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Mechanical unloading and food restriction (FR) are leading causes of bone loss, which increase the risk of fracture later in life. Leptin, a 16kDa cytokine like hormone principally produced by white adipocytes, may be involved in bone metabolism with physiological or mechanical changes causing bone loss. The hypotheses of the first study were aimed at determining if serum leptin is reduced by unloading or FR. The serum leptin level reduced by unloading or by global FR, is associated with the decline in bone formation rate. It was conjectured that decreased serum leptin may be due to reduced adipocyte number/size and/or sympathetic nervous system (SNS) activation of betaadrenoreceptors with unloading or FR, inhibiting the release of leptin from adipocytes. In the second experiment, we tested whether leptin or beta-adrenoreceptor blockade attenuates bone loss during unloading and whether such an effect due to beta blockade is associated with changes in serum leptin level. Beta-blockade mitigated unloading induced reduction in serum leptin and also beta blockade was as effective as leptin administration in mitigating a reduction in cancellous bone mineral density with unloading through both stimulation of bone formation and suppression of resorption. It was previously demonstrated that energy restriction (ER) is a major contributor to the bone loss during global FR. In the third study, we tested whether beta- blockade attenuates bone loss during ER and whether such an effect is associated with changes in serum leptin level and leptin localization in bone tissues. Beta blockade attenuated the ER induced reduction in serum leptin level, cancellous bone mineral density and bone formation rate, and also abolished the ER induced increase in bone resorption. Reduction in leptin expression in bone marrow adipocytes observed with ER was attenuated by beta-blockade. Reduction in the number of cells (bone lining cells, osteocytes and chondrocytes in cartilage) which are stained positive for leptin was also attenuated by beta-blockade. Collectively, these data identify circulating leptin effects on preventing bone loss during mechanical unloading or energy restriction. Also beta blockade is associated with mitigating reduction in serum leptin and subsequently with mitigating reduction in bone mass with unloading or ER.

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Chicken embryos were chronically exposed to the ?1- blocker atenolol during one of three stages: mesonephros (E7-E9), mesonephros-metanephros (E11-E13), or metanephros (E15-E17). Mesonephros group hearts were larger than all other groups (P < 0.01). Mesonephros and metanephros group kidneys were larger than all remaining groups (P < 0.0001). The mesonephros group nephron number was ~40% lower than control values (P = 0.002). Glomerular areas were 26% and 18% larger than the control group in the mesonephros and metanephros groups, respectively (P < 0.001). These data suggest an E7-E9 critical window of cardiovascular and renal development for atenolol. Acute atenolol exposure in E15 embryos showed an increase in mean arterial pressure with all but the highest dose. All doses significantly decreased heart rate.

<p>Environmental stress during embryonic development could lead to growth restriction of the embryo, and act as a risk factor for the development of cardiovascular disease in adult life. A common environmental stressor that causes growth restriction is prenatal hypoxia, which has been shown to adversely affect adult health in mammalian models. Prenatal hypoxia causes an increase in catecholamines which results in over stimulation of the cardiac β-adrenergic receptors. Previous work on chickens has shown that prenatal hypoxia causes an increase in the sensitivity of β-adrenergic receptors to epinephrine in the embryonic heart. The sensitivity of these receptors was found to be decreased in prenatal hypoxic juvenile. Prenatal hypoxia has no significant effect on the density of these receptors in neither the embryo nor the juvenile. The lack of change in receptor density implies that the effects of hypoxia are further down stream in the signalling cascade. The β2 adrenergic receptor can couple to both the stimulatory Gα subunit (Gsα) and the inhibitory Gα subunit (Giα). We hypothesized that prenatal hypoxia would cause an increase in the Gsα in the sensitized embryos, while increasing Giα in the desensitized juveniles. This study evaluated the relative levels of Gsα and Giα in the hypoxic chicken embryo, and in the prenatally hypoxic juvenile, Using western blotting. Hypoxia considerably increased Giα in the chicken embryo while having no effect on Gsα. In the prenatally hypoxic juvenile Gsα was significantly increased while no changes were found in Giα. This dissociation between the levels of Gα subunit and receptor sensitivity implies that that hypoxia affects the signaling cascade downstream of the Gα subunit.</p>

国立情報学研究所で電子化したコンテンツを使用している。

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Doctor of Philosophy / Department of Animal Sciences and Industry / Bradley J. Johnson / Zilpaterol (ZIL) is a β-adrenergic receptor (β-AR) agonist that has been recently approved for use in feedlot cattle to improve production efficiencies and animal performance. One of the mechanisms through which this occurs is increased skeletal muscle growth. Therefore, two experiments were conducted to determine the effects of ZIL both in vivo and in vitro. In the first experiment, ZIL addition to bovine satellite cells resulted in a tendency to increase IGF-I mRNA and increased myosin heavy chain IIA (MHC) mRNA with 0.001 [micro symbol]M and decreased MHC mRNA with 0.01 and 10 [micro symbol]M. There were no effects of ZIL on protein synthesis or degradation. In myoblast cultures, there was a decrease in all three β-AR mRNA, and this was also reported in western blot analysis with a reduction in β2-AR expression due to ZIL treatment. In myotubes, there was an increase in β2-AR protein expression. In the second and third experiment, ZIL improved performance and carcass characteristics of feedlot steers and heifers. Additionally, ZIL decreased MHC IIA mRNA in semimembranosus muscle tissue collected from both steers and heifers. An additional part of the third study was conducted to determine the effects of melengestrol acetate (MGA) on bovine satellite cell and semimembranosus muscle gene expression. There were no effects of MGA on the expression of genes analyzed from semimembranosus muscle tissue collected. However, the addition of MGA to cultured bovine satellite cells resulted in increased β1 and β2-AR mRNA. These experiments aid in our understanding of the mechanism of action of MGA in heifers, as well as the effects of ZIL on both steers and heifers. Furthermore, they increase our knowledge and understanding of the mechanism of action of ZIL, as well as other β-agonists used to promote growth and efficiency in feedlot animals.

Master of Science / Department of Animal Sciences and Industry / Bradley J. Johnson / Zilpaterol hydrochloride (ZH) is a growth promotant that is approved for use in finishing cattle to improve growth performance and increase lean tissue accumulation. Little is known about the combined effects of ZH with anabolic steroid hormone implants. There is also little published data on the effect these growth promotants have on genes that play a role in skeletal muscle synthesis and degradation. Therefore, two separate studies were conducted to address these issues. The first study evaluated the effects of ZH and the steroid implant Revalor-S (RS) on animal performance and skeletal muscle gene expression in feedlot steers. Four treatments were used to analyze the effects of RS implanted 58 days before ZH, which was fed for 30 days with a 3 day withdrawal. It was determined that ZH and RS additively contribute to improved live and carcass performance; however these compounds had different effects on the abundance of the receptors for ZH as well as the abundance of myosin heavy chain (MHC) mRNA in skeletal muscle of feedlot steers. It was also determined that ZH can cause a transition in the abundance of MHC mRNA isoforms in skeletal muscle that are available for the translation of larger, faster, more glycolytic fiber types of MHC. The second study evaluated the effects of two types of anabolic steroid hormones on myosin heavy chain gene expression. Four treatments were used to measure the effects of trenbolone acetate (TBA) and estradiol (E[subscript]2) on performance and the amount of MHC mRNA in skeletal muscle of finishing steers. It was determined that anabolic steroid implants improve live animal performance, however there was no alteration in the abundance of MHC mRNA in skeletal muscle of feedlot steer for 28 days after implantation; however there was an increase in intermediate fiber type IIA of MHC mRNA in skeletal muscle with increasing days on feed. From these studies we concluded that ZH and anabolic steroids do have an effect on growth performance; however they may differ in the distinct mechanism of action utilized to enhance lean tissue deposition in feedlot steers.