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Nutrient Requirements

Dietary Arginine Supplementation Enhances the Growth of Milk-Fed Young Pigs¹

Sung Woo Kim^*,2, Rebecca L. McPherson^* and Guoyao Wu^*,

^* Department of Animal and Food Sciences, Texas Tech University, Lubbock, TX 79409-2141 and Department of Animal Science, Texas A&M University, College Station, TX 77843-2471

²To whom correspondence should be addressed. E-mail:sungwoo.kim{at}ttu.edu.

	ABSTRACT

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
This study was conducted to determine the effect of dietary arginine supplementation on the growth of artificially reared piglets. The pigs (n = 24; 7 d old) were removed from sows to a nursery facility and assigned randomly to 1 of the 3 treatments representing diets supplemented with 0, 0.2, or 0.4% L-arginine (on the basis of milk replacer powder). Each milk feeder was assigned to 1 dietary treatment. Fresh liquid milk replacer (18.6% dry matter) was provided daily (0800 h) to piglets. Body weights of piglets were measured and jugular venous blood samples were obtained for metabolite analysis at d 7, 14, and 21 of age. Food intake did not differ between control and arginine-supplemented piglets [66.7 vs. 69.5 g dry matter/(kg body wt · d)]. Compared with control piglets, dietary supplementation with 0.2 and 0.4% L-arginine dose dependently increased (P < 0.05) plasma concentrations of arginine by 30 and 61%, and decreased (P < 0.05) plasma concentrations of ammonia by 20 and 35%, and those of urea by 19 and 33%, respectively. Dietary supplementation with 0.4% L-arginine also increased (P < 0.05) plasma concentrations of insulin and growth hormone by 24–27% in piglets, compared with controls. Between 7 and 21 d of age, the supplementation of 0.2 and 0.4% L-arginine to piglets enhanced (P < 0.05) average daily weight gain by 28 and 66%, and body weight by 15 and 32%, respectively, compared with control piglets. Collectively, both the metabolic and growth data demonstrate unequivocally that arginine is deficient in milk-fed young pigs and that this arginine deficiency represents a major obstacle to maximal growth in piglets.

KEY WORDS: • pigs • milk replacer • arginine • growth • nutrition

Recent artificial rearing data show that the biological potential for neonatal pig growth is at least 74% greater than that for sow-reared piglets (1). Remarkably, suckling piglets exhibit submaximal growth from d 8 after birth (1). The metabolic basis for the submaximal growth of sow-reared piglets is unknown, but it may be due to an inadequate intake of protein (or an essential amino acid) and/or energy. Interestingly, we and others demonstrated recently that arginine (an essential amino acid for neonates) is remarkably deficient in sow’s milk on the bases of lysine:arginine ratios in the milk and the piglet body, and arginine supply from sow’s milk vs. estimated arginine requirement in piglets (2,3). For example, on the bases of the supply of arginine from sow’s milk (1.06 g/d) and the arginine requirement of piglets (2.7 g/d, based on arginine deposition plus catabolism), we estimated that sow’s milk provides <40% of the daily total arginine requirement in 7-d-old suckling pigs (4). There is also more direct evidence supporting the proposition that endogenous synthesis of arginine is essential for maintaining arginine homeostasis in milk-fed piglets. For example, in 4-d-old sow-reared pigs, inhibition of arginine synthesis for 12 h decreased plasma concentration of arginine by 76% (5).

Enterocytes of the small intestine are almost the exclusive cells for the synthesis of citrulline and arginine from glutamine/glutamate and proline in piglets (6–8). Paradoxically, intestinal synthesis of citrulline and arginine decreases by 60–75% in 7-d-old pigs compared with newborn pigs, and declines further in 14- to 21-d-old suckling pigs (8). This intriguing finding raises the important question of whether arginine is deficient in milk-fed piglets. In support of this proposition, we showed recently that plasma concentrations of arginine and its immediate precursors (ornithine and citrulline) decreased progressively by 20–41%, whereas plasma concentration of ammonia increased progressively by 18–46%, between d 3 and 14 of life (9). Clearly, additional studies are warranted to determine whether arginine deficiency limits the growth of milk-fed piglets.

On the basis of the foregoing, we hypothesized that arginine is deficient in milk-fed young pigs and that this arginine deficiency represents a major obstacle to maximal growth in piglets. This hypothesis was tested using 7- to 21-d-old piglets artificially reared on a liquid milk feeding system.

	MATERIALS AND METHODS

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
Chemicals.

HPLC-grade water and methanol were obtained from Fisher Scientific. L-Arginine-HCl was generously provided by Ajinomoto. L-Alanine and o-phthaldialdehyde were procured from Sigma. Glucose dehydrogenase, hexokinase, glutamate dehydrogenase, urease, and orotate dehydrogenase were purchased from Roche.

Milk replacer diets.

Milk replacer powder for piglets, consisting of dried bovine whey protein concentrate, dried whey, vegetable and animal fat, and lactose, was purchased from Milk Specialties Company. The dietary composition is summarized in Table 1. Liquid diet was prepared by mixing 1 kg of milk replacer powder (88.0% dry matter) with 3.78 L of water to obtain 4.73 L of milk solution (dry matter 18.6%). This matched the dry matter content (18.6%) of sow’s milk on d 7–21 of lactation. Amino acids in the milk replacer and the whole sow’s milk obtained at d 7, 14, and 21 of lactation were analyzed by HPLC, as described previously (2). Expressed on the basis of dry matter, amino acid composition of the milk replacer was similar to that of sow’s milk (Table 1).

The piglets used this study were the offspring of PIC Cambrough-22 sows and PIC boars, and were maintained at the Texas Tech University Swine Research Center. Pregnant sows had free access to water and were daily fed 2 kg of a corn-soybean meal-based diet that met NRC requirements (10); dietary contents of metabolizable energy, protein, lysine, calcium, and available phosphorus were 13.06 kJ/kg, 12.2%, 0.56%, 0.94%, and 0.47%, respectively. Lactating sows had free access to water and a corn-soybean meal-based diet that met NRC requirements (10); dietary contents of metabolizable energy, protein, lysine, calcium, and phosphorus were 13.68 kJ/kg, 19.2%, 1.06%, 1.05%, and 0.55%, respectively.

This study involved four replicates. In each replicate, 7-d-old healthy piglets (n = 6) were removed from 1 sow to a nursery facility equipped with six plastic flooring pens (1.5 m x 1.5 m) and 3 automatic milk-feeders (Supp-Le-Mate, Soppe Systems; 2 pens/milk feeder). Piglets were assigned randomly to pens (1 piglet/pen) on the bases of body weight and litter. Each pen was equipped with heating lamps and rubber mats. The milk feeders were modified with tubing (1.9-cm diameter) to facilitate proper milk flow. Each milk feeder was assigned to 1 dietary treatment (0, 0.2, or 0.4% L-arginine on the basis of milk replacer powder). Pigs had free access to milk replacer. The doses of arginine were chosen on the basis of a previous study with early-weaned piglets fed a milk replacer powder diet (11). On the bases of the estimated arginine requirement of 1.08 g/(kg · d) (4), the average milk intake [60 g dry matter/(kg · d)] for 7-d-old piglets (4), arginine content in the milk replacer (7.63 g/kg dry matter) (Table 1), and the digestibility (90.4%) of milk arginine by piglets (12), we estimated that the basal milk replacer would provide 0.414 g arginine/(kg · d), or at most 40% of daily total arginine needs. Supplementing the basal milk replacer with 0.0, 0.2, or 0.4% crystalline arginine-HCl provided 0.671, 0.871, and 1.071% L-arginine (on the basis of milk replacer powder), respectively. Appropriate amounts of alanine were added to the milk replacer to formulate isonitrogenous diets (Table 2). The dietary supplementation with 0.2 and 0.4% arginine represented 30 and 60% of the arginine supply from the basal milk replacer, respectively.

Chemical analysis.

Amino acids in plasma were analyzed by HPLC methods involving precolumn derivatization with o-phthaldialdehyde, as previously described (13), except that quantification was performed using Millennium-32 software (Waters). Ammonia in plasma was analyzed using glutamate dehydrogenase, with ammonium chloride as a standard (14). Urea in plasma was analyzed by an enzymatic method involving urease and glutamate dehydrogenase, as previously described (15). Orotate in plasma was measured using orotate reductase (5). Plasma glucose was measured using glucose dehydrogenase (15). Plasma insulin and somatotropin (growth hormone) were determined using RIA kits (Linco) for porcine insulin and growth hormone, respectively.

Statistical analysis.

Data were analyzed by 2-way ANOVA (diet x day) using the PROC General Linear Model procedure of SAS (SAS Institute). Differences between means were determined using Duncan’s multiple range test. Probability values 0.05 were taken to indicate significant differences.

	RESULTS

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
Milk intake and growth performance.

Daily food intake per kilogram body weight did not differ control and arginine-supplemented piglets in wk 1 and 2 of the study (between d 7 and 21 of age) (Table 3). Dietary L-arginine supplementation (0.2 and 0.4%) had no effect (P > 0.05) on dry matter intake by 7- to 21-d-old piglets compared with control pigs. Milk spoilage did not differ among the three groups of piglets and accounted for 6 to 8% of the liquid milk replacer that disappeared from the feeder. Thus, the feed intake data (Table 3) overestimated food consumption of the piglets by 6–8%.

Plasma concentrations of arginine, citrulline, and ornithine were lower (P < 0.05) in 14- and 21-d-old control pigs than in 7-d-old pigs (Table 5). Dietary supplementation with 0.2 and 0.4% L-arginine dose dependently increased (P < 0.05) plasma concentrations of arginine by 30 and 61% and of ornithine by 12 and 23%, respectively. Plasma concentration of citrulline was 17% greater (P < 0.05) in piglets supplemented with 0.4% L-arginine compared with control pigs. Dietary supplementation with 0.2 and 0.4% L-arginine had no effect (P > 0.05) on plasma concentrations of alanine, lysine, histidine (Table 5), asparagine, aspartate, cysteine/cystine, glutamate, glutamine, glycine, isoleucine, leucine, methionine, phenylalanine, proline, serine, taurine, threonine, tryptophan, tyrosine or valine (data not shown).

Plasma concentrations of ammonia were greater (P < 0.05) in 14- and 21-d-old control pigs compared with 7-d-old pigs (Table 6). Dietary supplementation with 0.2 and 0.4% L-arginine dose dependently decreased (P < 0.05) plasma concentrations of ammonia by 20 and 35% and of urea by 19 and 33%, respectively. Plasma concentrations of orotate and glucose did not differ (P > 0.05) between control and arginine-supplemented piglets. However, in all groups of piglets, plasma concentrations of glucose were higher (P < 0.05) in 14- and 21-d-old pigs than in 7-d-old pigs.

In all groups of piglets, plasma concentrations of insulin and growth hormone did not differ (P > 0.05) between d 7 and 21 of life (Table 7). Compared with control pigs, dietary supplementation with 0.4% L-arginine increased (P < 0.05) plasma concentrations of insulin and growth hormone by 24–27%. Dietary supplementation with 0.2% L-arginine did not affect (P > 0.05) plasma concentrations of insulin and growth hormone during the 2-wk experimental period. Similarly, plasma concentrations of these two hormones did not differ (P > 0.05) between piglets supplemented with 0.2% L-arginine and those supplemented with 0.4% L-arginine.

	DISCUSSION

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION LITERATURE CITED

Arginine serves as the most abundant nitrogen carrier in body proteins (17) and takes part in multiple metabolic pathways (18). Thus, arginine requirements in young mammals (including piglets) are particularly high (19,20). In addition, as the physiologic nitrogenous precursor for the synthesis of nitric oxide (the endothelium-derived relaxing factor, a neurotransmitter, a mediator of immune response, and a signaling molecule), arginine plays an important role in whole-body homeostasis (21). Paradoxically, in neonatal pigs, intestinal synthesis of citrulline and arginine from glutamine/glutamate and proline (abundant amino acids in sow’s milk) decreases markedly within the first 3 wk of life via unknown mechanisms (8,14). Accordingly, plasma concentrations of arginine and its immediate precursors (citrulline and ornithine) decreased in 14- and 21-d-old artificially reared pigs compared with 7-d-old pigs (Table 5), as we reported for sow-reared piglets (9). Intriguingly, a substantial decrease in arginine availability occurs around the time (d 8 of life) (9) when suckling piglets start to exhibit submaximal growth (1).

Plasma concentrations of arginine and ammonia are sensitive indicators of arginine nutritional status in neonatal pigs (22) and human infants (23,24). As an allosteric activator of N-acetylglutamate synthase, which synthesizes N-acetylglutamate, an activator of carbamoylphosphate synthase I, arginine plays a crucial role in ammonia detoxification via the hepatic urea cycle (25). Thus, a hallmark of arginine deficiency is an elevated concentration of plasma ammonia in mammals (22–24). Consistent with this, plasma concentrations of ammonia were greater in 14- and 21-d-old control pigs than in 7-d-old pigs, but were decreased by dietary supplementation with 0.2 and 0.4% L-arginine (Table 6). Collectively, our results show that the arginine supply from protein plus endogenous synthesis cannot meet the metabolic needs of 7- to 21-d-old milk-fed pigs. The inability of young piglets to make sufficient arginine is clearly shown by the in vivo finding that 7- to 14-d-old pigs rapidly developed hypoargininemia and hyperammonemia when fed an arginine-free diet and died within 24 h (22). As a result of an increase in the entry of carbamoylphosphate from mitochondria into the cytosol (18), arginine deficiency increases plasma orotate concentrations and its urinary excretion in young rats (26), but not in young pigs (20,27), thereby indicating a species difference in the regulation of orotate synthesis. Although milk-fed piglets continue to grow, this does not necessarily mean that their growth is maximal, as exemplified by submaximal growth and impaired nitric oxide synthesis in arginine-deficient young rats (28).

There is experimental evidence supporting the view that a decrease in arginine availability may limit maximal growth in young pigs. For example, Leibholz (11) reported that in early weaned piglets, supplementing 0.2 and 0.4% L-arginine to a milk-protein-based powder diet (containing 19.2% crude protein) numerically improved weight gain between d 7 and 14 of life compared with control piglets. However, that study involved a small number of piglets (n = 4/treatment group) and the data were not subjected to statistical analysis (11).

Both the metabolic and growth data from the present study demonstrate unequivocally that arginine is deficient in milk-fed young pigs and that this deficiency contributes to the submaximal growth of the piglets. Importantly, dietary supplementation with 0.2 and 0.4% L-arginine dose dependently increased plasma concentrations of arginine (Table 5) and the body weight gain of piglets (Table 4). The efficacy of arginine supplementation was maximized by the low activity of intestinal arginase in neonatal pigs (29). It is noteworthy that plasma concentrations of lysine and histidine were not affected by dietary supplementation with 0.2 and 0.4% L-arginine (Table 5), suggesting a lack of either an antagonism or an imbalance among the basic amino acids. The ratios of lysine:arginine:histidine (g:g:g) in the milk replacer diets supplemented with 0, 0.2 and 0.4% L-arginine were 1:0.346:0.221, 1:0.449:0.221, and 1:0.552:0.221, respectively (Table 1), which would not be expected to impair intestinal absorption of lysine or histidine (30). Thus, supplementing the liquid milk replacer with 0.2 and 0.4% L-arginine ensured its continuous availability to piglets without affecting lysine and histidine utilization. Because dietary intake of all nutrients (including protein, fat, carbohydrates, vitamins, and minerals), except for arginine, did not differ between control and arginine-supplemented piglets (Table 3), the enhanced growth of piglets in response to arginine supplementation was attributed to the increase in arginine availability. Collectively, our results establish a crucial role for dietary arginine supplementation in promoting the growth of milk-fed piglets.

The daily weight gain of our piglets (Table 4) was lower than that (>350 g/d) reported by other investigators for artificially fed piglets (31,32). However, arginine content in the diets used by others (31,32) was not determined. In addition, the experimental conditions differed greatly between our study and those of others. For example, the initial age (11 d) and initial mean body weight (3.9 kg) of piglets in the study of Kim et al. (31) were greater than those of the piglets used in our study (7 d and 2.8 kg, respectively). Also, dietary crude protein content (31%) in the work of Oliver et al. (32) was higher than that in our study (25%). Despite these differences, an important finding of the present research is that piglets responded to supplemental arginine (0.2 and 0.4%) in a dose-dependent manner on the bases of both plasma arginine concentration (Table 5) and growth performance (Table 4).

Arginine is a potent stimulator of the secretion of insulin by pancreatic ß-cells and of growth hormone by the anterior pituitary gland in mammals (33), including young pigs (34). This is consistent with our finding that dietary supplementation with 0.4% L-arginine increased plasma levels of both insulin and growth hormone in artificially reared piglets (Table 7). Through an increase in arginine availability (Table 5) as well as the concurrent increases in plasma concentrations of anabolic hormones (Table 7), dietary arginine supplementation improved the efficiency of nutrient utilization for enhancing tissue protein synthesis and growth performance. In support of this view, plasma concentrations of urea (the major nitrogenous product of protein and amino acid catabolism) were markedly reduced in arginine-supplemented pigs compared with control pigs (Table 6). Of note, dietary supplementation with 0.2% L-arginine did not affect plasma levels of insulin and growth hormone (Table 7), yet improved the body weight gain of piglets (Table 4). This result suggests that the growth-promoting effect of arginine was not due solely to an increase in the secretion of insulin and growth hormone.

Although arginine was identified >50 years ago as an essential amino acid for young pigs (35), and it displays remarkable metabolic and regulatory versatility (36,37), it is surprising that little is known about its quantitative requirements in neonates (including milk-fed piglets) (38). According to Baker’s seminal work (39), the ideal dietary protein would comprise an optimal pattern of essential amino acids that corresponds to metabolic needs. On the basis of studies with postweaning pigs (>4 wk of age), an ideal dietary ratio of lysine to arginine was suggested to be 100:41 for 3- to 5-kg piglets (10). However, supplementing the milk replacer 0.2 and 0.4% L-arginine to elevate the ratio of lysine:arginine from 100:35 to 100:45 and 100:55, respectively, dose dependently reduced the plasma concentration of ammonia (Table 6) and increased the body weight gain of piglets (Table 4). This result indicates that the currently estimated ideal dietary ratio of lysine:arginine (100:41) for young pigs is low and that it should be increased to at least 100:55 to foster maximal weight gain in piglets < 21 d old.

In conclusion, dietary supplementation with 0.2 and 0.4% L-arginine to milk-fed young piglets dose dependently increases plasma concentration of arginine, decreases plasma concentration of ammonia, and promotes growth performance. These metabolic and growth data provide direct and compelling evidence of an arginine deficiency in 7- to 21-d-old milk-fed piglets. Importantly, increasing arginine availability holds great promise as a potent method for enhancing neonatal piglet growth.

	ACKNOWLEDGMENTS

 
We thank Tony Haynes and Wene Yan for technical assistance as well as Jon Self and Frances Mutscher for manuscript preparation.

	FOOTNOTES

 
¹ Supported by funds from Texas Tech University, the Texas Agricultural Experiment Station (#H-8200), and the U.S. Department of Agriculture (#2003–35206–13694).

Manuscript received 6 October 2003. Initial review completed 17 November 2003. Revision accepted 29 December 2003.

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TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 

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				O. T. Foye, P. R. Ferket, and Z. Uni The Effects of In Ovo Feeding Arginine, {beta}-Hydroxy-{beta}-Methyl-Butyrate, and Protein on Jejunal Digestive and Absorptive Activity in Embryonic and Neonatal Turkey Poults Poult. Sci., November 1, 2007; 86(11): 2343 - 2349. [Abstract] [Full Text] [PDF]

				X. Wang, S. Qiao, Y. Yin, L. Yue, Z. Wang, and G. Wu A Deficiency or Excess of Dietary Threonine Reduces Protein Synthesis in Jejunum and Skeletal Muscle of Young Pigs J. Nutr., June 1, 2007; 137(6): 1442 - 1446. [Abstract] [Full Text] [PDF]

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				J. W. Frank, J. Escobar, H. V. Nguyen, S. C. Jobgen, W. S. Jobgen, T. A. Davis, and G. Wu Oral N-Carbamylglutamate Supplementation Increases Protein Synthesis in Skeletal Muscle of Piglets J. Nutr., February 1, 2007; 137(2): 315 - 319. [Abstract] [Full Text] [PDF]

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