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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 25 August 2005 ; accepted in final form 1 November 2005
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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nutrition; eukaryotic initiation factor 4E; 4E-binding protein-1; eukaryotic initiation factor 4G; ribosomal protein S6 kinase
We (11, 13, 28, 29) have demonstrated that infusion of a balanced mixture of amino acids to mimic postprandial hyperaminoacidemia (7) results in activation of translation initiation factors and stimulation of protein synthesis in fast-twitch glycolytic skeletal muscles of neonatal pigs. It is not clear, however, whether this response is arbitrated by the increase in all amino acids or to the increase in an individual amino acid. Studies in cultured cells (19, 27, 31) and rats (1–3) suggest that leucine alone can increase protein synthesis in part by a mammalian target of rapamycin (mTOR)-dependent process that involves the phosphorylation of S6K1 and 4E-BP1 and eIF4F assembly. Because those studies were conducted in the presence of supraphysiological concentrations of leucine, the physiological relevance of leucine to activate translation initiation factors and to stimulate protein synthesis was questionable. We addressed this issue in a recent study wherein a physiological increase in circulating leucine stimulated protein synthesis in the longissimus dorsi, a muscle that contains primarily fast-twitch glycolytic muscle fibers, in neonatal pigs (18). Furthermore, the leucine-induced stimulation of protein synthesis was mediated by increased activation of translation initiation factors. The effect of a physiological increase in circulating isoleucine or valine on protein synthesis in neonates has not been evaluated. Thus the main objective of this study was to compare the effects of a physiological rise in each of the individual branched-chain amino acids (BCAA) on protein synthesis in neonatal pigs. Furthermore, we wished to investigate the mechanism(s) involved in the BCAA stimulation of protein synthesis in skeletal and cardiac muscles.
The growth of the heart after birth is asymmetrical, which is primarily driven by the increased hemodynamic workload of the left compared with the right ventricle. Indeed, the left ventricular wall of the pig's heart grows about three times faster than the right ventricular wall during the first 10 days of postnatal life (4, 30). The augmentation in mass of the left ventricular wall probably results from both increased hypertrophy and hyperplasia (4). The greater hypertrophy of the left ventricular wall compared with the right ventricular wall can be attributed mainly to an increase in the rate of protein synthesis rather than a change in the rate of protein degradation and is driven by both an enhanced efficiency of translation and an increased capacity for protein synthesis (30). The infusion of insulin in situ increases translational efficiency in the right ventricular wall but does not further enhance the high rate of translational efficiency in the left ventricular wall of 5-day-old pigs (8, 30). It is not known, however, whether the left ventricular wall is sensitive to direct nutrient stimulation. The potential to use BCAA therapy to increase protein synthesis in neonates at risk (e.g., extremely low birth weight infants) warrants the evaluation of cardiac and skeletal muscle responsiveness to BCAA administration. Thus an objective of the present study was to compare fast-twitch glycolytic and slow-twitch oxidative skeletal muscles, as well as the left and right ventricles, in their ability to stimulate protein synthesis and activate translation initiation factors in response to administration of individual BCAA.
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METHODS |
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Surgery.
Immediately before anesthesia, each piglet received 54 µg/kg body wt atropine sulfate intramuscularly (Phoenix Pharmaceuticals, St. Joseph, MO) and 2.27 mg/kg body wt enrofloxacin (Baytril, Bayer, Shawnee Mission, KS). An additional 4.54 mg of enrofloxacin were placed in the incision just before suturing. Anesthesia was induced with 5% isoflurane (AErrane; Baxter Healthcare, Deerfield, IL) and maintained with 2% isoflurane, both with 800 ml/min O2. The left external jugular vein and the left common carotid artery were surgically dissected, and an indwelling silicon catheter (HelixMark, 0.76 mm ID and 1.78 mm OD; Helix Medical, Carpinteria, CA) filled with heparinized saline (50 U/ml) was advanced posteriorly 
5 cm to the vena cava or the aortic arch, respectively. The jugular catheter was sutured to the scalene muscle and the carotid catheter to the sternothyroideus and/or sternohyoideus muscles. The distal end of each catheter was tunneled subcutaneously with a trocar and exteriorized between the dorsal neck region and the scapula. After recovering from anesthesia, piglets were returned to their respective sows until studied.
Treatments and infusion. Pigs were randomly assigned to one of four treatments and were infused with saline, leucine, isoleucine, or valine. All infusions were carried for 60 min as previously described (18). Infusion was initiated with a primed dose of 240 µmol/kg body wt for 10 min, followed by constant infusion at 400 µmol·kg–1·h–1 for each BCAA.
Tissue protein synthesis in vivo. Fractional rates of protein synthesis were measured with 10 ml/kg body wt of a flooding dose (1.5 mmol/kg body wt) of L-[4-3H]phenylalanine (0.5 mCi/kg body wt; Amersham Biosciences, Piscataway, NJ) injected 30 min before the infusion was ended, as previously described (20). At the end of the infusion, pigs were killed, and samples were obtained from the longissimus dorsi, which contains primarily fast-twitch muscle fibers, and the masseter muscle, which contains primarily slow-twitch muscle fibers, as well as the right and left ventricular walls. Samples were collected and immediately frozen in liquid nitrogen and stored at –70°C until analyzed, as previously described (14).
Protein synthesis (Ks; %protein mass 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. The majority of RNA in tissues is ribosomal RNA; hence, RNA-to-protein ratio (mg RNA/g protein) was used as an estimate of protein synthetic capacity (Cs). RNA content was determined by spectrophotometric absorbency. Protein synthetic efficiency (KRNA) was estimated as the total protein synthesized in a day per total RNA (g protein·day–1·g RNA–1).
Blood glucose, plasma insulin, and amino acids. Blood samples were collected every 10 min throughout the study. Whole blood glucose concentration (YSI 2300 STAT Plus; Yellow Springs Instruments, Yellow Springs, OH) was determined immediately after sample collection. Plasma concentrations of insulin were determined by radioimmunoassay as previously described (7). Individual plasma amino acid concentrations were measured with an HPLC method (PICO-TAG reverse-phase column; Waters, Milford, MA) as previously described (15).
Protein immunoblot analysis. Proteins were electrophoretically separated in polyacrylamide gels (23). For each assay, all samples were run at the same time in triple-wide gels (C.B.S. Scientific, Del Mar, CA) to eliminate interassay variation. Proteins were transferred to a PVDF membrane (Bio-Rad, Hercules, CA) and incubated with appropriate antibodies (all from Cell Signaling Technology, Beverly, MA, unless otherwise indicated). Blots were developed using an enhanced chemiluminescense kit (ECL, Amersham), visualized using ChemiDocIt (UVP, Upland, CA), and analyzed with LabWorks Image Acquisition and Analysis Software (UVP). Site-specific phosphorylation and total protein content were determined.
Quantification of eIF4E·4E-BP1 and eIF4E·eIF4G complexes. These complexes were immunoprecipitated using an anti-eIF4E monoclonal antibody (22) from aliquots of fresh tissue homogenates (26). Briefly, samples were homogenized in seven volumes of buffer (in mM: 20 HEPES, 2 EGTA, 50 NaF, 100 KCl, and 0.2 EDTA, pH 7.4) containing Sigma P3840 Protease Inhibitor Cocktail (Sigma Chemical, St. Louis, MO) and centrifuged at 10,000 g for 10 min at 4°C. Supernatants were incubated overnight at 4°C with constant rocking with anti-eIF4E antibody. Immunoprecipitates were recovered with goat anti-rabbit IgG magnetic beads (Polysciences, Warrington, PA), washed and resuspended in sample buffer as described elsewhere (22), and immediately subjected to protein immunoblot analysis using rabbit anti-4E-BP1 antibody or rabbit anti-eIF4G antibody kindly provided by Dr. Richard E. Lloyd (Dept. of Molecular Virology and Microbiology, Baylor College of Medicine). Amounts of 4E-BP1 and eIF4G were corrected by the eIF4E recovered from the immunoprecipitate.
Quantification of phosphorylated eIF4G in the eIF4E·eIF4G complex. Aliquots of immunoprecipitates were subjected to protein immunoblot analysis using a rabbit polyclonal antibody that recognizes site-specific phosphorylation of eIF4G at Ser1108.
Muscle and heart homogenates. Aliquots of supernatants obtained from tissue homogenates were diluted in sample buffer (23), boiled for 10 min, cooled to room temperature, frozen in liquid nitrogen, and stored at –70°C until protein immunoblot analyses.
Quantification of 4E-BP1 phosphorylation. Aliquots of homogenates were subjected to protein immunoblot analysis using a rabbit polyclonal antibody that recognizes site-specific phosphorylation of 4E-BP1 at Thr70 and total 4E-BP1 (Bethyl Laboratories, Montgomery, TX).
Quantification of S6K1 phosphorylation. Aliquots of homogenates were subjected to protein immunoblot analysis using a rabbit polyclonal antibody that recognizes site-specific phosphorylation of S6K1 at Thr389 or total S6K1 (Santa Cruz Biotechnology, Santa Cruz, CA). Phosphorylation of S6K1 was corrected by total S6K1.
Quantification of rpS6 phosphorylation. Aliquots of homogenates were subjected to protein immunoblot analysis using rabbit polyclonal antibodies that recognize site-specific phosphorylation of rpS6 at Ser235/236 and Ser240/244 or total rpS6. Phosphorylation of rpS6 was corrected by total rpS6.
Quantification of eukaryotic elongation factor-2 phosphorylation. Aliquots of homogenates were subjected to protein immunoblot analysis using rabbit polyclonal antibodies that recognize site-specific phosphorylation of eukaryotic elongation factor-2 (eEF2) at Thr56 or total eEF2. Phosphorylation of eEF2 was corrected by total eEF2.
Statistical analyses. To determine the effect of treatment on fractional protein synthesis rates 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 (21). A comparison of the responsiveness of skeletal muscle (fast-twitch glycolytic vs. slow-twitch oxidative) and ventricular walls (right vs. left) to BCAA stimulation was performed nesting muscle (skeletal or cardiac) within treatment (saline, leucine, isoleucine, and valine). No statistical comparison was made between skeletal and cardiac muscles. 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 (21). Least square means were compared using a t-test and Fisher adjustment by the PDIFF option of SAS (21).
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RESULTS |
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-isoform (Fig. 1B) of 4E-BP1, the repressor protein of eIF4E, was increased (P < 0.03) by infusion of leucine in longissimus dorsi and masseter muscles, as well as in the right and left ventricular walls (P < 0.03; Fig. 1, C and D) compared with saline infusion. Infusion of isoleucine or valine did not change the 4E-BP1 phosphorylation at Thr70 or -isoform in the skeletal and cardiac muscles (P = 0.22 to 0.87) compared with saline controls. A concomitant decrease in the amount of eIF4E associated with 4E-BP1 (P < 0.03) in longissimus dorsi and masseter muscles (Fig. 2A), but not in the right and left ventricular walls (P = 0.26 and P = 0.19, respectively; Fig. 2B), was observed for leucine compared with saline infusion. Infusion of isoleucine did not affect the amount of 4E-BP1 associated with eIF4E in any tissue (P = 0.10 to 0.89; Fig. 2). Infusion of valine, however, increased the amount of 4E-BP1 associated with eIF4E in longissimus dorsi (P = 0.01; Fig. 2A) and right and left ventricular walls (P < 0.04; Fig. 2B) compared with saline infusion. The eIF4G·eIF4E complex was increased by leucine infusion in both skeletal muscles (P < 0.003; Fig. 3A). Furthermore, the eIF4G·eIF4E complex tended to be higher (P = 0.08) in the masseter compared with the longissimus dorsi muscle. In the heart, infusion of leucine increased (P < 0.0001) eIF4G·eIF4E complex content in the left ventricular wall and tended to increase the amount of eIF4G·eIF4E complex in the right ventricular wall (P = 0.09; Fig. 3B) compared with saline infusion. Infusion of leucine also increased (P < 0.03) the phosphorylation of eIF4G at Ser1108 in the eIF4G·eIF4E complex in both skeletal muscles as well as in both ventricular walls (Fig. 4, A and B). The amount of eIF4G·eIF4E complex (Figs. 3A and 4A), as well as the phosphorylation of eIF4G at Ser1108 in the eIF4G·eIF4E complex (Figs. 3B and 4B), were unaffected by the infusion of isoleucine or valine in skeletal muscles (P = 0.22 to 0.99) and ventricular walls (P = 0.11 to 0.99) compared with saline infusion.
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DISCUSSION |
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Effect of BCAA infusion on plasma amino acids. Infusion of each individual BCAA resulted in a marked increase in the plasma concentration of the corresponding BCAA over baseline and saline-infused controls. Infusion of leucine and valine resulted in an approximately threefold increase in plasma levels, which falls within the postprandial range previously reported for neonatal pigs fed mature sow's milk, colostrum, or formula (7). Despite the fact that isoleucine was infused on an equimolar basis to leucine and valine (i.e., 400 µmol·kg–1·h–1), plasma isoleucine levels increased approximately sixfold compared with baseline values. Plasma levels of leucine were reduced by isoleucine infusion for 60 min in neonatal pigs. This observation raises the possibility that any potential stimulatory effect of isoleucine on protein synthesis may have been impaired by the reduction in plasma leucine. It is not known whether the elevation of one BCAA affects intracellular transport or flux rates, as well as the incorporation into protein of the other two BCAA. Infusion of leucine for 60 min, however, did not reduce plasma concentrations of other essential amino acids. These observations are in agreement with our previous study (18). Similarly, infusion of isoleucine and valine for 60 min did not affect plasma concentrations of other essential amino acids.
Effect of BCAA infusion on translation initiation factors.
A physiological increase in plasma leucine resulted in increased phosphorylation of 4E-BP1 on Thr70 and the -isoform, with a concomitant reduction in the 4E-BP1·eIF4E complex and an increase in the eIF4G·eIF4E complex in both skeletal muscles. Furthermore, phosphorylation of eIF4G in the eIF4G·eIF4E complex was also enhanced by the physiological increase in circulating leucine in both skeletal muscles. Interestingly, valine increased the amount of 4E-BP1·eIF4E complex in skeletal and cardiac muscles without a reciprocal reduction in eIF4G·eIF4E complex formation. Leucine enhanced the phosphorylation of S6K1 and rpS6 in the fast-twitch glycolytic longissimus dorsi muscle but not in the slow-twitch oxidative masseter muscle. We (18) have previously reported increased phosphorylation of 4E-BP1, S6K1, and rpS6 and reduced 4E-BP1·eIF4E complex content in the longissimus dorsi of neonatal pigs infused with leucine for 60 min. In addition, others (1–3) have also reported increased activation of translation initiation factors in response to oral administration of leucine in rats that resulted in supraphysiological concentrations of leucine in plasma. Moreover, a recent study (9) reported that a 3.5-fold increase in plasma leucine concentration in response to oral leucine administration increased phosphorylation of eIF4G and S6K1 and decreased the association of 4E-BP1 with eIF4E in rat skeletal muscle and maximally stimulated protein synthesis. Thus results reported herein for the activation of translation initiation factors by leucine in skeletal muscle are in agreement with several published reports. In the right and left ventricular walls, infusion of leucine caused a marked increase in the phosphorylation of 4E-BP1, as well as increased eIF4G·eIF4E complex formation and eIF4G phosphorylation in this active complex without a statistically significant reduction in the inactive 4E-BP1·eIF4E complex.
Leucine did not alter the phosphorylation state of S6K1 and rpS6 in either ventricle of the heart. Activation of S6K1 and rpS6 has been involved in the translational regulation of mRNAs containing a terminal oligopyrimidine tract. These mRNAs encode proteins involved in the protein synthetic machinery (17). Phosphorylation of S6K1 and rpS6 in the heart of mature rats has been reported to increase in response to oral administration of leucine that elevated plasma leucine to supraphysiological levels (24, 25). However, the experimental conditions of the present study are substantially different from those in previous reports. We elevated plasma leucine, within the postprandial range, in neonatal pigs via parenteral administration. Combined, these observations raise important questions about the involvement of S6K1 and rpS6 in the translation of mRNAs coding for components of the protein synthetic machinery as affected by nutrients, growth factors, and state of development of the animal. Furthermore, special consideration must be placed on the state of development of the neonatal heart, as well as the potential differential effects of long-term leucine administration on ribosome biosynthesis in cardiac and skeletal muscles.
Studies conducted in isolated adipocytes (19, 27) have suggested that isoleucine and valine can also activate translation initiation factors but to a lesser degree than leucine. These effects, however, have not been investigated in neonatal animals. In the present study, we found that an increase in circulating levels of isoleucine and valine failed to enhance translation initiation factor activation in the longissimus dorsi and masseter muscles, as well as in the left and right ventricular walls, of neonatal pigs. However, a potential stimulatory effect of isoleucine on the activation of translation initiation factors may have been blunted by the significant reduction in plasma leucine observed in isoleucine-treated animals compared with saline-treated animals. Infusion of valine significantly increased the 4E-BP1·eIF4E inactive complex in the longissimus dorsi, as well as in the right and left ventricular walls. Increased phosphorylation of eEF2 at Thr56 has been reported to reduce the rate of elongation in cultured cells (6). In the present study, phosphorylation of eEF2 at Thr56 was numerically lower in the longissimus dorsi and masseter muscle of leucine-infused pigs compared with controls. In the masseter muscle of valine-treated pigs, there was a numerical increase in the phosphorylation of eEF2 at Thr56 compared with controls. Therefore, a significant difference was obtained for the degree of phosphorylation of eEF2 at Thr56 between leucine-treated and valine-treated pigs. To the best of our knowledge, this is the first study to report the activation of translation initiation factors in skeletal and cardiac muscles of neonatal pigs in response to individual BCAA infusion. Collectively, these results indicate that leucine, but not isoleucine or valine, can enhance the activation of translation initiation factors in cardiac and skeletal muscles.
Effect of BCAA infusion on protein synthesis. We (28) have previously reported that the fractional rate of protein synthesis in longissimus dorsi, a muscle that contains primarily fast-twitch glycolytic muscle fibers, of neonatal pigs increases linearly when a balanced mixture of amino acids is infused. An amino acid-induced stimulation of protein synthesis has also been reported in the skeletal muscle of older pigs (33). Furthermore, the increases in protein synthesis in the skeletal muscle of neonatal pigs in response to amino acid infusion are mediated by translation initiation factor activation (29). More recently, we (18) reported that a physiological increase in circulating leucine alone can act as a nutrient signal to increase protein synthesis in the skeletal muscle of neonatal pigs, a response that was tissue specific, substrate dependent, and 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. Furthermore, skeletal muscle protein synthesis and the activation of translation initiation factors respond linearly to increased plasma levels of circulating leucine alone within the postprandial range (18). In the present study, we examined the efficacy of individual BCAA to stimulate protein synthesis in cardiac and skeletal muscles of neonatal pigs. The results indicate that a physiological increase in circulating leucine, but not isoleucine or valine, was sufficient to stimulate protein synthesis in skeletal muscles that contain either fast-twitch glycolytic or slow-twitch oxidative muscle fibers, as well as in the left ventricular wall of neonatal pigs.
The increase in protein synthesis in the longissimus dorsi muscle in response to leucine infusion was associated with increased phosphorylation of 4E-BP1, S6K1, and rpS6, reduced inactive 4E-BP1·eIF4E complex, increased active eIF4G·eIF4E complex assembly, and increased eIF4G phosphorylation in the active eIF4G·eIF4E complex. In the masseter muscle, as well as in the ventricular walls, we found no increase in the phosphorylation of S6K1 and rpS6. Nevertheless, protein synthesis was significantly increased in the masseter muscle, as well as in the left ventricular wall. These results suggest that phosphorylation of S6K1 and rpS6 does not appear to be involved in the leucine-induced stimulation of global rates of protein synthesis in neonatal pigs. The effects of leucine on the activation of translation initiation factors observed in the current study resemble the effects of growth factors, such as insulin and IGF-I, on the mTOR signaling leading to protein synthesis that we have observed in previous studies (3, 5, 27). Nevertheless, leucine can also act through an mTOR-independent mechanism controlled by PKC
, which is not activated by insulin (32).
The leucine-induced stimulation of protein synthesis was accompanied by a significant increase in protein synthetic efficiency in the left ventricular wall and a numeric increase in protein synthetic efficiency in both skeletal muscles, as well as the right ventricular wall. The greater hypertrophy of the left ventricular wall compared with the right ventricular wall has been associated with enhanced efficiency of translation (30). In the present study, protein synthetic efficiency was significantly higher in the left ventricular wall compared with the right ventricular wall regardless of treatment. It has been previously reported (8, 30) that, during the enhanced hypertrophy phase of the left ventricular wall compared with the right ventricular wall, the RNA content and ribosome formation is higher in the left ventricular wall compared with the right ventricular wall of pigs. In the present study, however, we found that protein synthetic capacity did not differ between the left and right ventricular walls. This discrepancy could be attributed to differences in the experimental approaches. For example, results from Camacho et al. (8) were obtained from free ventricular walls perfused in situ, whereas we obtained our results directly from nonmanipulated free ventricular walls. It has also been reported that the difference in RNA content between the right and left ventricular walls is not present at 10 days in piglets (30). Therefore, the timing of sample collection and the experimental approach used can potentially affect the measured RNA content of the tissue.
Collectively, results from this study indicate that leucine, but not isoleucine or valine, at physiological levels, can act as a nutrient signal to increase protein synthesis in skeletal muscles as well as in the left ventricular wall of neonatal pigs. These changes in protein synthesis were not dependent on changes in circulating insulin levels, which is in agreement with our previous report (18). The increases in protein synthesis in cardiac and skeletal muscles were mediated by enhanced activation of translation initiation factors involved in the binding of mRNA to the 43S ribosomal complex. Finally, the activation of S6K1 and rpS6 does not appear to be involved in the leucine-induced stimulation of global rates of protein synthesis in neonatal pigs.
Perspectives. We (18) have recently reported that a physiological increase in circulating leucine alone is sufficient to stimulate protein synthesis in neonatal pig skeletal muscle that contains primarily fast-twitch glycolytic muscle fibers. In the present study, we found that leucine, but not isoleucine or valine, can act as a nutrient signal to stimulate protein synthesis in skeletal muscles that contain either fast-twitch glycolytic or slow-twitch oxidative muscle fibers. However, leucine stimulation of protein synthesis was higher in the left ventricular wall compared with the right ventricular wall, suggesting the potential for alterations in heart size during prolonged leucine administration. In addition, the present study describes the responsiveness of cardiac and skeletal muscles to short-term administration (i.e., 60 min) of individual BCAA. We (18) have previously reported that the leucine stimulation of protein synthesis cannot be maintained during a longer period of administration of leucine (i.e., 120 min), likely because of a 50% reduction in plasma essential amino acids. Moreover, liver protein synthesis was unaffected by short-term leucine infusion and was reduced by a longer period of infusion. Therefore, studies specifically designed to determine the effect of prolonged elevation of circulating leucine on tissue protein synthesis, circulating essential amino acids, and tissue mass must be conducted before any potential use of BCAA therapy can be implemented in neonates.
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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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REFERENCES |
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is mediated by leucine, not insulin, in skeletal muscle. Am J Physiol Endocrinol Metab 289: E684–E694, 2005.This article has been cited by other articles:
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-, 
-, and 
Mean differs from right and left VW saline at P = 0.09.
Mean differs from right VW saline at P = 0.09.
