Journal of Nutrition

Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Yao, K.
Right arrow Articles by Wu, G.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Yao, K.
Right arrow Articles by Wu, G.
© 2008 American Society for Nutrition J. Nutr. 138:867-872, May 2008

Nutrient Physiology, Metabolism, and Nutrient-Nutrient Interactions

Dietary Arginine Supplementation Increases mTOR Signaling Activity in Skeletal Muscle of Neonatal Pigs1,2

Kang Yao3, Yu-Long Yin3,*, Wuyin Chu3, Zhiqiang Liu3, Dun Deng3, Tiejun Li3, Ruilin Huang3, Jianshe Zhang3, Bie Tan3, Wence Wang3 and Guoyao Wu3,4

3 Laboratory of Animal Nutrition and Health and Key Laboratory of Agro-Ecology, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha, Hunan 410125, P. R. China and 4 Department of Animal Science, Texas A&M University, College Station, TX 77843-2471

* To whom correspondence should be addressed. E-mail: yinyulong{at}isa.ac.cn.


   ABSTRACT
TOP
 ABSTRACT
Introduction
 Materials and Methods
 Results
 Discussion
 LITERATURE CITED
 
Dietary arginine supplementation increases growth of neonatal pigs, but the underlying mechanisms are unknown. This study was conducted to test the hypothesis that the arginine treatment activates translation initiation factors and protein synthesis in skeletal muscle. Piglets were fed milk-based diets supplemented with 0 or 0.6% L-arginine between 7 and 14 d of age. Following a 7-d period of arginine supplementation, at 1 h after the last meal, jugular venous blood samples were obtained for metabolite analysis, whereas longissimus muscle and liver were collected to determine the abundance and phosphorylation state of the mammalian target of the rapamycin (mTOR), ribosomal protein S6 kinase 1 (S6K1), eukaryotic initiation factor (eIF) 4E-binding protein-1 (4E-BP1), eIF4E, and eIF4G. Fractional rates of protein synthesis were measured in muscle and liver using the [3H]phenylalanine flooding-dose technique. Arginine supplementation increased (P < 0.05) daily gain, the plasma insulin concentration, and protein synthesis in skeletal muscle but not in liver. The arginine treatment enhanced the formation of the active eIF4E·eIF4G complex but reduced the amount of the inactive 4E-BP1·eIF4E complex in muscle. These changes were associated with elevated levels of phosphorylated mTOR and 4E-BP1 in muscle of arginine-supplemented piglets (P < 0.05). Neither the total amounts nor phosphorylation levels of the translation initiation factors in the liver differed between control and arginine-supplemented piglets. Collectively, these results suggest that dietary arginine supplementation increases mTOR signaling activity in skeletal muscle, but not in liver, of milk-fed neonatal pigs. The findings provide a molecular mechanism for explaining the previous observation that increased circulating arginine stimulated muscle protein synthesis and promoted weight gain in neonatal pigs.


   Introduction
TOP
 ABSTRACT
 Introduction
Materials and Methods
 Results
 Discussion
 LITERATURE CITED
 
Arginine is an essential amino acid for maximal growth of neonatal pigs (1). There is growing evidence that arginine displays remarkable metabolic and regulatory versatility in cells (2). Arginine takes part in multiple pathways of enormous nutritional and physiological importance, including the synthesis of protein, nitric oxide, creatine, proline, glutamate, polyamines, and agmatine (3). Notably, piglets have a high requirement of arginine for growth (4), but sow milk provides at most 40% of arginine requirements by the 7-d-old pig (5,6). On the basis of plasma concentrations of arginine, ammonia, and nitric oxide metabolites, Wu et al. (1) have suggested that an arginine deficiency is a major factor limiting maximal growth of sow-reared piglets. In support of this proposition, dietary arginine supplementation markedly enhances protein accretion and the efficiency of nutrient utilization in milk-fed piglets (7). Additionally, an increase in circulating arginine was associated with enhanced protein synthesis in skeletal muscle of neonatal pigs (8).

Many studies have demonstrated that increasing the overall availability of amino acids can enhance protein synthesis in skeletal muscle and liver by enhancing the activities of positive regulators of translation initiation factors (9–13). Interestingly, an acute infusion of leucine to piglets also stimulates the phosphorylation of the mammalian target of the rapamycin (mTOR),5 ribosomal protein S6 kinase (S6K1), and eukaryotic initiation factor (eIF)-4E-binding protein-1 (4E-BP1) (9,11), which in turn releases eIF4E from the inactive 4E-BP1·eIF4E complex (14–19). Free eIF4E binds to eIF4G and eIF4A to form the active eIF4F complex, which mediates the binding of mRNA to the 43S ribosomal complex (20–23). However, a role for arginine in the activation of these regulatory initiation factors has not been studied in neonatal pigs, whose growth is highly sensitive to arginine availability (8). We hypothesized that arginine can enhance the activation of translation initiation factors and protein synthesis in skeletal muscle and liver of milk-fed piglets.


   Materials and Methods
TOP
 ABSTRACT
 Introduction
 Materials and Methods
Results
 Discussion
 LITERATURE CITED
 
    Dietary treatment. Milk replacer powder for piglets was prepared according to a previous study (7), which consisted of whey protein concentrate, milk fat powder, {alpha}- casein, lactose, glucose, calcium lactate, vitamin mixture, and mineral mixture purchased from Tianke Company. L-Arginine and L-alanine were provided by Ajinomoto. The basal milk replacer powder (87.5% dry matter) was supplemented with 0.6% L-arginine or 1.23% L-alanine (isonitrogenous control) (dietary composition is summarized in Table 1). The liquid diet was prepared by mixing 1 kg of milk replacer powder with 4 L of water to obtain a milk solution (dry matter 17.5%). The level of arginine in the basal milk replacer powder was 0.58%, as analyzed by HPLC (7). The dosage of supplemental arginine (0.6%) was chosen because it was shown in our previous studies to further increase the weight gain of milk-fed piglets compared with piglets supplemented with 0.4% L-arginine (7).


View this table:
[in this window]
[in a new window]

  		TABLE 1 Composition and nutrient content of diets1

 
    Animals and tissue collection. We conducted the experiment in accordance with the Chinese guidelines for animal welfare and it was approved by the animal welfare committee of the Institute of Subtropical Agriculture, Chinese Academy of Sciences. Twenty-four, 7-d-old healthy piglets (Landrace x Yorkshire) with a mean body weight (BW) of 2.76 ± 0.41 kg were removed from 5 sows and housed individually in plastic-floored pens (1.5 m x 0.5 m) at an ambient temperature of 33°C in an environmentally controlled room. Piglets were fed every 4 h at 73 mL/kg BW per meal. At 14 d of age, blood samples were collected into EDTA-coated tubes from the jugular vein at 1 h after the last meal in the morning. Ten piglets were then killed after anesthesia with an intraperioneal injection of sodium pentobarbital (50 mg/kg BW) followed by quick dissection of liver and longissimus muscle. Blood samples were immediately centrifuged at 3000 x g; 5 min at 4°C and the supernatant (plasma) was stored at –80°C for analysis of amino acids and hormones. Liver and muscle samples were rapidly frozen in liquid nitrogen and stored at –80°C for Western blotting analysis.

    Measurement of tissue protein synthesis. Seven-d-old piglets received dietary supplementation with alanine (control) or arginine for 7 d, as described above. At d 14 of age, 1 h after feeding in the morning, we determined rates of protein synthesis in longissimus muscle and liver using i.p. administration of a flooding dose of phenylalanine as described (13), except that [3H]phenylalanine was used as a tracer (8). Blood samples were obtained from the jugular vein at 10, 20, and 30 min after the injection of [3H]phenylalanine to determine its specific activity in plasma (10). Specific activities of [3H]phenylalanine in the tissue free pool and protein of muscle and liver were measured to calculated fractional rates of protein synthesis, as described by Watford and Wu (10).

    Chemical analysis. Amino acids in plasma were analyzed by HPLC, as previously described (5). Concentrations of insulin in plasma were determined using porcine RIA kits (Shanghai Biological Manufacturing). The intra- and inter-assay CV were 8.2 and 12.4%, respectively, for insulin.

    Protein immunoblot analysis. Frozen liver or muscle samples were powdered under liquid nitrogen using a mortar and pestle. The powdered tissue was homogenized in 7 volumes of buffer (20 mmol/L HEPES, pH 7.4, 100 mmol/L KCl, 0.2 mmol/L EDTA, 2 mmol/L EGTA, 1 mmol/L dithiothreitol, 50 mmol/L NaF, 50 mmol/L β-glycerolphosphate, 0.1 mmol/L phenylmethanesulphonylfluoride, 1 mmol/L benzamidine, 0.5 mmol/L sodium vanadate, and 1 µmol/L microcystin, leucine and arginine). The homogenate was centrifuged at 10,000 x g; 10 min at 4°C. This solution was mixed with an equal volume of a 2x sample buffer (2 mL of 0.5 mol/L Tris, pH 6.8, 2 mL glycerol, 2 mL of 10% SDS, 0.2 mL of β-mercaptoethanol, 0.4 mL of a 4% solution of bromphenol blue, and 1.4 mL of water). The samples were boiled for 5 min and cooled on ice before being used for Western blot analysis. The samples were subjected to electrophoresis on a 7.5% polyacrylamide gel for detection of S6K1, a 15% polyacrylamide gel for detection of 4E-BP1, or a 6% polyacrylamide gel for detection of mTOR. Proteins were electrophoretically transferred to polyvinylidene difluoride membranes. The blots were incubated with primary antibodies for total eIF4E, phosphospecific eIF4E (Ser209), total S6K1, phosphospecific S6K1 (Thr389), and total mTOR (all were rabbit polyclonal antibodies from Santa Cruz Biotechnology); a goat anti-eIF4G antibody (Santa Cruz Biotechnology); and phosphorylated (Ser2448) mTOR (Cell Signaling). The membrane was then washed with 1xTris-buffered saline containing 0.1% Tween 20 and incubated with a secondary antibody (horseradish peroxidase-conjugated goat anti-mouse; Zhongsan Gold Bridge) at 4°C for 3 h. The blots were exposed to X-ray film in a cassette equipped with a DuPont Lightning Plus intensifying screen. After development, films were scanned using a Microtek ScanMaker V scanner connected to a Lenovo Y300 computer. Images were obtained for Adobe Photoshop and quantitated using Scanimage software.

    Quantification of the 4E-BP1·eIF4E and eIF4G·eIF4E complexes. The 4E-BP1·eIF4E and eIF4G·eIF4E complexes were quantified as described previously (14–18). Briefly, eIF4E was immunoprecipitated with an anti-eIF4E polyclonal antibody (Santa Cruz biotechnology) from aliquots of the supernatants obtained from centrifugation of the liver and muscle homogenates at 10,000 x g for 10 min. Antibody-antigen complexes were collected using magnetic beads and subjected to electrophoresis using a 15% polyacrylamide gel. Proteins were then electrophoretically transferred to a polyvinylidene difluoride membrane. The blots were incubated with a rabbit polyclonal anti-eIF4E antibody, a rabbit polyclonal anti-4EBP1 antibody, or a goat anti-eIF4G antibody for 12 h at 4°C. The phosphorylated forms of 4E-BP1 were measured after immunoprecipitation of 4E-BP1 from the tissue homogenates after centrifugation at 10,000 x g. The various phosphorylated forms of 4E-BP1 were separated by SDS-PAGE and analyzed by protein immunoblotting. The blots were developed with enhanced chemiluminescence and the autoradiographs were scanned for analysis, as described above.

    Statistical analysis. Experimental data for each group are expressed as means with pooled SEM. Statistical evaluation of the data were carried out using the General Linear Model procedure of the Analysis Systems Institute (SAS, 2000) followed by the Student-Newman-Keuls multiple comparison test. Differences between the groups were considered significant at P < 0.05.


   Results
TOP
 ABSTRACT
 Introduction
 Materials and Methods
 Results
Discussion
 LITERATURE CITED
 
    Milk intake and growth performance. Daily food intake did not differ between control and arginine-supplemented piglets during a 7-d experimental period (Table 2). The initial BW at d 7 of age did not differ between the 2 groups (Table 2). However, dietary supplementation with arginine increased (P < 0.05) BW and daily weight gain of piglets by 10% and 38%, respectively. The ratio of dry matter intake: BW gain (g/g) was 1.93 and 1.52, respectively, for control and arginine-supplemented piglets (SEM = 0.13; n = 12; P < 0.05).


View this table:
[in this window]
[in a new window]

  		TABLE 2 Effect of dietary L-arginine supplementation on food intake and growth performance of piglets1

 
    Plasma amino acids and insulin. Plasma concentrations of arginine, citrulline, and ornithine were 25, 20, and 19% greater (P < 0.05) in arginine-supplemented piglets than in control piglets, respectively (Table 3). Dietary supplementation with L-arginine did not affect plasma concentrations of lysine, histidine, methionine (Table 3), isoleucine, glutamate, leucine, phenylalanine, threonine, tyrosine, or valine (data not shown). Compared with control piglets, plasma insulin concentration was enhanced (P < 0.05) in arginine-supplemented piglets (Table 3).


View this table:
[in this window]
[in a new window]

  		TABLE 3 Effects of dietary arginine supplementation on plasma concentrations of insulin and amino acids and fractional rates of protein synthesis in skeletal muscle and liver in 14-d-old piglets1

 
    Tissue protein synthesis. Fractional rates of protein synthesis were higher (P < 0.01) in liver than in skeletal muscle of piglets (Table 3). Dietary supplementation with arginine enhanced (P < 0.05) the fractional rate of protein synthesis in longissimus muscle by 24%. However, hepatic protein synthesis did not differ between control and arginine-supplemented piglets (Table 3).

    Amounts of eIF4G·eIF4E and 4E-BP1·eIF4E complexes. Compared with piglets fed the control diet, dietary arginine supplementation reduced (P < 0.05) the association of eIF4E with 4E-BP1 (Fig. 1) but increased (P < 0.05) the formation of the active eIF4G·eIF4E complex (Fig. 2) in longissimus muscle. In liver, the abundance of eIF4E·eIF4G or 4E-BP1·eIF4E complex did not differ between control piglets and arginine-supplemented piglets. The arginine treatment did not affect the percentage levels (%) of phosphorylated eIF4E in skeletal muscle (2.24 and 2.30 in control and arginine-treated piglets, respectively; SEM = 0.46, n = 10) or liver (3.62 and 4.05 in control and arginine-treated piglets, respectively; SEM = 0.29, n = 10).


Figure 1
View larger version (18K):
[in this window]
[in a new window]

  		FIGURE 1  Effect of high dietary arginine on the association of 4E-BP1 with eIF4E in skeletal muscle and liver of pigs. The diets of piglets were supplemented with 0.6% L-arginine or 1.23% L-alanine (isonitrogenous control) between d 7 and 14 after birth. At d 14, 1 h after feeding, muscle and liver were obtained from piglets. Extracts of samples were immunoprecipitated with an anti-eIF4E antibody. Data are means ± SEM, n = 10. *Different from the control, P < 0.05.

 

Figure 2
View larger version (21K):
[in this window]
[in a new window]

  		FIGURE 2  Effect of high dietary arginine on the association of eIF4G with eIF4E in skeletal muscle and liver of pigs. The diets of piglets were supplemented with 0.6% L-arginine or 1.23% L-alanine (isonitrogenous control) between d 7 and 14 after birth. At d 14, 1 h after feeding, muscle and liver were obtained from piglets. Extracts of samples were immunoprecipitated with an anti-eIF4E antibody. Data are means ± SEM, n = 10. *Different from the control, P < 0.05.

 
    Phosphorylation levels for 4E-BP1, S6K1, and mTOR. Phosphorylation at Thr46 and the {gamma}-isoform of 4E-BP1, the repressor protein of eIF4E, is illustrated in Figure 3. Three forms of phosphorylated 4E-BP1 ({alpha}, β, and {gamma}) were detected in both muscle and liver. The {gamma}-form is most phosphorylated (Fig. 3). Dietary arginine supplementation markedly stimulated (P < 0.05) the phosphorylation of 4E-BP1 (Fig. 3) and mTOR (Fig. 4) in longissimus muscle. However, in liver, the levels of phosphorylated 4E-BP1 (Fig. 3) and mTOR (Fig. 4) did not differ between control and arginine-supplemented piglets. The arginine treatment did not affect S6K1 phosphorylation in skeletal muscle (0.86 and 0.98 in control and arginine-treated piglets, respectively; SEM = 0.06, n = 10) or liver (0.89 and 1.04 in control and arginine-treated piglets, respectively; SEM = 0.14, n = 10).


Figure 3
View larger version (24K):
[in this window]
[in a new window]

  		FIGURE 3  4E-BP1 phosphorylation in skeletal muscle and liver of piglets supplemented with 0.6% L-arginine or 1.23% L-alanine (isonitrogenous control) between d 7 and 14 after birth. At d 14, 1 h after feeding, muscle and liver were obtained from piglets. The phosphorylated forms of 4E-BP1 were measured after immunoprecipitation of 4E-BP1 from the tissue homogenates after centrifugation at 10,000 x g for 10 min at 4°C. Position of {alpha}-, β-, and {gamma}-forms are denoted. Data are means ± SEM, n = 10. *Different from the control, P < 0.05.

 

Figure 4
View larger version (20K):
[in this window]
[in a new window]

  		FIGURE 4  Phosphorylation state of mTOR in skeletal muscle and liver of piglets supplemented with 0.6% L-arginine or 1.23% L-alanine (isonitrogenous control) between d 7 and 14 after birth. At d 14, 1 h after feeding, muscle and liver were obtained from piglets. Tissue extracts were separated by 2 6% SDS-polyacrylamide gel electrophoresis and 1 was for determination of phosphorylation of mTOR at Ser2448 and another was for total mTOR. Values for phosphorylated mTOR were normalized for total mTOR content. Data are means ± SEM, n = 10. *Different from the control, P < 0.05.

 
In either skeletal muscle or liver, the relative abundance of total mTOR, eIF4E, S6K1, and 4E-BP1 proteins did not change between the 2 groups of piglets.


   Discussion
TOP
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
LITERATURE CITED
 
To our knowledge, this is the first study to determine the effect of dietary arginine supplementation on the activation of translation initiation factors in muscle and liver of neonatal pigs after a meal. We confirmed the previous report that supplementing piglets with L-arginine increased plasma concentrations of insulin, as well as the growth of milk-fed piglets (7). Notably, novel and important findings from the present study are that the growth-promoting effect of arginine supplementation was associated with increased formation of the active eIF4G·eIF4E complex, activation of positive regulators of protein synthesis, and fractional rate of protein synthesis in skeletal muscle (Figs. 1–4; Table 3).

Arginine is an essential amino acid for young pigs (24) but is severely deficient in milk-fed piglets (25) due to relative low concentrations in milk protein and reduced intestinal release of citrulline, an effective precursor of arginine (5). Recent studies have demonstrated that enhanced protein accretion in skeletal muscle and the whole body of milk-fed piglets can be achieved by elevating plasma levels of arginine through either dietary arginine supplementation (7,26) or enhancing endogenous arginine synthesis (8). This can now be explained by an arginine-induced increase in muscle protein synthesis (Table 3). It is noteworthy that recent studies have shown that arginine can increase protein synthesis in the small intestine of neonatal pigs (27) and that it also activates mTOR and other kinase-mediated signaling pathways in intestinal epithelial cells (28), where arginase activity is limited. Consistent with these reports, our results indicate that dietary supplementation with L-arginine can activate the mTOR signaling pathways in skeletal muscle of neonatal pigs (Figs. 1–4). Because muscle growth depends on the balance between protein synthesis and degradation, future studies are necessary to determine the effect of arginine on protein degradation in cells and the whole body.

In contrast to skeletal muscle, addition of arginine to culture medium did not affect mTOR expression or phosphorylation in mammalian hepatocytes (29), which rapidly degrade arginine by an exceedingly high activity of arginase (2). This is consistent with our finding that dietary supplementation with L-arginine did not affect the levels of total and phosphorylated mTOR or the fractional synthesis of proteins in piglet liver. However, because the flooding-dose method was used to measure global protein synthesis in this study (9), we cannot exclude the possibility that dietary arginine supplementation may increase the synthesis of specific protein(s) in the liver.

Another novel and important finding from this work is that dietary arginine supplementation affected the phosphorylation of 4E-BP1 in piglet muscle. When 4E-BP1 is phosphorylated, it is dissociated from the inactive eIF4E·4E-BP1 complex, thereby releasing eIF4E for binding with eIF4G to form the active eIF4G·eIF4E complex (19–21). Accordingly, dietary supplementation with L-arginine reduced concentrations of the eIF4E·4E-BP1 complex and increased the formation of the active eIF4G·eIF4E complex in longissimus muscle of milk-fed neonatal pigs (Fig. 2). This would be expected to stimulate the formation of the 43S complex for initiating muscle protein synthesis (30). The changes in the abundance of 4E-BP1·eIF4E or eIF4G·eIF4E complex in muscle were not the result of altered expression of eIF4E protein, because the 2 groups did not differ in the content of phosphorylated or total eIF4E in skeletal muscle. Because piglet tissues were obtained at a single time point for the determination of the phosphorylation state of various protein factors, the finding that there was no detectable alteration in S6K1 phosphorylation at 60 min after the last meal does not exclude the possibility that a transient change in tissues might have been missed. In addition, it should be noted that the results of the current study indicate only associations between dietary arginine supplementation and components of the mTOR signaling pathway but do not unequivocally demonstrate causality.

Arginine is a potent stimulator of insulin and somatotropin secretion (30). Considerable work has demonstrated that both insulin (31–33) and amino acids (34–36) play critical roles in the regulation of protein synthesis in piglets. Except for arginine, ornithine, and citrulline, plasma concentrations of other measured amino acids did not differ between control and arginine-supplemented piglets (Table 3). It is noteworthy that published studies show that an increase in arginine availability enhanced the growth of neonatal pigs in the absence of a change in plasma levels of insulin or growth hormone (7,8). Therefore, the effect of arginine could be brought about independent of alterations in these hormones. In support of this notion, there is emerging evidence from studies with cultured muscle cells that arginine can directly stimulate the phosphorylation of proteins in the mTOR signaling pathway (37; G. Wu, unpublished data). However, it is possible that the maximum effect of dietary arginine supplementation on muscle protein synthesis and growth may be mediated in part by elevated levels of the circulating anabolic hormones via the insulin signaling pathway. This possibility can be examined by using the in vivo techniques of insulin and amino acid clamps that were developed by Davis et al. (34–36) for studies with neonatal pigs.

In conclusion, dietary supplementation with L-arginine to milk-fed piglets increased the phosphorylation of 4E-BP1, thereby enhancing the assembly of the active eIF4G·eIF4E complex and protein synthesis in skeletal muscle. These novel findings provide a molecular mechanism for explaining the previous observation that arginine supplementation enhanced piglet growth.


   ACKNOWLEDGMENTS
 
We thank X. F. Kong for assistance in this study.


   FOOTNOTES
 
1 Supported by grants from the National Basic Research Program of China (2004CB117502), the National Natural Science Foundation of China (30528006, 30671517, 30771558, 30700581, and 30371038), Hunan Key Project (2007FJ1003), National Scientific and Technological Supporting Projects (2006BAD12B07 and 2006BAD12B02-5), Chinese Academy of Sciences and Knowledge Innovation Projects (Kscx2-Yw-N-051, KZCX3-SW-441, YW-N-022, and KSCX2-SW323), Texas Agricultural Experiment Station (H-8200), National Research Initiative Competitive Grant (2008-35206-18764) from the USDA Cooperative State Research, Education, and Extension Service, and K. C. Wong Education Foundation, Hong Kong. Back

2 Author disclosures: K. Yao, Y. L. Yin, W. Chu, Z. Q. Liu, D. Deng, T. J. Li, R. L. Huang, J. S. Zhang, B. E. Tan, W. Wang, and G. Wu, no conflicts of interest. Back

5 Abbreviations used: BW, body weight; 4E-BP1, eukaryotic initiation factor 4E-binding protein-1; eIF, eukaryotic initiation factor; mTOR, mammalian target of the rapamycin; S6K1, ribosomal protein S6 kinase 1. Back

Manuscript received 26 November 2007. Initial review completed 20 December 2007. Revision accepted 21 February 2008.


   LITERATURE CITED
TOP
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
 LITERATURE CITED
 

1. Wu G, Knabe DA, Kim SW. Arginine nutrition in neonatal pigs. J Nutr. 2004;134:S2783–90.[Abstract/Free Full Text]

2. Jobgen WS, Fried SK, Fu WJ, Meininger CJ, Wu G. Regulatory role for the arginine-nitric oxide pathway in metabolism of energy substrates. J Nutr Biochem. 2006;17:571–8.[Medline]

3. Wu G, Morris SM Jr. Arginine metabolism: nitric oxide and beyond. Biochem J. 1998;336:1–17.[Medline]

4. Flynn NE, Meininger CJ, Haynes TE, Wu G. The metabolic basis of arginine nutrition and pharmacotherapy. Biomed Pharmacother. 2002;56:427–38.[Medline]

5. Wu G, Knabe DA. Arginine synthesis in enterocytes of neonatal pigs. Am J Physiol. 1995;269:R621–9.[Medline]

6. Wu G. Synthesis of citrulline and arginine from proline in enterocytes of postnatal pigs. Am J Physiol. 1997;272:G1382–90.[Medline]

7. Kim SW, Wu G. Dietary arginine supplementation enhances the growth of milk-fed young pigs. J Nutr. 2004;134:625–30.[Abstract/Free Full Text]

8. Frank J, Escobar J, Nguyen HV, Jobgen SC, Jobgen WS, Davis TA, Wu G. Oral N-carbamylglutamate supplementation increases protein synthesis in skeletal muscle of pigets. J Nutr. 2007;137:315–9.[Abstract/Free Full Text]

9. Davis TA, Fiorotto ML, Beckett PR, Burrin DG, Reeds PJ, Wray-Cahen D, Nguyen HV. Differential effects of insulin on peripheral and visceral tissue protein synthesis in neonatal pigs. Am J Physiol Endocrinol Metab. 2001;280:E770–9.[Abstract/Free Full Text]

10. Watford M, Wu G. Glutamine metabolism in uricotelic species: variations in skeletal muscle glutamine synthetase, glutaminase, glutamine levels and rates of protein synthesis. Comp Biochem Physiol B. 2005;140:607–14.[Medline]

11. O'Connor PM, Bush JA, Suryawan A, Hguyen HV, Jefferson LS, Davis TA. Insulin and amino acids independently stimulate skeletal muscle protein synthesis in neonatal pigs. Am J Physiol Endocrinol Metab. 2003;284:E110–9.[Abstract/Free Full Text]

12. Davis TA, Nguyen HV, Suryawan A, Bush JA, Jefferson LS, Kimball SR. Developmental changes in the feeding-induced stimulation of translation initiation in muscle of neonatal pigs. Am J Physiol Endocrinol Metab. 2000;279:E1226–34.[Abstract/Free Full Text]

13. Wang X, Qiao SY, Yin YL, Yue LY, Wang ZY, Wu G. A deficiency or excess of dietary threonine reduces protein synthesis in jejunum and skeletal muscle of young pigs. J Nutr. 2007;137:1442–6.[Abstract/Free Full Text]

14. Vary TC, Lynch CJ. Meal feeding enhances formation of eIF4F in skeletal muscle: role of increased eIF4F availability and eIF4G phosphorylation. Am J Physiol Endocrinol Metab. 2005;290:E631–42.[Medline]

15. Vary TC, Deiter G, Goodman SA. Acute alcohol intoxication enhances myocardial eIF4G phosphorylation despite reducing mTOR signaling. Am J Physiol Heart Circ Physiol. 2005;288:H121–8.[Abstract/Free Full Text]

16. Vary TC, Jefferson LS, Kimball SR. Insulin fails to stimulate muscle protein synthesis in sepsis despite unimpaired signaling to 4E-BP1 and S6K1. Am J Physiol Endocrinol Metab. 2001;281:E1045–53.[Abstract/Free Full Text]

17. Vary TC, Jefferson LS, Kimball SR. Role of eIF4E in stimulation of protein synthesis by IGF-I in perfused skeletal muscle. Am J Physiol Endocrinol Metab. 2000;278:E58–64.[Abstract/Free Full Text]

18. Vary TC, Kimball SR. Effect of sepsis on eIF4E availability in skeletal muscle. Am J Physiol Endocrinol Metab. 2000;279:E1178–84.[Abstract/Free Full Text]

19. Gingras AC, Gygi SP, Raught B. Regulation of 4E-BP1 phosphorylation: a novel 2-step mechanism. Genes Dev. 1999;13:1422–37.[Abstract/Free Full Text]

20. Raught B, Gingas AC, Sonenberg N. The target of rapamycin(TOR) proteins. Proc Natl Acad Sci USA. 2001;98:7037–44.[Abstract/Free Full Text]

21. Raught B, Gingras AC. eIF4E activity is regulated at multiple levels. Int J Biochem Cell Biol. 1999;31:43–57.[Medline]

22. Vary TC, Jefferson LS, Kimball SR. Amino acid induced stimulation of translation initiation in rat skeletal muscle. Am J Physiol. 1999;277:1077–86.

23. Yonezawa K, Yoshino KI, Tokunaga C, Hara K. Kinase activities associated with mTOR. Curr Top Microbiol Immunol. 2004;279:271–82.[Medline]

24. Wu G, Jaeger LA, Bazer FW, Rhoads JM. Arginine deficiency in premature infants: biochemical mechanisms and nutritional implications. J Nutr Biochem. 2004;15:442–51.[Medline]

25. Flynn NE, Knabe DA, Mallick BK, Wu G. Postnatal changes of plasma amino acids in suckling pig. J Anim Sci. 2000;78:2369–75.[Abstract/Free Full Text]

26. Wu G, Bazer FW, Davis TA, Jaeger LA, Johnson GA, Kim SW, Knabe DA, Meininger CJ, Spencer TE, et al. Important roles for the arginine family of amino acids in swine nutrition and production. Livest Prod Sci. 2007;112:8–22.

27. Rhoads JM, Cori BA, Harrell R, Niu X, Gatlin L, Phillips O, Blikslager A, Moeser A, Wu G, et al. Intestinal ribosomal p70S6K signaling is increased in piglet rotavirus enteritis. Am J Physiol Gastrointest Liver Physiol. 2007;292:G913–22.[Abstract/Free Full Text]

28. Ban H, Shigemitsu K, Yamatsuji T, Haisa M, Nakajo T, Takaoka M, Nobuhisa T, Gunduz M, Tanaka N, et al. Arginine and leucine regulate p70 S6 kinase and 4E-BP1 in intestinal epithelial cells. Int J Mol Med. 2004;13:537–43.[Medline]

29. Meijer AJ, Dubbelhuis PF. Amino acid signaling and the integration of metabolism. Biochem Biophys Res Commun. 2004;313:397–403.[Medline]

30. Cochard A, Guilhermet R, Bonneau M. Plasma growth hormone (GH), insulin and amino acid responses to arginine with or without aspartic acid in pigs. Effect of the dose. Reprod Nutr Dev. 1998;38:331–43.[Medline]

31. Garlick PJ, Fern M, Preedy VR. The effect of insulin infusion and food intake on muscle protein synthesis in postabsorptive rats. Biochem J. 1983;210:669–76.[Medline]

32. Harmon CS, Proud CG, Pain VM. Effects of starvation, diabetes, and acute insulin treatment on the regulation of polypeptide-chain initiation in rat skeletal muscle. Biochem J. 1984;223:687–96.[Medline]

33. Karinch AM, Kimball SR, Vary TC, Jefferson LS. Regulation of eukaryotic initiation factor-2B activity in muscle of diabetic rats. Am J Physiol Endocrinol Metab. 1993;264:E101–8.[Abstract/Free Full Text]

34. Davis TA, Burrin DG, Fiorotto ML, Reeds PJ, Jahoor F. Role of insulin and amino acids in the regulation of protein synthesis in the neonate. J Nutr. 1998;128:S347–50.[Medline]

35. Wray-Cahen D, Nguyen HV, Burrin DG, Beckett PR, Fiorotto ML, Reeds PJ, Wester TJ, Davis TA. Response of skeletal muscle protein synthesis to insulin in suckling pigs decreases with development. Am J Physiol Endocrinol Metab. 1998;275:E602–9.[Abstract/Free Full Text]

36. Davis TA, Fiorotto ML, Burrin DG, Reeds PJ, Nguyen HV, Beckett PR, Vann RC, O'Connor P. M.J. Stimulation of protein synthesis by both insulin and amino acids is unique to skeletal muscle in neonatal pigs. Am J Physiol Endocrinol Metab. 2002;282:E880–90.[Abstract/Free Full Text]

37. Jobgen WS. Dietary L-arginine supplementation reduces fat mass in diet-induced obese rats [dissertation]. College Station (TX): Texas A&M University; 2007.




This article has been cited by other articles:


Home page
 J. Nutr.Home page
J. L. Nall, G. Wu, K. H. Kim, C. W. Choi, and S. B. Smith
Dietary Supplementation of L-Arginine and Conjugated Linoleic Acid Reduces Retroperitoneal Fat Mass and Increases Lean Body Mass in Rats
J. Nutr., July 1, 2009; 139(7): 1279 - 1285.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Yao, K.
Right arrow Articles by Wu, G.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Yao, K.
Right arrow Articles by Wu, G.

Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
Copyright © 2008 by American Society for Nutrition