results from the present study further support our previous findings (41) that epinephrine can stimulate HSL activation but increased plasma epinephrine does not always stimulate HSL activity during exercise. Plasma insulin was also extremely low at 120 min, yet HSL activity declined considerably. A break in the temporal relation between HSL activity and insulin does not imply the absence of a physiological role for insulin, but it is debatable that the small decrease in insulin would affect HSL activity.
AMPK phosphorylation on Thr172 is progressively increased during prolonged (3.5 h) low-intensity exercise, resulting in increased activity of the 2-isoform of AMPK (43). On the basis of these observations and the marked increase in free AMP and concomitant decline in HSL activity at 120 min (Table 2, Fig. 1), it is possible that AMPK may have exerted an inhibitory effect on HSL activity late in prolonged exercise. This proposal is supported by a recent study in C2C12 myotubes that demonstrated inhibition of intracellular triacylglycerol hydrolysis with 5-aminoimidazole-4-carboxamide (27). Also, endogenous fatty acid oxidation was unaffected by 5-aminoimidazole-4-carboxamide in incubated soleus muscle strips (2). Another line of research suggests that AMPK activities are increased with low compared with high glycogen concentrations during contraction (10). This supports the possibility of increased AMPK activity late in prolonged exercise secondary to reduced muscle glycogen, because glycogen stores are significantly depleted (468 vs. 217 mmol/kg dry mass) after 2 h of moderate-intensity exercise (40).
The marked increase in LCFA CoA at 2 h and our previous observation of decreased IMTG utilization late in prolonged exercise (40) are consistent with an inhibitory role of LCFA CoA on flux through HSL (22). The increase in FFA availability (Table 3) late in exercise and the finding of enhanced uptake of plasma-derived FFA with increased FFA availability (28, 39) and exercise duration (40) suggest that LCFA derived from IMTG are not required to maintain ATP turnover. Taken together, these data suggest that the exercising muscle preferentially utilizes plasma-derived fatty acids when supply is sufficient but is able to upregulate HSL activity and IMTG hydrolysis when plasma FFA supply is limited. However, these conclusions must be tempered by the possibility that the measured LCFA CoA is not reflective of the free content but a combination of free LCFA CoA and those complexed with acyl-CoA-binding proteins. Also the possibility exists that LCFA CoA are located within the cytoplasm and mitochondria, although we believe that the majority of the LCFA CoA are located in the cytosol, because -oxidation is generally thought to be limited by substrate supply, deeming mitochondrial LCFA CoA accumulation unlikely. Nevertheless, our data support an inhibitory role of LCFA CoA on HSL activity and may explain the apparent reduction in IMTG hydrolysis late in prolonged exercise.
Why is LCFA carnitine accumulating during exercise? An interesting finding of the present study was the progressive increase in LCFA carnitine with exercise duration. LCFA carnitine is the product of the carnitine palmitoyltransferase (CPT) 1 reaction and is thought to be moved across the inner mitochondrial membrane and converted to LCFA CoA by CPT2 and used as a substrate for -oxidation. Traditionally, CPT1 is thought to be the final rate-limiting enzyme for fat oxidation in skeletal muscle. However, in the present study, LCFA carnitine accumulated during the 2nd h of exercise (Fig. 2), suggesting a limitation distal to CPT1. The increased LCFA carnitine was unexpected, because the activities of fatty acid translocase, CPT2, and the enzymes of -oxidation are believed to be near equilibrium. Also, fatty acid oxidation progressively increases with exercise duration, demonstrating that the maximal rate for fatty acid utilization is not reached at 2 h (40). Although there is no readily apparent explanation for LCFA carnitine stockpiling, we cannot discount the possibility that changes in the downstream regulators of LCFA CoA oxidation, such as mitochondrial matrix contents of NADH, CoA, and ADP, are slowing the activities of CPT2 or the acylcarnitine-carnitine translocase, leading to accumulation of LCFA carnitine. Clearly, further studies aimed at investigating this effect are warranted.
Summary. In conclusion, the present findings demonstrated that HSL was activated above resting levels by 10 min of exercise, increased further by 60 min, and returned to near-basal levels at 120 min. The increased epinephrine and decreased insulin concentrations appeared to stimulate HSL activity from 10 to 60 min of exercise, although the possibility exists that some other intra- or extramuscular factor contributed to the further increase in HSL activity. Despite the increased HSL activity at 60 min, the potential inhibitory effect of increased LCFA CoA content may have decreased flux through HSL. From 60 to 120 min of exercise, it appeared that some intramuscular inhibitory factor (e.g., AMPK) was more powerful than -adrenergic stimulation, and HSL activity decreased to near-basal levels. Moreover, LCFA CoA increased markedly and may have decreased flux through HSL further. These events may explain the apparent reduction in IMTG use late in prolonged exercise. These data also support the notion that regulatory factors inherent to the muscle cell are likely to override hormonal regulators of HSL during the later stages of prolonged exercise.
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ACKNOWLEDGMENTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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This study was supported by the Natural Sciences and Engineering Research Council of Canada (L. L. Spriet) and the Canadian Institute of Health Research (G. J. F. Heigenhauser).
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FOOTNOTES |
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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.
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REFERENCES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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2 activity and ACC phosphorylation during exercise. Am J Physiol Endocrinol Metab 282: E688-E694, 2002. phosphorylation in human muscle during prolonged exercise. Biochem Biophys Res Commun 298: 309-316, 2002.[Web of Science][Medline]
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significantly different from 30 min; 
significantly different from 60 min; 
significantly different from 90 min (P
< 0.05).
