Ractopamine HCl improved cardiac hypertrophy but not poor growth, metabolic inefficiency, or greater white blood cells associated with heat stress in concentrate-fed lambs

Heat stress decreases livestock performance and well-being (Hahn, 1999; Nienaber and Hahn, 2007), causes metabolic dysfunction that decreases growth efficiency (O’Brien et al., 2010), and alters cardiovascular function (Crandall et al., 2008). Each year, heat stress costs the livestock industry up to $2.5 billion (St-Pierre et al., 2003). Ractopamine HCl acts as a nutrient repartitioning agent (Beermann, 2002); classified as a β adrenergic agonist (βAA), it shares pharmacological properties with adrenaline (Beermann, 2002). βAA increase muscle mass and decreases fat deposition through unknown mechanisms (Beermann, 2002). In feedlot cattle, they increase growth efficiency and improve carcass yield and merit (Scramlin et al., 2010; Buntyn et al., 2017), which increases profit and allows more meat to be produced from fewer animals. However, because βAA act via a stress system, it is unclear how the products affect animals under stress conditions. β1AA and β2AA can also cause tachycardia, heart palpitations, and arrhythmias (Sears, 2002). We hypothesize that β1AA combined with heat stress may overstimulate the adrenergic system, resulting is metabolic dysfunction and decreased performance. Sheep are a common model for cattle, and thus, the objective of this study was to determine the impact of ractopamine HCl on health and cardiovascular parameters, growth, and metabolic efficiency in feeder lambs

Body composition estimated by bioelectrical impedance analyses is diminished by prenatal stress in neonatal lambs and by heat stress in feedlot wethers

Body composition correlates to carcass value in livestock, which makes the ability to accurately estimate body composition in the live animal beneficial (Berg and Marchello, 1994). Bioelectrical impedance analysis (BIA) is a clinical tool used to assess body composition in humans (Lukaski et al., 1985), but its use in livestock has been minimal. Lean and fat content contribute to profitability for livestock producers, and poor body composition can be caused by stress that occurs either during in utero development (De Blasio et al., 2007) or during postnatal growth (Boyd et al., 2015). Maternal hyperthermia-induced placental insufficiency (Brown et al., 2015) and sustained maternal inflammation (Cadaret et al., 2018) are two established causes of intrauterine growth restriction (IUGR). IUGR-born animals are characterized by asymmetrical growth restriction that alters lifelong body composition due to impaired muscle growth capacity (Yates et al., 2018). In addition, acute heat stress during periods of peak postnatal growth can alter body composition in livestock (Boyd et al., 2015). We postulate that BIA can detect these changes in the live animal. Thus, the objective of this study was to determine whether BIA measurements can predict changes to body composition in live neonatal lambs exposed to intrauterine stress and in heat-stressed feedlot lambs

Maternal inflammation at 0.7 gestation in ewes leads to intrauterine growth restriction and impaired glucose metabolism in offspring at 30 d of age

Fetal programming associated with intrauterine growth restriction (IUGR) leads to lifelong deficits in growth and metabolic function (Hales and Barker, 2013). IUGR arises when fetuses respond to poor in utero conditions by developing adaptations that repartition nutrients to critical tissues and away from skeletal muscle (Yates et al., 2012, 2018). This fetal programming is beneficial in utero but leads to persistent reductions in muscle mass and glucose homeostasis in offspring (DeFronzo et al., 1981). Recent studies by our laboratory in sheep and rats demonstrate that maternal inflammation during gestation induces fetal inflammatory adaptations that impair growth and disrupt muscle glucose metabolism (Cadaret et al., 2017, 2018). IUGR fetal skeletal muscle exhibits indicators of enhanced inflammatory sensitivity, which could disrupt glucose uptake and oxidation (Yates et al., 2016; Cadaret et al., 2018). Enhanced inflammatory responsiveness would help explain growth and metabolic deficits observed in IUGR offspring. We hypothesize that fetal programming induced by maternal inflammation persists in offspring and contributes to impaired growth and glucose metabolism at 30 d. Therefore, the objective of this study was to determine whether sustained maternal inflammation induced by bacterial endotoxin at 0.7 gestation leads to fetal programming that contributes to deficits in growth and glucose metabolism in offspring

Deficits in growth, muscle mass, and body composition following placental insufficiency-induced intrauterine growth restriction persisted in lambs at 60 d of age but were improved by daily clenbuterol supplementation

Low birthweight in livestock results from stress-induced intrauterine growth restriction (IUGR; Yates et al., 2018). IUGR fetuses exhibit diminished muscle growth that persists in the neonatal stage, leading to asymmetric body composition and decreased weight gain (Cadaret et al., 2019). Ultimately, low birthweight diminishes yield and carcass merit at harvest (Greenwood et al., 2000), making effective postnatal treatment strategies to improve IUGR growth outcomes necessary. In this study, we examined the benefits of injecting the β2 agonist clenbuterol daily to target adrenergic adaptations that we previously observed in IUGR muscle (Posont et al., 2018; Yates et al., 2018). We hypothesized that IUGRinduced growth deficits would persist at the juvenile stage, manifesting in inferior body composition and carcass traits. We also postulated that clenbuterol would at least partially recover growth and body symmetry. Our objective was to test this hypothesis by assessing growth metrics and body composition in IUGR-born lambs hand-reared to 60 d of age and supplemented daily with injectable clenbuterol

Beef cows with atypical estrous cyclicity at puberty produced calves with deficits in preweaning muscling, metabolic indicators, and myoblast function but not in feedlot performance

In cattle, age at puberty and number of estrous cycles prior to first breeding contribute to lifetime reproductive success (Perry et al., 1991). In our university beef herd, we have identified a subset of cows that exhibited irregular pubertal cyclicity patterns between weaning and their first breeding season, which we postulate is associated with high androstenedione in follicular fluid (Cupp et al., 2019). Cows with high androstenedione are subfertile but wean calves that average 17 kg heavier than the herd average (Summers et al., 2014). We hypothesized that this additional weight at weaning in their offspring is due to superior muscling and growth efficiency, characterized by better myoblast function, lean mass, and metabolic efficiency. The objective of this study was to test this hypothesis by evaluating growth and metabolic parameters in calves prior to weaning and in the feedlot, as well as carcass characteristics at harvest. We compared calves from cows that were classified as having typical pubertal cyclicity, start–stop pubertal cyclicity, or noncyclic puberty

Ractopamine HCl improved cardiac hypertrophy but not poor growth, metabolic inefficiency, or greater white blood cells associated with heat stress in concentrate-fed lambs

Heat stress decreases livestock performance and well-being (Hahn, 1999; Nienaber and Hahn, 2007), causes metabolic dysfunction that decreases growth efficiency (O’Brien et al., 2010), and alters cardiovascular function (Crandall et al., 2008). Each year, heat stress costs the livestock industry up to $2.5 billion (St-Pierre et al., 2003). Ractopamine HCl acts as a nutrient repartitioning agent (Beermann, 2002); classified as a β adrenergic agonist (βAA), it shares pharmacological properties with adrenaline (Beermann, 2002). βAA increase muscle mass and decreases fat deposition through unknown mechanisms (Beermann, 2002). In feedlot cattle, they increase growth efficiency and improve carcass yield and merit (Scramlin et al., 2010; Buntyn et al., 2017), which increases profit and allows more meat to be produced from fewer animals. However, because βAA act via a stress system, it is unclear how the products affect animals under stress conditions. β1AA and β2AA can also cause tachycardia, heart palpitations, and arrhythmias (Sears, 2002). We hypothesize that β1AA combined with heat stress may overstimulate the adrenergic system, resulting is metabolic dysfunction and decreased performance. Sheep are a common model for cattle, and thus, the objective of this study was to determine the impact of ractopamine HCl on health and cardiovascular parameters, growth, and metabolic efficiency in feeder lambs

Maternal inflammation at 0.7 gestation in ewes leads to intrauterine growth restriction and impaired glucose metabolism in offspring at 30 d of age

Fetal programming associated with intrauterine growth restriction (IUGR) leads to lifelong deficits in growth and metabolic function (Hales and Barker, 2013). IUGR arises when fetuses respond to poor in utero conditions by developing adaptations that repartition nutrients to critical tissues and away from skeletal muscle (Yates et al., 2012, 2018). This fetal programming is beneficial in utero but leads to persistent reductions in muscle mass and glucose homeostasis in offspring (DeFronzo et al., 1981). Recent studies by our laboratory in sheep and rats demonstrate that maternal inflammation during gestation induces fetal inflammatory adaptations that impair growth and disrupt muscle glucose metabolism (Cadaret et al., 2017, 2018). IUGR fetal skeletal muscle exhibits indicators of enhanced inflammatory sensitivity, which could disrupt glucose uptake and oxidation (Yates et al., 2016; Cadaret et al., 2018). Enhanced inflammatory responsiveness would help explain growth and metabolic deficits observed in IUGR offspring. We hypothesize that fetal programming induced by maternal inflammation persists in offspring and contributes to impaired growth and glucose metabolism at 30 d. Therefore, the objective of this study was to determine whether sustained maternal inflammation induced by bacterial endotoxin at 0.7 gestation leads to fetal programming that contributes to deficits in growth and glucose metabolism in offspring

A Nuclear Export Signal in KHNYN Required for Its Antiviral Activity Evolved as ZAP Emerged in Tetrapods

The zinc finger antiviral protein (ZAP) inhibits viral replication by directly binding CpG dinucleotides in cytoplasmic viral RNA to inhibit protein synthesis and target the RNA for degradation. ZAP evolved in tetrapods and there are clear orthologs in reptiles, birds, and mammals. When ZAP emerged, other proteins may have evolved to become cofactors for its antiviral activity. KHNYN is a putative endoribonuclease that is required for ZAP to restrict retroviruses. To determine its evolutionary path after ZAP emerged, we compared KHNYN orthologs in mammals and reptiles to those in fish, which do not encode ZAP. This identified residues in KHNYN that are highly conserved in species that encode ZAP, including several in the CUBAN domain. The CUBAN domain interacts with NEDD8 and Cullin-RING E3 ubiquitin ligases. Deletion of the CUBAN domain decreased KHNYN antiviral activity, increased protein expression and increased nuclear localization. However, mutation of residues required for the CUBAN domain-NEDD8 interaction increased KHNYN abundance but did not affect its antiviral activity or cytoplasmic localization, indicating that Cullin-mediated degradation may control its homeostasis and regulation of protein turnover is separable from its antiviral activity. By contrast, the C-terminal residues in the CUBAN domain form a CRM1-dependent nuclear export signal (NES) that is required for its antiviral activity. Deletion or mutation of the NES increased KHNYN nuclear localization and decreased its interaction with ZAP. The final 2 positions of this NES are not present in fish KHNYN orthologs and we hypothesize their evolution allowed KHNYN to act as a ZAP cofactor. IMPORTANCE The interferon system is part of the innate immune response that inhibits viruses and other pathogens. This system emerged approximately 500 million years ago in early vertebrates. Since then, some genes have evolved to become antiviral interferon-stimulated genes (ISGs) while others evolved so their encoded protein could interact with proteins encoded by ISGs and contribute to their activity. However, this remains poorly characterized. ZAP is an ISG that arose during tetrapod evolution and inhibits viral replication. Because KHNYN interacts with ZAP and is required for its antiviral activity against retroviruses, we conducted an evolutionary analysis to determine how specific amino acids in KHNYN evolved after ZAP emerged. This identified a nuclear export signal that evolved in tetrapods and is required for KHNYN to traffic in the cell and interact with ZAP. Overall, specific residues in KHNYN evolved to allow it to act as a cofactor for ZAP antiviral activity

Heat stress and β-adrenergic agonists alter the adipose transcriptome and fatty acid mobilization in ruminant livestock

Growth and feed efficiency of cattle are improved by supplementation with the beta-adrenergic agonists (βAA), ractopamine hydrochloride (RH; β1AA) or zilpaterol hydrochloride (ZH; β2AA) (Elam et al., 2009). βAA supplementation alters adipose deposition by inhibiting fatty acid biosynthesis and promoting lipolysis of stored triacylglycerols into free fatty acids (FFAs) (Johnson et al., 2014). However, β2 adrenoceptors (βAR) desensitize with chronic activation (Re et al., 1997); supplementation is thus limited to the last 20 to 40 d of feeding. The annual economic impact of heat stress (HS) has been estimated to exceed $2.4 billion (St-Pierre et al., 2003). Heat-stressed livestock have reduced growth rates, dry matter intake, and average daily gain (Mitlöhner et al., 2001; St-Pierre et al., 2003). In response to acute stress, signaling pathways for lipolysis of circulating and stored triglycerides are activated, while chronic stress increases lipogenesis and adipogenesis (Campbell et al., 2009; Peckett et al., 2011). In cattle, HS also increases the responsiveness of adipocytes to lipolytic signals, increasing lipolysis (Faylon et al., 2015). The objective of this study was to understand how HS and βAA independently and interactively affect adipose tissue. Prior work identified minimal impact of RH on metabolic properties (Barnes et al., 2019) and on the transcriptome of skeletal muscle (Kubik et al., 2018). We therefore hypothesized that RH may be primarily affecting adipose; specifically, that lipolytic activity is increased due to heat and βAA in an additive fashion. We tested this hypothesis in RH-supplemented lambs and ZH-supplemented cattle exposed to HS for 30 and 21 d, respectively