Journal of Fisheries & Livestock Production
Open Access

Somatotropin; Endocrine effects; Protein synthesis; IGF-I

Introduction

Due to the down-regulation of -adrenergic receptors, this response is momentary. Feeding insufficient doses of total protein or particular, limiting amino acids attenuates the maximum responses of muscle protein accretion to both ST and -AA. With predicted effects on dietary protein and amino acid requirements, this effect in growing pigs is somewhat compensated by higher efficiency of use of absorbed amino acids for protein deposition for ST but not for -AA. In extremely young animals, ST and -AA are equally ineffective at promoting the deposition of muscle proteins. For ST, this is connected to the somatotropic axis’ postnatal development; a molecular explanation for the same lack of action of -AA is lacking [1]. In both situations, these phenomena must be weighed against the new-born’s extremely high capacity and efficiency for accumulating lean tissue protein.

A wide range of substances that have been demonstrated to impact the rate and/or content of growth in farm cattle and other species, including humans in some circumstances, have attracted unheardof study interest over the past 15 years. The common term for these substances is metabolic modifiers. They consist of anabolic steroids, some of which are permitted for use commercially in certain species in the United States, somatotropin (ST), and a class of artificial phenethanolamine derivatives, also known as -adrenergic agonists, which share many chemical and pharmacological similarities with catecholamines found in nature [2]. The reader is directed to NRC for details on the chemical make-up, methods of action, and a full assessment of their impacts on growth performance as reported in publications prior to 1994.

The somatotropins and chosen -AA, which have been widely researched in developing pigs and cattle, will be the subject of the current review. This discussion will centre on the control of protein metabolism to support the development of skeletal muscle and address recent insights into mechanisms of action involving control of nutrition partitioning between lean and fat. Following that, the primary issues of nutritional and developmental modulation of actions’ efficacy on rate, composition, and efficiency of growth will be covered.

Methods and Methodology

Exogenous pST treatment in pigs results in remarkable increases of up to 90% in the rate of protein accretion in lean tissues, including muscle; ruminants exhibit considerably less dramatic, but no less striking, responses. To investigate the concurrent, in vivo effects of ST on protein synthesis and degradation in tissues of the hindlimb, we used the arteriovenous difference/blood flow approach in conjunction with isotope dilution. These studies confirmed that ST’s chronic protein anabolic effect is solely achieved by promoting protein synthesis, with no discernible impact on protein degradation, and they highlighted the relatively subtle stimulation of synthesis needed to cause a much larger increase in net protein accretion [3].

There is strong circumstantial evidence that the insulin-like growth factor pathway mediates the effects of ST on protein accretion in skeletal muscle and other lean tissues. In numerous crucial areas, the precise mechanisms at play are unclear, though. First off, it is unknown how systemic vs. local sources of IGF and IGF-binding proteins affect the growth and metabolism of proteins muscle. The plasma levels of IGF-I and its main binding protein, IGFBP3, are markedly increased in pigs and ruminants treated with ST during later stages of growth. The liver, where ST particularly controls transcription of IGF-I, IGFBP3, and the acid-labile subunit, the third component of the ternary binding complex, is most likely the primary tissue source of this systemic response. The increase in circulating IGF-I caused by ST may also come from other tissues, such as adipose tissue. It has been demonstrated in some investigations, but not all, that IGF-I expression in muscle responds to ST, raising the hypothesis that at least some of the proteinanabolic effects of ST are mediated by local IGF system actions [3]. However, it is unclear what the reported differences in reaction among species, anatomical muscles, and developmental stages mean.

The degree to which IGF-effects I’s on in vivo muscle protein turnover match those of ST is a second area of molecular ambiguity. Oddy and Owens, for instance, discovered that short-term, closearterial infusion of recombinant human IGF-I into the hindlimb of developing lambs increased protein accretion in infused tissues by lowering protein catabolism without affecting protein synthesis. This response is in line with earlier findings of decreased whole-body proteolysis in lambs and humans receiving acute IGF-I administration. Yet, it is noteworthy that a modest increase in apparent protein synthesis was seen in patients given low dosages of IGF-I over 5-7 days. The ensuing drop in circulation quantities of essential amino acids may contribute in part to the lack of a protein synthesis response to acute therapy [4]. It is need to conduct more research to ascertain whether the reaction may be induced by administering additional amino acids along with the IGF-I and whether longer-term IGF treatment results in an adaptive return to normal aminoacidemia. It is noteworthy that despite the prolonged use of ST and the resulting rise in plasma IGF-I, plasma amino acid concentrations are hardly affected.

Last but not least, in connection with one of the symposium’s themes, it is unknown to what extent ST’s effects on muscle protein metabolism are mediated by altered tissue responses to other endocrine factors, particularly insulin, either directly or via modulation of the expression or actions of IGF system components. Future research should make use of the hyperinsulinemia amino acid clamp method described elsewhere in these proceedings, similar to how we previously used the glucose clamp technique to show how ST attenuated the effects of insulin on glucose synthesis and utilisation in developing pigs and steers.

β-adrenergic agonists

Similar to ST, the most well-studied synthetic -AA, such as clenbuterol, cimaterol, ractopamine, and L-644,969, have diverse effects on different facets of food metabolism that result in increased lean and decreased fat deposition in meat animals and other species. However, in contrast to ST, these benefits are typically more significant in ruminants than in pigs, and the beneficial responses in lean tissue protein accretion are primarily restricted to skeletal muscle [5]. It has also become evident that the effects on muscle protein metabolism are mediated directly by binding of the agonist to specific -1- or -2-adrenergic receptors in muscle, and that the first significant reactions gradually diminished by down-regulation of these receptors.

By closely artery infusing cimaterol into a single hindlimb for 21 days in developing steers, we recently got solid evidence for the direct impact of -AA on muscle protein accretion in vivo. On the basis of assessments of the net uptake of amino acids by each limb, it was calculated that net protein accretion in the treated leg had increased by 65% in comparison to that in the contralateral, saline-infused limb [6]. When animals were killed at the conclusion of the trial, detailed confirmation of variations in weight and protein composition of hindlimb muscles provided support for this exceptional reaction. The test also supported the temporary nature of the anabolic response, which peaked at 14 days but was significantly diminished by 21 days of treatment. In line with the decrease in -1 receptor density in the longissimus dorsi muscle of pigs treated with ractopamine for three weeks, it is generally considered that this effect is caused by desensitisation of the -adrenergic receptor.

There is some disagreement in the literature regarding how the -AA affects muscle protein turnover. Others contend that the majority, if not all, of the increase in net protein accretion is due to decreased protein degradation, which may be mediated by decreased activity of calpains and other particular proteolytic systems. Some studies have demonstrated observable increases in protein synthesis and in the abundance of mRNA for muscle-specific proteins. The consensus is that both arms of protein turnover are impacted, though to different degrees and in different ways over time [7]. The ability of hypophysectomised and severely diabetic rats to respond to therapy suggests that the effects of -AA on muscle protein metabolism are most likely not indirectly mediated by hormonal effects in addition to the direct, -receptor-mediated mode of action.

Protein Sustenance and Adequacy of Development Modifiers

Protein consumption or restricting amino acids, such as lysine, have an impact on growth modifiers’ capacity to induce the deposition of muscle protein. The increased protein deposition also affects how well the diet meets the needs for total protein and a few key necessary amino acids [8]. A number of investigations on the responses to pST and the -AA, ractopamine, in developing swine provide the strongest experimental support for the hypothesis that growth modifiers have an impact on the relationships between protein/amino acid consumption and protein deposition.

The effects of caloric and protein consumption on body protein deposition in pigs at various stages of growth, including effects of sex, genotype, and other factors, were defined by Campbell and others in an elegant set of experiments. The pattern of response to dietary protein is now well documented to be linear up to a plateau that, assuming energy is not a limiting factor, is dictated by the animal’s inherent capability for protein deposition. The relationship’s slope during the protein-dependent phase measures how well absorbed amino acids are used. Growth modifiers could theoretically boost protein deposition by merely raising the maximal response plateau without changing the effectiveness of amino acid usage, as shown and addressed by Boyd and NRC [9]. In this case, the rate of protein accretion would directly affect how much more dietary protein or amino acids were needed. Instead, the impact of the growth modifier on needs would be less than in the first scenario if the efficiency of amino acid utilisation was raised in addition to the maximum protein deposition. Both scenarios have supporting data.

Impact of pST

There is strong proof that giving pST to growing pigs boosts their ability to use ingested amino acids for protein synthesis much more effectively. Growth stage, the quality of dietary protein, and possibly sex all appear to have an impact on the size of this effect and its implications for determining protein/amino acid requirements [10]. Yet, the majority of investigations have revealed a 25–50% increase in the apparent efficiency of using dietary protein, showing that pST enhances both the maximum capacity for protein accretion and the efficiency with which amino acids are used for protein accretion. The effect of therapy on dietary needs for total protein and lysine is countered by enhanced efficiency of amino acid consumption, which increases the slope of the relationship between protein deposition and protein intake. Although the exact mechanism by which pST increases the effectiveness of absorbed amino acid consumption in growing pigs has not been thoroughly investigated, there are some hints. Growing pigs show a noticeable decrease in plasma urea nitrogen content shortly after receiving the first of a series of daily intramuscular injections of pST. This decrease increases over the course of many days of treatment. The most likely explanation is that pST causes an abrupt decrease in the catabolism of amino acids, particularly in the liver [11]. This was subsequently verified by findings of significant reductions in lysine -ketoglutarate reductase activity and lysine, methionine, and valine hepatic oxidation in rats treated with bST for 5 days.

Impact of ractopamine

Growing pigs given the -AA ractopamine experience considerable increases in body protein deposition, but slightly less than with pST at its highest doses. In the only protein titration study of its kind, Dunshea found no proof that any of this reaction was brought on by decreased amino acid usage efficiency in female pigs maturing from 60 to 90 kg. Hence, the amount of dietary protein needed increased in direct proportion to the amount of protein deposited, and no ractopamine response was visible at dietary crude protein concentrations below 140 g/kg [12]. While therapy also led to moderate decreases in PUN in growing pigs, it is impossible to rule out the potential that ractopamine has undetectable effects on the effectiveness of amino acid usage.

Physiological Advancement and Viability of Development Modifiers

In ruminants and pigs approaching market weight, when the capacity for lean growth is fading and the propensity for fattening is noticeably increasing, investigations on the effects of ST or -AA on lean tissue protein accretion and underlying mechanisms have been conducted [13]. There is mounting evidence that growth modifier administration is less efficient during earlier growth phases, when protein deposition efficiency and capacity are higher naturally.

Somatotropic pivot advancement and reaction to ST

The very minor effects of hypophysectomy on prenatal muscle and bone development demonstrate that the somatotropic axis is not fully engaged in the regulation of lean tissue growth during foetal life in the precocial sheep. Extremely high ST concentrations and low IGF-I levels in foetal plasma are consistent with the foetal liver’s limited capacity to bind and react to ST. Consequently, even while the foetal liver produces ST receptor mRNA for a large portion of the prenatal period in sheep, calves, or pigs, significant abundance of functional receptors does not develop until after delivery [14]. Young pigs’ gradual increases in plasma IGF-1 are correlated with subsequent postnatal patterns of rise in hepatic ST binding.

Discussion and Conclusion

These findings in young pigs treated for 4 days with pST at intervals between 10 and 125 days of age are perfectly compatible with this concept of developmental improvements in hepatic sensitivity and/or responsiveness to ST. Pigs under 20 kg had minor treatment-induced increases in plasma concentrations of both IGF-I and IGFBP3, but as they grew older, these increases became steadier. Exogenous pST’s potential to enhance body tissue protein deposition in young pigs likewise rises with development in a manner that is well correlated with this pattern of response. In a series of trials at Cornell University, castrated male or female pigs of comparable genotype weighing 10–20, 20–55, and 55–100 kg live weight, respectively, showed peak responses in protein deposition of 16, 25, and 74%. Extrapolating, a minimal response would be anticipated in pigs smaller than those investigated at 10–20 kg, which are already growing very quickly and using food protein very efficiently.

In younger pigs and ruminants, the effects of -AA on growth performance and carcass composition were substantially smaller than in animals that were close to market weight, according to NRC. In contrast to the 35% increase shown in weaned lambs of the same genotype, weighing 36-42 kg and treated with cimaterol for 3 wk, protein accretion in semitendinosus muscle was scarcely altered in immature lambs weighing 7-15 kg and fed milk replacer and cimaterol for 3 wk. It is unclear whether young animals’ lack of responsiveness to -adrenergic agonists results from an earlier decline in receptor abundance and/or affinity in skeletal muscle or from a quicker rise in refractoriness to these substances.

Acknowledgement

None

Conflict of Interest

None

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