Review: Nutritional regulation of muscle growth in neonatal swine

Abstract

Despite advances in the nutritional support of low birth weight and early-weaned piglets, most experience reduced extrauterine growth performance. To further optimize nutritional support and develop targeted intervention strategies, the mechanisms that regulate the anabolic response to nutrition must be fully understood. Knowledge gained in these studies represents a valuable intersection of agriculture and biomedical research, as low birth weight and early-weaned piglets face many of the same morbidities as preterm and low birth weight infants, including extrauterine growth faltering and reduced lean growth. While the reasons for poor growth performance are multifaceted, recent studies have increased our understanding of the role of nutrition in the regulation of skeletal muscle growth in the piglet. The purpose of this review is to summarize the published literature surrounding advances in the current understanding of the anabolic signaling that occurs after a meal and how this response is developmentally regulated in the neonatal pig. It will focus on the regulation of protein synthesis, and especially the upstream and downstream effectors surrounding the master protein kinase, mechanistic target of rapamycin complex 1 (mTORC1) that controls translation initiation. It also will examine the regulatory pathways associated with the postprandial anabolic agents, insulin and specific amino acids, that are upstream of mTORC1 and lead to its activation. Lastly, the integration of upstream signaling cascades by mTORC1 leading to the activation of translation initiation factors that regulate protein synthesis will be discussed. This review concludes that anabolic signaling cascades are stimulated by both insulin and amino acids, especially leucine, through separate pathways upstream of mTORC1, and that these stimulatory pathways result in mTORC1 activation and subsequent activation of downstream effectors that regulate translation initiation Additionally, it is concluded that this anabolic response is unique to the skeletal muscle of the neonate, resulting from increased sensitivity to the rise in both insulin and amino acid after a meal. However, this response is dampened in skeletal muscle of the low birth weight pig, indicative of anabolic resistance. Elucidation of the pathways and regulatory mechanisms surrounding protein synthesis and lean growth allow for the development of potential targeted therapeutics and intervention strategies both in livestock production and neonatal care.

Introduction

Two common issues faced by the swine industry each year are pigs born of a low birth weight (piglets with a birth weight in the bottom 10% in a litter) (Riddersholm et al., 2021; Wu, 2018) and failure of piglets to thrive in early weaning scenarios (Valentim et al., 2021). Low birth weight in piglets is largely due to the genetic pressures of increasing hyperprolific sows (Riddersholm et al., 2021; Wu, 2018), while early weaning is typically done in response to market pressures from the highly vertically integrated pork market (Valentim et al., 2021). Nevertheless, both represent considerable issues facing the growth of neonatal pigs. Low birth weight, alone, represents a considerable loss to the swine industry each year (Wu et al., 2006). This is due to multiple factors including piglet losses at birth from discarded low birth weight animals, and indirect profit loss from wasted resources related to sow breeding and care (Wu et al., 2006; Mota-Rojas et al., 2011). Early weaning is done with the goal of decreasing the time between farrowing and rebreeding, leading to increased annual sow productivity (Valentim et al., 2021). However, young piglets have a decreased ability to digest grain due to enzyme activity in the gut that favors milk digestion and will only gradually adapt to digest other carbohydrates and protein approaching D42 of age (Engelsmann et al., 2022; Wei et al., 2021; Santos et al., 2018). This can lead to reduced digestibility and enteric disorders, similar to those seen in preterm and low birth weight human infants (Gomez et al., 2015). Therefore, the neonatal piglet model represents a valuable “dual purpose for dual benefits” model that has the potential to provide valuable findings in both animal agriculture and medicine.

Despite recent, modest reductions in the percentage of children affected, low birth weight remains the second highest cause of infant mortality in the United States (Mathews and Driscoll, 2017). Low birth weight in humans is defined as a birth weight of less than 2 500 g, per the World Health Organization, and in piglets is defined as the bottom 10% of litter birth weight. The majority of low birth weight infants are also born preterm (Alexander, 2007). Worldwide each year, approximately 15 million infants are born preterm, including over 10% of babies in the U.S. (Narwal et al., 2012), and this represents a significant healthcare concern (McIntire et al., 1999; March of Dimes, 2022).

Along with the increased risk of neonatal and postneonatal death, low birth weight piglets and infants are at increased risk for short-term adverse health outcomes such as respiratory distress, sepsis, decreased digestibility in the gut, and necrotizing enterocolitis, sometimes associated with parenteral feeding in low birth weight human infants, a necessary component of preterm infant management (Goldenberg and Culhane, 2007; Sondheimer et al., 1998; Kao et al., 2006). Extrauterine growth restriction is also a commonality between low birth weight piglets and infants, with growth curves faltering early in neonatal life and leading to decreased linear growth and an increased fat-to-lean mass body mass ratio, which likely contributes to an increased risk of undesirable carcass yields (“fatty carcass”) in low birth weight piglets, and obesity and related metabolic disease in low birth weight infants (Johnson et al., 2012; Markopoulou et al., 2019). This underscores the importance of meeting neonatal protein requirements and understanding the nutritional regulation of muscle growth in the neonate, especially those born low birth weight.

However, to develop effective therapies to optimize the nutritional management and growth of low birth weight piglets and infants, the nutritional mechanisms regulating perinatal growth must be firmly established. Growth and protein turnover rates are higher during the neonatal period than in any other period of postnatal or adult life (Davis et al., 1989). This high growth rate is largely attributable to the high rate of protein synthesis in skeletal muscle (Davis and Fiorotto, 2009; Suryawan et al., 2007). We have shown that this high rate of protein synthesis in muscle of the neonate is driven by the high ribosomal abundance and the ability to accelerate protein synthesis after a meal. This response to feeding in muscle is regulated independently by the postprandial increase in insulin and amino acids that activate nutrient signaling cascades (Wilson et al., 2009; El-Kadi et al., 2012; Suryawan et al., 2009) that increase activation of mechanistic target of rapamycin complex 1 (mTORC1), the master regulator of translation initiation (Davis and Fiorotto, 2009). However, low birth weight neonates often fall behind established extrauterine growth curves (Zhang et al., 2021; Bhatia, 2013), indicating a potential dysregulation in the activation of translation initiation.

Studies in the low birth weight piglet suggest that this extrauterine growth restriction is due to a reduced response to the feeding-induced stimulation of protein synthesis (Naberhuis et al., 2019). This reduced anabolic response results from the resistance of both the insulin and amino acid anabolic signaling pathways that regulate mTORC1-dependent translation initiation (Rudar et al., 2021a). Understanding these complex nutrient signaling pathways, how they impact the overall growth of the neonate, and the physiological differences that occur due to developmental regulation are vital to the development of new strategies to optimize the nutritional management of at-risk piglets and infants and promote their lean growth.

Role of nutrient intake in neonatal growth regulation

Feeding increases protein synthesis in neonatal skeletal muscle and this response is developmentally regulated

During the neonatal period, neonates undergo rapid growth. While all body tissues contribute to this rapid increase in mass, skeletal muscle tissue is the primary driver, in addition to being the most sensitive to nutrient deficiencies during this critical period in terms of meeting growth potential. For example, in neonatal rats, skeletal muscle tissue increases from 30% of total body protein at birth to 45% of total body protein at weaning (D28) (Davis and Fiorotto, 2009). Supporting this period of early muscle growth through a sufficient supply of nutrients, including amino acids, is vital for maximizing swine growth performance and productivity.

Skeletal muscle protein deposition occurs when the rate of protein synthesis exceeds the rate of protein degradation (Rudar et al., 2019; Reeds et al., 1980). Following ingestion of a meal, plasma levels of amino acids and glucose sharply increase, resulting in increased circulating levels of amino acids and insulin (in response to increased glucose levels). We have previously shown that feeding profoundly stimulates muscle protein synthesis in the neonatal pig and that this postmeal response decreases with age, noticeably diminishing even over the first 28 days of life (Suryawan and Davis, 2018; Suryawan et al., 2007; Davis et al., 1996), and further decreases through the postnatal period and into adulthood (Markofski et al., 2015; Paddon-Jones and Rasmussen, 2009; Volpi et al., 2000). To determine the metabolic mechanisms underlying this response, we developed a modified pancreatic-substrate clamp method which allows precise control of not only insulin and glucose (DeFronzo et al., 1979) but also amino acids (Davis et al., 1998) so that the independent effects of both insulin and amino acids could be identified using hyperinsulinemic-euaminoaci demic-euglycemic, euinsulinemic-hyperaminoacidemic-euglyc miec, and euinsulinemic-euaminoacidemic-euglycemic clamps. The results showed that the stimulation of protein synthesis by both insulin and amino acids is unique to skeletal muscle in neonatal pigs and is independently regulated by both anabolic agents (O’Connor et al., 2003; Davis et al., 2002). This is notable as studies with adult skeletal muscle tissue showed no response to insulin in terms of activating protein synthesis pathways (Barazzoni et al., 2012), and protein synthesis in the viscera of neonatal pigs is also not affected by the presence of insulin (Davis et al., 2001). Because skeletal muscle of the neonatal pig can respond independently to both postprandial signaling molecules, it poises the skeletal muscle to be able to undergo more pronounced protein accretion.

Insulin and amino acids act separately as anabolic signals to increase protein synthesis in skeletal muscle of the neonatal pig through stimulation of upstream activators of mTORC1 (Suryawan et al., 2001; Suryawan et al., 2006) (Fig. 1). This complex, named for the mTOR enzyme that acts as its catalytic site, is the master regulating kinase of protein synthesis (Saxton and Sabatini, 2017). mTORC1 then acts through its downstream signaling cascades to activate translation initiation factors that regulate the binding of messenger RNA (mRNA) to the ribosome. These downstream effectors of mTORC1, together with factors that recruit the binding of methionyl-transfer RNA (met-tRNA) to the ribosome (Ma and Blenis, 2009), allow for newly synthesized proteins to be produced, leading to increased skeletal muscle deposition in the neonate.

Fig. 1.

Insulin and amino acids act through separate intracellular signaling pathways to stimulate mTORC1, resulting in increased skeletal muscle protein synthesis and increased lean growth in neonatal pigs. Insulin acts through PI3K/Akt inhibition of TSC2 (a potent inhibitor of mTORC1) while amino acids facilitate mTORC1 association with Rag proteins (a necessary component of mTORC1 activation). Adapted from Rudar et al. (2021b). Abbreviations: Akt = Ak strain transforming; IRS1 = insulin receptor substrate 1; mTORC1 = mechanistic target of rapamycin complex 1; PI3K = phosphoinositide 3 kinase; Rag = RAS-related GTP-binding; TSC2 = tuberous sclerosis complex 2.

Skeletal muscle in neonatal swine is exceptionally sensitive to feeding-induced changes in the plasma concentrations of nutrients due to an enhanced sensitivity of the signaling pathways both upstream and downstream of mTORC1 (Rudar et al., 2019). Therefore, adequate nutrient intake, especially protein intake, is vital for neonatal health, as insufficient protein intake in neonatal pigs leads to growth faltering and decreased response of skeletal muscle protein synthesis to meal feeding (Columbus et al., 2015; Frank et al., 2006). Amino acid-specific stimulation of these protein synthesis signaling cascades also underscores an important, but often misunderstood aspect of nutrition—there is no simple “whole protein” requirement. Instead, there are multiple requirements each day for different amino acids and the amino acid content of a meal will impact the postprandial response of protein synthesis in skeletal muscle (Posey et al., 2021; Devries et al., 2018; Hou and Wu, 2017). This can significantly impact the growth of the neonatal pig, especially early-weaned piglets when they are switched from sow’s milk (a comparatively good source of proteinogenic and protein synthesis-stimulating amino acids, including leucine and glycine [Wu and Knabe, 1994]) to traditional plant-based swine diets (low in leucine, glycine, and arginine [Li and Wu, 2020; Hou et al., 2019]) during the critical growth period from birth to traditional weaning age (approximately 21–28 days after birth). Therefore, having a thorough understanding of the mechanisms by which insulin and amino acids stimulate translation initiation and protein synthesis, including the upstream and downstream signaling pathways of mTORC1 activation, is vital for optimizing swine growth performance and overall productivity.

Insulin regulates mechanistic target of rapamycin complex 1 activity

In the neonatal pig, protein synthesis markedly increases following a meal, though studies have shown this effect decreases with age and is blunted in the low birth weight neonatal pig (Davis et al., 1996; Paddon-Jones and Rasmussen, 2009; Naberhuis et al., 2019; Rudar et al., 2021a). One reason for this dramatic response to meal feeding is the rapid rise in plasma insulin, as insulin induces mTORC1 activation in skeletal muscle (Garami et al., 2003). This insulin-induced response is notable as this is unique to the skeletal muscle of the neonatal monogastric, as studies with neonatal ruminants have not shown an increase in protein synthesis in response to infusion with insulin (Wester et al., 2004; Bequette et al., 2002; Oddy et al., 1987). While insulin infusion alone did not appear to stimulate protein synthesis in these studies, it should be noted that insulin reduced circulating levels of amino acids, potentially limiting protein synthesis activation by insulin.

In early neonatal life, when insulin binds to the transmembrane insulin receptor on the surface of a skeletal myocyte, it initiates an intracellular signaling cascade that results in the induction of mTORC1 activation. While insulin can signal through multiple pathways, affecting different processes within a cell, stimulation of the phosphoinositide 3 kinase (PI3K)-Ak strain transforming (Akt)/protein kinase B (PKB) pathway results in increased protein synthesis. The binding of insulin to its receptor on the surface of insulin-responsive cells induces autophosphorylation of the receptor, leading to the recruitment of insulin receptor substrate 1 (IRS1) and activation of PI3K. This in turn phosphorylates and activates Akt (also known as PKB) (Hoxhaj and Manning, 2020) which stimulates the rapid phosphorylation, and subsequent inactivation, of tuberous sclerosis complex 2 (TSC2), an inhibitor of mTORC1 (Hoxhaj and Manning, 2020; Menon et al., 2014). The phosphorylation and inhibition of TSC2 cause TSC to release its inhibitory hold on mTOR, allowing mTOR to associate with Rheb on the lysosomal membrane, leading to mTORC1 activation (Saxton and Sabatini, 2017; Inoki et al., 2003; Garami et al. 2003). Notably, previous work utilizing the neonatal piglet pancreatic-clamp technique (described in Davis et al., 1998) to increase insulin to fed levels leads to stimulation of the insulin signaling pathway, including activation of PI3K and Akt, the phosphorylation of TSC2, and formation of the RAS-homolog enriched in brain (Rheb)-mTOR association complex (Suryawan et al., 2007; O’Connor et al., 2003). However, the activation of this pathway is blunted in skeletal muscle of the preterm piglet, with hyperinsulinemic-euaminoa cidemic-euglycemic clamps showing lower phosphorylation of Akt and TSC2 and reduced Rheb-mTOR association in response to insulin in muscle of preterm compared to term neonates (Rudar et al., 2021a). Notably, this specific cellular signaling pathway was shown to not be affected by amino acids using the euinsulinemic-hyperaminoacidemic-euglycemic clamp technique (Suryawan et al., 2009; Suryawan et al., 2007; Suryawan et al., 2004; O’Connor et al., 2003).

Amino acids regulate mechanistic target of rapamycin complex 1 activity

Feeding increases protein synthesis in part due to the increase in amino acids that make up the protein source in the meal. We have previously shown that a rise in leucine, a branched-chain amino acid that is both proteinogenic and an anabolic signaling molecule, is sufficient nutrient stimulus to increase the rate of protein synthesis in skeletal muscle of the neonatal pig (Suryawan et al. 2008; Escobar et al., 2005, 2006, and 2007). This increase in protein synthesis is a result of the activation of mTORC1 due to the activation of upstream amino acid sensing pathways that are independent of the insulin stimulatory pathway. While more work is needed to fully elucidate all pathways involved in mTORC1 stimulation by amino acids, studies largely conducted in vitro have led to acceptance of the following model (Yao et al., 2017; Chantranupong et al., 2016; Wolfson et al., 2016; Bar-Peled and Sabatini, 2014). Upon amino acid transport into the cell, these nutrients signal through the heterodimeric RAS-related GTPbinding (Rag) A/B and Rag C/D proteins. In association with Rag A/B GTPase (bound to GTP) or Rag C/D GTPase (bound to GDP), mTOR moves to the lysosomal membrane. This occurs with concurrent activity of the Ragulator proteins (LAMPTOR1–5) and vacuolar H⁺-ATPase (V-ATPase). The movement of mTOR to the lysosomal membrane allows it to interact with the lysosome-associated Rheb protein (a potent stimulator of mTORC1), leading to the activation of mTORC1 (Bar-Peled and Sabatini, 2014). The Rheb protein becomes active following the removal of TSC inhibition via the insulin-sensing pathway or via an insulinindependent adenosine monophosphate-activated protein kinase (AMPK) phosphorylation pathway. However, there is no evidence of changes in acetyl-CoA carboxylase (ACC) (an indicator protein of AMPK activity) abundance or phosphorylation due to amino acids, insulin, or age. Additionally, results from previous work show no change in AMPK phosphorylation following amino acid supplementation, indicating a low likelihood that AMPK plays a vital role in amino acid-driven mTORC1 activation in neonatal muscle (Rudar et al., 2021a; Manjarín et al., 2020; Suryawan and Davis, 2018; Manjarín et al., 2018; Boutry et al., 2013).

Leucine is a potent stimulator of amino acid-driven mTORC1 activation. This is due to the activity of stress response protein 2 (Sestrin2) and its interaction with the GTPase-activating protein activation toward Rags (GATOR) proteins (Sadria and Layton, 2021; Chantranupong et al., 2016; Wolfson et al., 2016; Kim et al., 2015). During fasting, Sestrin2 binds to GATOR2, acting as a potent inhibitor of GATOR1. Active GATOR1 binds to mTOR and prevents it from associating with Rag A/B or Rag C/D for localization to the lysosome (the location of the master activator, Rheb). However, Sestrin2 also acts as a nutrient sensor and is especially sensitive to the presence of leucine. Upon transport of leucine into the cell, the amino acid binds to Sestrin2 (Wolfson et al., 2016), leading to Sestrin2 inhibition. Inhibiting Sestrin2 releases active GATOR2 to associate with GATOR1. Upon GATOR protein interaction, GATOR1 releases its inhibition on mTOR allowing for interaction with the Rag proteins. Once released from GATOR1, mTOR is free to associate with the Rag proteins to be translocated to the lysosomal membrane for activation. In this way, leucine stimulates the binding of Rag A and Rag C to mTOR, leading to increased protein synthesis (Suryawan and Davis, 2018; Hong-Brown et al., 2012). Our previous work has shown an increased formation of the Rag A-mTOR and Rag C-mTOR complexes in skeletal muscle of the neonatal pig in response to feeding or in response to ingestion of a leucine-supplemented diet (Rudar et al., 2021a; Suryawan et al., 2020; Suryawan and Davis, 2018; Boutry et al., 2016).

Arginine is also a possible stimulator of mTORC1 activation that functions through the putative arginine sensor, SLC38A9 (Rebsamen et al., 2015; Wang et al., 2015). SLC38A9, an amino acid transporter, has been shown to regulate mTORC1 activation through the Rag-Ragulator complex in vitro (Jung et al., 2015). However, other results showed that the abundance of SLC38A9 was not affected by amino acids, insulin, or age in the neonatal pig (Suryawan and Davis, 2018). Therefore, as no other in vivo skeletal muscle data are available, further work is needed to determine the role of SLC38A9 in the integration of anabolic amino acid signaling.

Activation of mechanistic target of rapamycin complex 1 by insulin and amino acids leads to translation initiation in neonatal skeletal muscle

Following the integration of the nutrient signaling components in the insulin and amino acid signaling pathways, these signals are then conveyed through mTOR kinase, the master regulator of translation initiation that controls the overall rate-limiting step of protein synthesis. The mTOR catalytic subunit associates with two protein complexes, mTORC1 and mTORC2, with mTORC1 serving as the primary anabolic signal integrating complex (Liu and Sabatini, 2020). However, in vitro results suggest that mTORC2 may reinforce the upstream anabolic signaling components necessary for mTORC1 activation (Sarbassov et al., 2002). Following localization to the lysosomal membrane by the Rag proteins (Rag A-mTOR, Rag C-mTOR), and subsequent activation through association with membrane-bound Rheb, mTORC1 initiates a series of downstream signaling cascades that activate translation initiation (Saxton and Sabatini, 2017). The most well-characterized downstream effectors are p70 ribosomal protein S6 kinase 1 (S6K1) and eukaryotic initiation factor (eIF)4E binding protein 1 (4EBP1). Both factors are recruited by Raptor, a critical component of mTORC1, which binds proteins at their TOR signaling motifs (TOS), facilitating phosphorylation by mTOR kinase (Nojima et al., 2003). When active, 4E-BP1 binds and sequesters eIF4E, preventing the formation of the eIF4E·eIF4G complex required for the recruitment of mRNA to the 43S preinitiation complex and translation initiation (Ma and Blenis, 2009). Upon multisite phosphorylation by mTORC1 (Böhm et al., 2021), 4E-BP1 becomes inactive, releasing eIF4E and allowing for eIF4E·eIF4G complex formation and promoting translation initiation (Liu and Sabatini, 2020). Unlike its inhibitory effect on 4E-BP1, mTORC1 phosphorylation results in S6K1 activation. S6K1 activation results in phosphorylation of many downstream target proteins involved in translation initiation and elongation including eIF4B (enhances the RNA helicase activating of eIF4A), ribosomal protein (rp) S6 (a component of the small ribosomal subunit), and eukaryotic elongation factor (eEF)2 kinase (prevents inactivation of eEF2) (Saxton and Sabatini, 2017). Our previous work has shown that phosphorylation of mTORC1 and its downstream targets S6K1 and 4E-BP1 increases, as does the abundance of active eIF4E eIF4G complex, in skeletal muscle of neonatal pigs after feeding or in response to a rise in either amino acids or insulin to simulate fed levels (Boutry et al., 2013, 2016; Columbus et al., 2015; Suryawan et al., 2008, 2012; Gazzaneo et al., 2011; Escobar et al., 2005, 2010; Wilson et al., 2009; O’Connor et al., 2003).

Additionally, we have shown that the skeletal muscle of young neonatal pigs is especially sensitive to activation of these anabolic pathways. Amino acid and insulin signaling to mTORC1, the activation of translation initiation, and the stimulation of protein synthesis following a meal are elevated in the newborn and decrease with age (Suryawan et al., 2013; Suryawan and Davis, 2010; Escobar et al., 2007; Suryawan et al., 2007; Suryawan et al., 2001; Davis et al., 2000). This developmentally regulated sensitivity is due to an elevated abundance and postprandial activity of upstream and downstream mTORC1 effectors in skeletal muscle of the newborn that decreases with age (Suryawan and Davis, 2018; Kimball et al., 2000). These developmental differences in expression and activity would explain the increased sensitivity to both insulin and leucine signaling in young neonates and the heightened activation response of mTORC1. Growth factor receptor bound protein (GRB)10 phosphorylation has been reported to diminish IRS functionality, inhibiting the mTORC1 signaling pathway, in cell culture (Hsu et al. 2011; Yu et al. 2011). Neonatal pigs showed less GRB10 abundance than older pigs, resulting in a more stabilized signaling pathway (Suryawan and Davis, 2018). Additionally, DEP-containing mTOR-interacting protein (DEPTOR) is a strong inhibitor of mTORC1 (Peterson et al., 2009; Gao et al., 2011). Our results showed a decreased abundance of DEPTOR in skeletal muscle of the newborn pig compared to skeletal muscle of pigs 20 -days older (Suryawan and Davis 2018). There was also a greater abundance of both Sestrin2 (the “Leu sensing” protein that leads to the removal of GATOR1’s inhibitory action on mTORC1) (Wolfson et al., 2016) and LAMTOR 1 (a component of the critical Ragulator complex necessary for mTORC1 activation) (Bar-Peled and Sabatini, 2014) in skeletal muscle of 6- compared to 26-day-old pigs (Suryawan and Davis, 2018). These results suggest an increased sensitivity to leucine and increased mTORC1 activation threshold in neonatal pig skeletal muscle. Additionally, these results offer explanation for the sharp developmental decline in postmeal protein synthesis rates.

The neonatal pig is a highly translatable animal model of human infants

Livestock animals can provide valuable research insights for both agricultural and biomedical research (Spencer et al, 2022; Smith and Govoni, 2022; Polejaeva et al., 2016). The success of utilizing livestock animals, especially the piglet, as models for biomedical research highlights an important role for these animals as “dual purpose” models (Eicher et al, 2014; Hamernik, 2019). The piglet is a highly translatable animal model for studying human infant nutrition due to their high degree of similarity in physiology, metabolism, and stage of development in gestation (Bergen, 2022; Burrin et al., 2020). Additionally, many of the challenges of the newborn period faced by neonatologists are also seen in the swine industry, including low birth weight and concerns around early weaning. Therefore, utilizing livestock models creates collaborative research that can improve the efficiency and production of animal agriculture and the healthcare outcomes of humans. Providing “dual benefits” allows for greater access to resources, the formation of valuable collaborative efforts, and a shared goal of improving outcomes for all.

Conclusions

The rapid increase in swine growth during early neonatal life is driven by enhanced skeletal muscle sensitivity to feeding. Feeding results in the activation of mTORC1 and increased protein synthesis. This postmeal sensitivity of anabolic signaling is developmentally regulated, with marked responsiveness in early postnatal life which declines into adulthood. Thus, this enhanced sensitivity during the neonatal period provides a critical window for maximizing overall growth. Elucidation of the different signaling pathways that are activated in response to meal feeding have provided valuable insight into the developmental regulation of neonatal metabolism and growth, providing a metabolic understanding for the period of rapid growth seen in early neonatal life. Further, determining the upstream effectors of protein synthesis provides important metrics for assessing the effectiveness of targeted intervention strategies. With animal agriculture moving toward improved sustainability, targeted interventions represent opportunities for improving animal efficiency and decreasing waste, resulting in improved public perception of livestock production. For biomedical research, targeted intervention strategies in low birth weight infants to improve lean growth that results in lowered adiposity and risk of metabolic disease should decrease the economic and healthcare system impacts associated with these long-term morbidities. Overall improved understanding of the complex pathways regulating protein synthesis in the neonate has important implications for both agriculture and biomedical research.

Implications.

Understanding the mechanisms that regulate protein synthesis and lean growth in the neonate is instrumental for optimizing the nutritional support for neonatal pigs. Additionally, challenges faced by low birth weight and early-weaned piglets are similar to morbidities in preterm and low birth weight infants, making the neonatal piglet a valuable model for both agriculture and biomedical research in elucidating anabolic pathway regulation. Improved understanding of the pathways regulating lean growth in the neonatal pig will provide important information to promote sustainability and efficiency for swine production and to improve health outcomes for at-risk infants.

Data and model availability statement

None of the data were deposited in an official repository. Data sharing is not applicable to this article as no new data were created or analyzed.