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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.

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 induces intrauterine growth restriction (MI-IUGR) of the fetus, which compromises metabolic health in human offspring and reduces value in livestock. The objective of this study was to determine the effect of maternal inflammation at midgestation on fetal skeletal muscle growth and myoblast profiles at term. Pregnant Sprague-Dawley rats were injected daily with bacterial endotoxin (MI-IUGR) or saline (controls) from the 9th to the 11th day of gestational age (dGA; term = 21 dGA). At necropsy on dGA 20, average fetal mass and upper hindlimb cross-sectional areas were reduced (P < 0.05) in MI-IUGR fetuses compared with controls. MyoD+ and myf5+ myoblasts were less abundant (P < 0.05), and myogenin+ myoblasts were more abundant (P < 0.05) in MI-IUGR hindlimb skeletal muscle compared with controls, indicating precocious myoblast differentiation. Type I and Type II hindlimb muscle fibers were smaller (P < 0.05) in MI-IUGR fetuses than in controls, but fiber type proportions did not differ between experimental groups. Fetal blood plasma TNFα concentrations were below detectable amounts in both experimental groups, but skeletal muscle gene expression for the cytokine receptors TNFR1, IL6R, and FN14 was greater (P < 0.05) in MI-IUGR fetuses than controls, perhaps indicating enhanced sensitivity to these cytokines. Maternal blood glucose concentrations at term did not differ between experimental groups, but MI-IUGR fetal blood contained less (P < 0.05) glucose, cholesterol, and triglycerides. Fetal-to-maternal blood glucose ratios were also reduced (P < 0.05), which is indicative of placental insufficiency. Indicators of protein catabolism, including blood plasma urea nitrogen and creatine kinase, were greater (P < 0.05) in MI-IUGR fetuses than in controls. From these findings, we conclude that maternal inflammation at midgestation causes muscle-centric fetal programming that impairs myoblast function, increases protein catabolism, and reduces skeletal

• Intrauterine growth restriction (IUGR) continues to be a global epidemic that is associated with high early-life mortality rates and greater risk for developing metabolic disorders that lower length and quality of life in affected individuals. • Fetal programming of muscle growth and metabolic function associated with IUGR is often comparable among nonlitter bearing mammalian species, which allows much of the information learned in domestic animal models to be applicable to humans (and other animals). • Recent studies in sheep models of IUGR have begun to uncover the molecular mechanisms linking adaptive fetal programming and metabolic dysfunction. • Targets of adaptive fetal programming indicated by sheep studies include adrenergic and inflammatory pathways that regulate skeletal muscle growth and glucose metabolism. Adaptive changes in these pathways represent potential focus areas for prenatal interventions or postnatal treatments to improve outcomes in IUGR-born offspring.

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.

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.

Intrauterine growth restriction (IUGR) is a leading cause of perinatal morbidity and mortality (Alisi et al., 2011). Skeletal muscle growth is disproportionately reduced in IUGR fetuses and offspring (Padoan et al. 2004; Yates et al. 2014). These individuals present with reduced muscle mass and increased risk for metabolic disorders at all stages of life (Godfrey and Barker, 2000; Yates et al. 2016.). Muscle growth requires proliferation, differentiation, and fusion of myoblasts (muscle stem cells) to form muscle fibers early in gestation and to increase myonuclear content of existing fibers during late gestation and after birth (Yates et al., 2014). These processes can be disrupted by inflammation, which is a potential factor in impaired muscle development in the IUGR fetus (Yates et al., 2012; Cadaret et al., 2017). Tumor necrosis factor-alpha (TNFα) and interleukin 6 (IL-6) are potent multifunctional cytokines involved in inflammatory and noninflammatory skeletal muscle disorders (Tüzün et al., 2006). We recently found that changes in gene expression of these cytokines and muscle sensitivity to them differed between IUGR and control rats (Cadaret et al., 2017), and that maternal inflammation induced fetal leukocyte adaptations, increasing gene expression of TNFα and its receptor TNFR1, but decreasing gene expression of IL-6 receptor. Both cytokines also regulate myoblast proliferation and differentiation outside of inflammatory states (Al-Shanti et al., 2008). These findings indicate TNFα and IL-6 are essential factors in proper growth and development of muscle, and thus, we postulate that expression and sensitivity changes contribute to decreased muscle growth capacity in IUGR fetuses. The objective of this study was to determine the effects of cytokines on fetal myoblast function and to determine if altered responsiveness is intrinsic in IUGR myoblasts, which would represent a potential adaptive mechanism for reduced muscle mass in IUGR offspring.

Intrauterine growth restriction (IUGR) is linked to metabolic dysfunction in offspring, but the mediating mechanisms are still under investigation (Barker et al., 1993). IUGR fetuses adapt to their poor intrauterine environment by repartitioning nutrients to organs critical for survival (i.e., brain, heart) at the expense of tissues such as muscle (Yates et al., 2012c). These developmental adaptations help the fetus to survive in utero but have lifelong consequences in offspring; persistent reduction of highly metabolic muscle mass is detrimental to glucose homeostasis (DeFronzo et al., 1981). Glucose metabolism is regulated primarily by insulin, and nutrient depravation is associated with impaired β-cell mass, insulin secretion, and insulin action in the IUGR fetus (Limesand et al., 2006). Moreover, inflammation disrupts insulin action and aids in the development of insulin resistance (Bach et al., 2013). We recently showed that inflammatory cytokines acutely stimulate glucose metabolism despite their antagonistic effects on insulin signaling (Cadaret et al., 2017b). However, we hypothesize that chronic exposure alters responsiveness to cytokines and results in basal cytokine concentrations having a greater inhibitory tone. Furthermore, chronic maternal inflammation may induce fetal inflammatory adaptations that impair muscle growth and metabolism. Therefore, our objective was to determine the effects of sustained maternal inflammation on fetal growth, islet function, and muscle glucose metabolism.

Recent studies show that adrenergic agonists and inflammatory cytokines can stimulate skeletal muscle glucose uptake, but it is unclear if glucose oxidation is similarly increased. Thus, the objective of this study was to determine the effects of ractopamine HCl (β1 agonist), zilpaterol HCl (β2 agonist), TNFα, and IL-6 on glucose uptake and oxidation rates in unstimulated and insulin-stimulated soleus muscle strips from adult Sprague-Dawley rats. Effects on phosphorylation of Akt (phospho-Akt), p38 MAPK (phospho-p38), and p44/42 MAPK (phospho-p44/42) was also determined. Incubation with insulin increased (P < 0.05) glucose uptake by ~47%, glucose oxidation by ~32%, and phospho-Akt by ~238%. Insulin also increased (P < 0.05) phospho-p38, but only after 2 hours in incubation. Muscle incubated with β2 agonist alone exhibited ~20% less (P < 0.05) glucose uptake but ~32% greater (P < 0.05) glucose oxidation than unstimulated muscle. Moreover, co-incubation with insulin + β2 agonist increased (P < 0.05) glucose oxidation and phospho-Akt compared to insulin alone. Conversely, β1 agonist did not appear to affect basal or insulin-stimulated glucose metabolism, and neither β agonist affected phospho-p44/42. TNFα and IL-6 increased (P < 0.05) glucose oxidation by ~23% and ~33%, respectively, in the absence of insulin. This coincided with increased (P < 0.05) phospho-p38 and phospho-p44/42 but not phospho-Akt. Furthermore, co-incubation of muscle with insulin + either cytokine yielded glucose oxidation rates that were similar to insulin alone, despite lower (P < 0.05) phospho-Akt. Importantly, cytokine-mediated increases in glucose oxidation rates were not concomitant with greater glucose uptake. These results show that acute β2 adrenergic stimulation, but not β1 stimulation, directly increases fractional glucose oxidation in the absence of insulin and synergistically increases glucose oxidation when combined with insulin. The cytokines, TNFα and IL-6, likewise directly increas

Intrauterine growth restriction (IUGR) is the second leading cause of perinatal mortality and predisposes offspring to metabolic disorders at all stages of life. Muscle-centric fetal adaptations reduce growth and yield metabolic parsimony, beneficial for IUGR fetal survival but detrimental to metabolic health after birth. Epidemiological studies have reported that IUGRborn children experience greater prevalence of insulin resistance and obesity, which progresses to diabetes, hypertension, and other metabolic disorders in adulthood that reduce quality of life. Similar adaptive programming in livestock results in decreased birth weights, reduced and inefficient growth, decreased carcass merit, and substantially greater mortality rates prior to maturation. High rates of glucose consumption and metabolic plasticity make skeletal muscle a primary target for nutrient-sparing adaptations in the IUGR fetus, but at the cost of its contribution to proper glucose homeostasis after birth. Identifying the mechanisms underlying IUGR pathophysiology is a fundamental step in developing treatments and interventions to improve outcomes in IUGR-born humans and livestock. In this review, we outline the current knowledge regarding the adaptive restriction of muscle growth and alteration of glucose metabolism that develops in response to progressively exacerbating intrauterine conditions. In addition, we discuss the evidence implicating developmental changes in β adrenergic and inflammatory systems as key mechanisms for dysregulation of these processes. Lastly, we highlight the utility and importance of sheep models in developing this knowledge.

Intrauterine growthrestricted sheep fetuses exhibit smaller hindlimb muscle fibers and lower proportions of insulin-sensitive Type I fibers near term. Am J Physiol Regul Integr Comp Physiol 310: R1020–R1029, 2016. First published April 6, 2016; doi:10.1152/ajpregu.00528.2015.—Intrauterine growth restriction (IUGR) reduces muscle mass and insulin sensitivity in offspring. Insulin sensitivity varies among muscle fiber types, with Type I fibers being most sensitive. Differences in fibertype ratios are associated with insulin resistance in adults, and thus we hypothesized that near-term IUGR sheep fetuses exhibit reduced size and proportions of Type I fibers. Placental insufficiency-induced IUGR fetuses were 54% smaller (P < 0.05) than controls and exhibited hypoxemia and hypoglycemia, which contributed to 6.9- fold greater (P < 0.05) plasma norepinephrine and 53% lower (P < 0.05) plasma insulin concentrations. IUGR semitendinosus muscles contained less (P < 0.05) myosin heavy chain-I protein (MyHC-I) and proportionally fewer (P < 0.05) Type I and Type I/IIa fibers than controls, but MyHC-II protein concentrations, Type II fibers, and Type IIx fibers were not different. IUGR biceps femoris muscles exhibited similar albeit less dramatic differences in fiber type proportions. Type I and IIa fibers are more responsive to adrenergic and insulin regulation than Type IIx and may be more profoundly impaired by the high catecholamines and low insulin in our IUGR fetuses, leading to their proportional reduction. In both muscles, fibers of each type were uniformly smaller (P < 0.05) in IUGR fetuses than controls, which indicates that fiber hypertrophy is not dependent on type but rather on other factors such as myoblast differentiation or protein synthesis. Together, our findings show that IUGR fetal muscles develop smaller fibers and have proportionally fewer Type I fibers, which is indicative of developmental adaptations that may help explain the link between IUGR and adulthood