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1United States Department of Agriculture/Agricultural Research Service, Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, Texas; and 2Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania
Submitted 26 October 2004 ; accepted in final form 30 December 2004
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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nutrition; liver; amino acids; ribosomal protein S6 kinase; eukaryotic initiation factor-4E
The enhanced responsiveness of protein synthesis to stimuli in neonatal animals is associated with an increased efficiency of the translation process (7, 11). Furthermore, this increase in translational efficiency is primarily driven by enhanced activation of translation initiation factors involved in the binding of mRNA to the 43S ribosomal complex and not by those involved in the binding of the initiator methionyl-tRNAi to the 40S ribosomal subunit (13, 26). In skeletal muscle and liver of neonates, feeding or the acute infusion of amino acids to raise levels to within the physiological fed range increases the phosphorylation of the 70-kDa ribosomal protein S6 kinase (S6K1) and the eukaryotic initiation factor (eIF)-4E-binding protein-1 (4E-BP1), which in turn releases eIF4E from the inactive 4E-BP1·eIF4E complex. Thus freed eIF4E binds to eIF4G and eIF4A to form the active eIF4F complex, which mediates the binding of mRNA to the 43S ribosomal complex (26, 27).
Although our studies have demonstrated that amino acids regulate the feeding-induced stimulation of protein synthesis in skeletal muscle and liver of neonatal pigs by changes in the activation of translation initiation factors that regulate mRNA binding to the ribosomal complex (25, 26), it is not clear whether this response to amino acids is mediated by the presence of higher levels of all amino acids or whether it is attributable to specific effects of individual amino acids. In vitro studies suggest that leucine alone can stimulate protein synthesis by a mammalian target of rapamycin (mTOR)-dependent process involving both S6K1 and 4E-BP1 phosphorylation and eIF4F formation (15, 21, 31). The response to leucine is greater than the response to other amino acids, including the other branched-chain amino acids isoleucine and valine. These studies, however, used leucine doses similar to a 4- to 10-fold increase in plasma leucine compared with amino acid absence. Hence, the physiological relevance of these findings is questionable.
In a recent study, mature rats were gavage fed the amount of leucine normally consumed in a 24-h period (1). Plasma leucine increased 12- to 18-fold, and skeletal muscle protein synthesis was stimulated (1–(3). The results showed that high doses of leucine stimulate protein synthesis by an mTOR-dependent process that involves S6K1 and 4E-BP1 phosphorylation, and eIF4F assembly (1, 2). In contrast, oral administration of leucine had no effect on global rates of protein synthesis in rat liver but did promote S6K1 and 4E-BP1 phosphorylation (29). Therefore, our objectives were to determine whether a physiological increase in plasma leucine, similar to that observed after a meal (i.e., 2- to 4-fold increase over fasting levels), stimulates protein synthesis in neonatal pigs and whether this response is modulated by changes in the activation of translation initiation factors that regulate the binding of mRNA to the ribosomal complex. We further wished to determine whether the responses differ in skeletal muscle and liver and are time and dose dependent.
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METHODS |
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Treatments and infusion. Piglets were food deprived for 12–14 h before infusion and placed in a sling restraint system. The carotid catheter was used to infuse saline, leucine, and L-[4-3H]phenylalanine, whereas the jugular catheter was used for repeated blood sample collection. Pigs were randomly assigned to one of three constant leucine infusion rates of 0, 200, or 400 µmol·kg–1·h–1 and one of two infusion times of 60 or 120 min (n = 6, 8, and 7, respectively, for each time point). Piglets assigned to the 0 µmol leucine·kg–1·h–1 group were infused with a 0.9% saline solution. During a 30-min basal period preceding leucine infusion, blood samples were collected and immediately analyzed for whole blood glucose (YSI 2300 STAT Plus; Yellow Springs Instruments, Yellow Springs, OH) to establish the average basal concentration used to determine changes in blood glucose during the leucine infusion. Leucine infusion was initiated with a primed dose for 10 min, followed by the appropriate constant infusion rate. The prime dose of leucine received by piglets infused for 60 min was 80 µmol/kg for the 200 µmol·kg–1·h–1 group and 240 µmol/kg for the 400 µmol·kg–1·h–1 group. The prime dose of leucine received by piglets infused for 120 min was 74 µmol/kg for the 200 µmol·kg–1·h–1 group and 148 µmol/kg for the 400 µmol·kg–1·h–1 group. During the priming period, regardless of infusion length, saline-infused piglets received an equal volume to the priming received by the 200 µmol·kg–1·h–1 group.
Tissue protein synthesis in vivo. Fractional rates of protein synthesis were measured with a flooding dose of L-[4-3H]phenylalanine (Amersham Biosciences, Piscataway, NJ) injected 30 min before the end of the infusion (16). We (9) have demonstrated that, after a flooding dose of phenylalanine is administered, the specific radioactivity of tissue-free phenylalanine is in equilibrium with the aminoacyl-tRNA specific radioactivity; thus the tissue-free phenylalanine is a valid measure of the tissue precursor pool specific radioactivity. Protein synthesis (Ks expressed as %protein synthesized in a day) was calculated as: Ks (%/day) = [(Sb/Sa) x (1,440/t)] x 100, where Sb is the specific radioactivity of the protein-bound phenylalanine; Sa is the specific radioactivity of the tissue free phenylalanine for the labeling period, determined from the value of the animal at the time of tissue collection, corrected by the linear regression of the blood specific radioactivity of the animal against time; and t is the time of labeling in minutes. Pigs were killed at 60 and 120 min, and longissimus dorsi muscle and liver tissue samples were collected and immediately frozen in liquid nitrogen and stored at –70°C until analyzed, as previously described (10).
Blood glucose and plasma insulin and amino acids. Blood samples were collected every 10 min throughout the study. Whole blood glucose concentration (YSI) was determined immediately after sample collection. To obtain plasma, whole blood was collected in heparinized tubes, centrifuged at 10,000 g for 1 min at room temperature, and stored at –20°C until analyzed. By use of a porcine insulin radioimmunoassay kit (Linco, St. Louis, MO) that used porcine insulin antibody and human insulin standards, plasma radioimmunoreactive insulin concentrations were measured as previously described (33). The concentrations of individual amino acids from frozen plasma samples obtained at 0, 30, 60, 90, and 120 min after the start of the leucine infusion were measured with an HPLC method (PICO-TAG reverse-phase column; Waters, Milford, MA) as previously described (11).
Protein immunoblot analysis. Proteins were electrophoretically separated in polyacrylamide gels (20) and transferred to a PVDF membrane (Bio-Rad, Hercules, CA), which was incubated with appropriate antibodies, as previously described (13). Blots were developed using an enhanced chemiluminescense kit (ECL, Amersham), visualized using a GeneGnome bioimaging system, and analyzed using Gene Tools software (Syngene, Frederick, MD).
Quantification of the 4E-BP1·eIF4E complex. The association of eIF4E with 4E-BP1 was determined as previously described (19). The obtained supernatants were subjected to an overnight immunoprecipitation at 4°C using a monoclonal antibody against eIF4E (19). Immunoprecipitates were subjected to protein immunoblot analysis, as described above, using a rabbit polyclonal anti-4E-BP1 antibody (Bethyl Laboratories, Montgomery, TX) and the mouse monoclonal anti-eIF4E antibody.
Muscle and liver homogenates. Freshly collected longissimus dorsi muscle and liver tissue samples were homogenized, centrifuged at 10,000 g for 10 min at 4°C, heated at 100°C for 10 min, and cooled to room temperature. Supernatants were diluted in sample buffer (20), frozen in liquid nitrogen, and stored at –70°C until protein immunoblot analyses.
Quantification of 4E-BP1 phosphorylation. An aliquot of muscle and liver homogenates was subjected to protein immunoblot analysis as previously described (13), using a rabbit polyclonal antibody that recognizes phosphorylation at Thr70 (Cell Signaling Technology, Beverly, MA).
Quantification of S6K1 phosphorylation. An aliquot of muscle and liver homogenates was subjected to protein immunoblot analysis as previously described (13), using a rabbit polyclonal antibody that recognizes p70 S6K1 (Santa Cruz Biotechnology, Santa Cruz, CA).
Quantification of rpS6 phosphorylation. An aliquot of muscle and liver homogenates was subjected to protein immunoblot analysis, as described above, using rabbit polyclonal antibodies that recognize phosphorylation at Ser235/236 and Ser240/244 of rpS6 (Cell Signaling Technology).
Statistical analyses. To determine the effect of treatment on fractional protein synthesis rate and the abundance of translation initiation factors, analysis of variance (ANOVA) was performed using the GLM procedure of SAS (release 8.02; SAS Institute, Cary, NC) for randomized complete-block design (18), where the piglet was considered the experimental unit. An ANOVA for repeated measurements was used to analyze the concentration of whole blood glucose as well as plasma insulin and amino acids (18). Least square means were compared using a t-test and Fisher adjustment by the PDIFF option of SAS (18). Finally, slope-ratio analysis was used to compare multiple linear regression curves of plasma amino acid concentration (plasma amino acid concentration vs. time) among leucine treatments (28). Data are presented according to the new guidelines of the American Physiological Society (5).
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RESULTS |
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50% by 120 min. Plasma concentrations of arginine (P = 0.95), histidine (P = 0.41), proline (P = 0.16), serine (P = 0.78), aspartate (P = 0.83), asparagine (P = 0.20), glutamate (P = 0.99), glutamine (P = 0.84), glycine (P = 0.40), and alanine (P = 0.13) were unaffected by leucine infusion. Plasma levels of phenylalanine and tyrosine after the isotope tracer was administered were not included in the statistical analysis, because a large dose of phenylalanine was given along with L-[4-3H]phenylalanine to determine fractional rates of protein synthesis. Due to the high concentration in plasma of phenylalanine after the flooding procedure, we were unable to obtain separation of the tryptophan peak from the phenylalanine peak in our HPLC method. Blood glucose (P = 0.78; Fig. 2A) and plasma insulin (P = 0.99; Fig. 2B) were not different among treatments at any time during the 2-h leucine infusion.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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Effect of leucine infusion on plasma amino acids. As expected, infusion of leucine resulted in 1.5- to 3.0-fold increases in the plasma concentration of leucine compared with baseline levels. This increase in circulating leucine was within the postprandial range observed when neonatal pigs are fed colostrum, mature sow's milk, or formula (4). However, the physiological increase in circulating leucine resulted in a reduction in the concentrations of the other branched-chain amino acids by 120 min of infusion. In our study, plasma concentrations of isoleucine and valine significantly decreased after 120 min of leucine infusion and in a dose-dependent manner. The reduction in plasma amino acids after leucine infusion was not exclusive to the branched-chain amino acids. Slope-ratio analysis of plasma concentrations of individual amino acids indicated a significant linear decrease in plasma lysine, methionine, phenylalanine, threonine, tyrosine, and tryptophan as the time of leucine infusion progressed and in a dose-dependent manner. The reduction in circulating essential amino acid concentrations with leucine infusion is consistent with studies in healthy human subjects in whom leucine levels were increased four- to sixfold for 2.5 to 7 h, and this resulted in a reduction in plasma concentrations of essential amino acids from 35 to 70% (17, 23).
Effect of leucine infusion on translation initiation factors. In the present study, a physiological increase in plasma leucine enhanced the phosphorylation of S6K1 and S6 and reduced the inhibitory effect of 4E-BP1 over eIF4E in muscle, but not in liver. Moreover, translation initiation factors in muscle were still activated after 120 min of leucine infusion. We (26) have previously reported that infusion of a balanced mixture of amino acids to increase all circulating amino acids to mimic the fed level enhances the activation of S6K1, the assembly of the active eIF4G·eIF4E complex, and dissociation of the inactive 4E-BP1·eIF4E complex as a result of a lower inhibitory effect of 4E-BP1 over eIF4E in muscle of neonatal pigs. Furthermore, the activation of translation initiation factors in muscle increases in an amino acid dose-dependent manner (26). Previous studies have reported increased phosphorylation of 4E-BP1, reduced 4E-BP1·eIF4E complex assembly, and enhanced eIF4G·eIF4E complex assembly with supraphysiological increases (i.e., 16-fold increase over fasted controls) in circulating levels of leucine in mature rats (1, 3, 29). To the best of our knowledge, however, this is the first study to report enhanced activation of translation initiation factors in muscle in response to a physiological increase in the plasma concentration of leucine in neonates.
In a recent study, mature rats were gavage fed a bolus of leucine equivalent to the amount of leucine consumed over a 24-h period (2). This protocol resulted in a circulating leucine concentration that was 18-fold higher than in controls after 30 min of bolus administration. This increase in circulating leucine resulted in enhanced phosphorylation of 4E-BP1, S6K1, and S6, a reduction in the 4E-BP1·eIF4E complex assembly, and an increase in the eIF4G·eIF4E complex assembly in muscle. Two hours after the bolus of leucine, however, phosphorylation of 4E-BP1 and eIF4E, as well as the association of the 4E-BP1·eIF4E and eIF4G·eIF4E complexes in muscle, had returned to baseline levels despite a circulating leucine concentration about sevenfold above baseline levels. By contrast, phosphorylation of S6K1, S6, and 4E-BP1 was enhanced, and assembly of the inactive 4E-BP1·eIF4E complex was reduced in muscle of neonatal pigs after a 2-h leucine infusion that resulted in circulating leucine concentration 2.8-fold higher than baseline levels. These observations suggest that translation initiation factors that regulate mRNA binding to the ribosomal complex are more sensitive to leucine stimulation in muscle of neonates than in muscle of mature animals.
We (27) recently reported that infusion of a balanced mixture of amino acids to increase all circulating amino acids to mimic the fed level enhances the phosphorylation of S6K1 and 4E-BP1 and reduces 4E-BP1·eIF4E complex assembly in the liver of neonatal pigs in an amino acid dose-dependent manner. In the present study, however, translation initiation factors in liver of neonatal pigs were not affected by a physiological increase in circulating leucine. This suggests that additional amino acids, other than leucine, may be required for the stimulation of translation initiation factors in neonatal liver. However, increased phosphorylation of S6K1 and 4E-BP1 in liver has been reported in mature rats gavage fed a bolus of leucine that resulted in an 18-fold increase in circulating leucine compared with controls with no change in global rates of protein synthesis (22, 29). Because neonatal animals are more sensitive to amino acid availability than mature rats (8), differences in the effect of leucine in studies using mature animals and neonates may be surprising. However, supraphysiological levels of leucine stimulated mTOR signaling in the liver of mature animals, whereas physiological levels of leucine had no effect in neonatal liver in the present study. Therefore, the results suggest that the effect of leucine on translation initiation in liver may be dose dependent. Collectively, results from this study indicate that a physiological increase in circulating leucine, acting as a nutrient signal, is sufficient to induce phosphorylation of S6K1, S6, and 4E-BP1, as well as a reduction in inactive 4E-BP1·eIF4E complex assembly in muscle, but not in liver, of neonatal pigs.
Effect of leucine infusion on protein synthesis.
We (26, 27) have previously reported that protein synthesis in both muscle and liver increases linearly when a balanced mixture of amino acids is infused to neonatal pigs. Others have also reported an amino acid-induced stimulation of protein synthesis in muscle of older pigs (32). Furthermore, the increases in protein synthesis in both muscle and liver in response to amino acid infusion are mediated by modulation of translation initiation factor activation (26, 27). In the present study, we examined the leucine-induced stimulation of protein synthesis in muscle and liver of neonatal pigs. Results indicate that a physiological increase in circulating leucine alone was sufficient to stimulate protein synthesis in muscle. This increase in muscle protein synthesis, which was mediated by increased phosphorylation of 4E-BP1, S6K1, and S6, as well as reduced 4E-BP1·eIF4E complex assembly, was significant only when neonatal pigs were infused for a short period of time (i.e., 60 min). When the infusion time was extended (i.e., 120 min), a numeric but not significant increase in muscle protein synthesis was measured, despite significant increases in 4E-BP1, S6K1, and S6 phosphorylation, as well as a significant reduction in assembly of the inactive 4E-BP1·eIF4E complex. This lack of response in muscle protein synthesis can likely be explained by the marked decline in circulating levels of several essential amino acids (50%) after 120 min of leucine infusion. In previous studies using weaned but growing rats, supraphysiological increases in circulating leucine (i.e., 16- to 18-fold from controls) have resulted in increases in muscle protein synthesis, which were mediated by enhanced activation of translation initiation factors (1–(3, (22). Similarly, muscle protein synthesis was increased by leucine infusion in adult sheep (30).
Protein synthesis in liver is sensitive to circulating levels of plasma amino acids. In fact, protein synthesis in the liver increases linearly as concentrations of all amino acids are raised from below fasting levels to fed levels, a response that is mediated by enhanced phosphorylation of S6K1 and 4E-BP1, as well as reduced 4E-BP1·eIF4E complex assembly (27). Results presented herein indicated that a physiological increase in plasma leucine was unable to stimulate protein synthesis or the phosphorylation of 4E-BP1, S6K1, and S6 as well as the dissociation of the 4E-BP1·eIF4E complex in liver. Similarly, protein synthesis in the liver was unaffected in rats experiencing a supraphysiological increase in circulating leucine (i.e., 18-fold from controls), despite enhanced activation of translation initiation factors (22, 29).
In the present study, infusion of leucine for 120 min reduced liver protein synthesis rates below baseline levels in a leucine dose-dependent manner, whereas biomarkers of mRNA translation were unaffected. This reduction in liver protein synthesis was associated with a marked reduction in circulating levels of essential amino acids, suggesting that these amino acids had become limiting and unable to sustain the basal rate of liver protein synthesis. Similarly, liver protein synthesis was reduced by leucine infusion in adult sheep (30).
Collectively, results from this study indicate that leucine, at physiological levels, can act as a nutrient signal to increase protein synthesis in muscle, but not in liver, of neonatal pigs. These changes in protein synthesis were not dependent on changes in circulating insulin levels. Similarly, no changes in plasma insulin were reported in healthy men infused with leucine for 7 h to raise plasma leucine levels fourfold (24). By contrast, when a bolus of leucine is administered orally, leucine acts as an insulin secretagogue and can increase circulating insulin levels (e.g., 3.0- to 4.5-fold) (2, 22). In the present study, a physiological increase in plasma leucine stimulated muscle protein synthesis of neonatal pigs and this response was not only tissue specific and substrate dependent but was also insulin independent in the sense that a physiological increase in circulating leucine did not increase plasma insulin and, hence, could not have contributed to the increase in muscle protein synthesis of neonatal pigs reported herein.
Perspectives. Previous studies from our group (8, 25–27) have demonstrated the ability of neonatal pigs to increase protein synthesis in both muscle and liver in response to a physiological increase in all circulating amino acids to mimic the fed state. In addition, several in vitro and in vivo studies have reported increased protein synthesis in response to supraphysiological doses of leucine. However, to the best of our knowledge, this is the first study to report a significant increase in protein synthesis in the muscle of neonatal pigs as a response to a physiological increase in circulating leucine. Thus the results suggest that leucine, provided at physiological levels, can act as a nutrient signal to stimulate protein synthesis in muscle of neonatal pigs and that this response is time specific and dose dependent. When the infusion of leucine was prolonged, a numeric but not significant increase in muscle protein synthesis was measured despite significant increases in the activation of factors that regulate mRNA binding to the ribosomal complex. This lack of response in muscle protein synthesis can likely be explained by the marked decline in circulating levels of several essential amino acids. We speculate that these essential amino acids became limiting because they were used for protein synthesis and that protein synthesis in muscle of neonatal pigs would be increased during prolonged leucine infusion if circulating levels of essential amino acids were maintained at fasting levels. Nevertheless, studies specifically designed to maintain euaminoacidemia during the infusion of leucine must be conducted to address this issue.
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ACKNOWLEDGMENTS |
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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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