18 research outputs found
Acute exposure of primary rat soleus muscle to zilpaterol HCl (β2 adrenergic agonist), TNFα, or IL-6 in culture increases glucose oxidation rates independent of the impact on insulin signaling or glucose uptake
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 \u3c 0.05) glucose uptake by ~47%, glucose oxidation by ~32%, and phospho-Akt by ~238%. Insulin also increased (P \u3c 0.05) phospho-p38, but only after 2 hours in incubation. Muscle incubated with β2 agonist alone exhibited ~20% less (P \u3c 0.05) glucose uptake but ~32% greater (P \u3c 0.05) glucose oxidation than unstimulated muscle. Moreover, co-incubation with insulin + β2 agonist increased (P \u3c 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 \u3c 0.05) glucose oxidation by ~23% and ~33%, respectively, in the absence of insulin. This coincided with increased (P \u3c 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 \u3c 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 increased glucose oxidation in the absence of insulin, but were not additive in combination with insulin and in fact appeared to disrupt Akt-mediated insulin signaling. Rather, cytokines appear to be acting through MAPKs to elicit effects on glucose oxidation. Regardless, stimulation of glucose oxidation by these key stress factors did not rely upon greater glucose uptake, which may promote metabolic efficiency during acute stress by increasing fractional glucose oxidation without increasing total glucose consumption by muscle
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
Maternal inflammation at midgestation impairs subsequent fetal myoblast function and skeletal muscle growth in rats, resulting in intrauterine growth restriction at term
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 \u3c 0.05) in MI-IUGR fetuses compared with controls. MyoD+ and myf5+ myoblasts were less abundant (P \u3c 0.05), and myogenin+ myoblasts were more abundant (P \u3c 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 \u3c 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 \u3c 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 \u3c 0.05) glucose, cholesterol, and triglycerides. Fetal-to-maternal blood glucose ratios were also reduced (P \u3c 0.05), which is indicative of placental insufficiency. Indicators of protein catabolism, including blood plasma urea nitrogen and creatine kinase, were greater (P \u3c 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 muscle growth near term. Fetal muscle sensitivity to inflammatory cytokines appeared to be enhanced after maternal inflammation, which may represent a mechanistic target for improving these outcomes in MI-IUGR fetuses
Impaired muscle stem cell function in cows with high concentrations of androstenedione in their follicular fluid
It is unclear whether androstenedione (A4) increases muscle mass and strength similar to testosterone or whether it produces primarily catabolic effects on muscle-like estrogen (Rasmussen et al., 2000). Summers et al. (2014) observed two populations of cows that exhibit either high (\u3e40 ng/mL; High A4) or low (\u3c20 ng/mL; Low A4) concentrations of A4 within the fluid of the dominant follicle just prior to ovulation. High A4 cows had decreased reproductive rates and shorter times before falling out of the herd, but those that did produce calves weaned them ~10-kg heavier than their low A4 counterparts (Summers et al., 2014). It appears that the difference in weights is due to faster growing and more efficient skeletal muscle. High A4 cows share many characteristics with women suffering from polycystic ovary syndrome (PCOS), whose high levels of circulating androgens are associated with changes in body composition (Kirchengast and Huber, 2001)
ASAS-SSR Triennnial Reproduction Symposium: Looking Back and Moving Forward—How Reproductive Physiology has Evolved: Fetal origins of impaired muscle growth and metabolic dysfunction: Lessons from the heat-stressed pregnant ewe
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
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
Intrauterine growth-restricted sheep fetuses exhibit smaller hindlimb muscle fibers and lower proportions of insulin-sensitive Type I fibers near term
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 \u3c 0.05) than controls and exhibited hypoxemia and hypoglycemia, which contributed to 6.9- fold greater (P \u3c 0.05) plasma norepinephrine and 53% lower (P \u3c 0.05) plasma insulin concentrations. IUGR semitendinosus muscles contained less (P \u3c 0.05) myosin heavy chain-I protein (MyHC-I) and proportionally fewer (P \u3c 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 \u3c 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 insulin resistanc
Maternofetal Stress Impairs Skeletal Muscle Growth and Glucose Metabolism in the IUGR-Born Neonatal Lamb; The Effects of Varying the Cognitive Processes Required by Retrieval Practice on the Retention of Knowledge
Our first study sought to identify if intermittent maternofetal oxygen supplementation (IUGR+O2) during late gestation rescued growth and skeletal muscle glucose metabolism impaired by hyperthermia-induced intrauterine growth restriction (IUGR) in lambs. Birthweight, bodyweight (BW), and brain:BW was less in IUGR lambs but did not differ between IUGR+O2 and controls. Glucose-stimulated insulin secretion (GSIS) tended to be lower in IUGR lambs but was recovered by IUGR+O2. Insulin stimulated glucose oxidation rates in hindlimb tissues of lambs and in primary skeletal muscle at necropsy were decreased by IUGR but rescued in IUGR+O2 lambs. However, hindlimb and ex vivo skeletal muscle glucose uptake did not differ among groups. These data show that fetal hypoxemia drives the development of IUGR and metabolic deficiencies but that intermittent maternofetal oxygen supplementation improves skeletal muscle growth and glucose metabolism. To evaluate inflammatory factors involved in adaptive fetal programming, we developed a maternofetal inflammation-induced IUGR (MI-IUGR) model. For this study, we evaluated the effects of sustained maternal inflammation on fetal inflammation, growth, and skeletal muscle glucose metabolism. Near-term fetuses demonstrated elevated circulating leukocytes and ~22% reduction in size 2 weeks after induction of inflammation ceased. Fetal inflammation impaired muscle glucose metabolism; in vivo and ex vivo insulin-stimulated glucose oxidation was reduced in MI-IUGR fetuses. In vivo glucose uptake did not differ, but ex vivo uptake was reduced under basal and insulin-stimulated conditions. Thus, maternofetal inflammation resulted in an IUGR phenotype characterized by adaptive fetal growth restriction and impaired skeletal muscle glucose metabolism. Lastly, we performed a study to determine the effects of retrieval practices in the form of homework assignments requiring higher-order cognitive skills (HOC) compared to those requiring lower-order cognitive skills (LOC) on students’ long-term retention of knowledge. There were no differences in short-term or long-term knowledge retention between retrieval practice types. However, students completing HOC retrieval practices had decreased performance scores for 9 of 11 topics. Retrieval practices create desirable difficulties that benefit knowledge retention, but only when an equal degree of success is achieved. These data indicate that desirable difficulties were not created, as students were not equally successful on both types of retrieval practices
Maternofetal Stress Impairs Skeletal Muscle Growth and Glucose Metabolism in the IUGR-Born Neonatal Lamb; The Effects of Varying the Cognitive Processes Required by Retrieval Practice on the Retention of Knowledge
Our first study sought to identify if intermittent maternofetal oxygen supplementation (IUGR+O2) during late gestation rescued growth and skeletal muscle glucose metabolism impaired by hyperthermia-induced intrauterine growth restriction (IUGR) in lambs. Birthweight, bodyweight (BW), and brain:BW was less in IUGR lambs but did not differ between IUGR+O2 and controls. Glucose-stimulated insulin secretion (GSIS) tended to be lower in IUGR lambs but was recovered by IUGR+O2. Insulin stimulated glucose oxidation rates in hindlimb tissues of lambs and in primary skeletal muscle at necropsy were decreased by IUGR but rescued in IUGR+O2 lambs. However, hindlimb and ex vivo skeletal muscle glucose uptake did not differ among groups. These data show that fetal hypoxemia drives the development of IUGR and metabolic deficiencies but that intermittent maternofetal oxygen supplementation improves skeletal muscle growth and glucose metabolism. To evaluate inflammatory factors involved in adaptive fetal programming, we developed a maternofetal inflammation-induced IUGR (MI-IUGR) model. For this study, we evaluated the effects of sustained maternal inflammation on fetal inflammation, growth, and skeletal muscle glucose metabolism. Near-term fetuses demonstrated elevated circulating leukocytes and ~22% reduction in size 2 weeks after induction of inflammation ceased. Fetal inflammation impaired muscle glucose metabolism; in vivo and ex vivo insulin-stimulated glucose oxidation was reduced in MI-IUGR fetuses. In vivo glucose uptake did not differ, but ex vivo uptake was reduced under basal and insulin-stimulated conditions. Thus, maternofetal inflammation resulted in an IUGR phenotype characterized by adaptive fetal growth restriction and impaired skeletal muscle glucose metabolism. Lastly, we performed a study to determine the effects of retrieval practices in the form of homework assignments requiring higher-order cognitive skills (HOC) compared to those requiring lower-order cognitive skills (LOC) on students’ long-term retention of knowledge. There were no differences in short-term or long-term knowledge retention between retrieval practice types. However, students completing HOC retrieval practices had decreased performance scores for 9 of 11 topics. Retrieval practices create desirable difficulties that benefit knowledge retention, but only when an equal degree of success is achieved. These data indicate that desirable difficulties were not created, as students were not equally successful on both types of retrieval practices