Thyroid hormones and the mRNA of the GH receptor and IGFs in skeletal muscle of fetal sheep

2002 ◽  
Vol 282 (1) ◽  
pp. E80-E86 ◽  
Author(s):  
A. J. Forhead ◽  
J. Li ◽  
R. S. Gilmour ◽  
M. J. Dauncey ◽  
A. L. Fowden
Keyword(s):  
Gene Expression ◽  
Skeletal Muscle ◽  
Thyroid Hormones ◽  
Gestational Age ◽  
Plasma Cortisol ◽  
Mrna Abundance ◽  
Late Gestation ◽  
Fetal Sheep ◽  
Igf I ◽  
I Gene

Thyroid hormones are required for the normal development of skeletal muscle in utero, although their mechanism of action is poorly understood. The present study examined the effects of the thyroid hormones on the gene expression of the growth hormone receptor (GHR) and the insulin-like growth factors (IGFs) IGF-I and IGF-II, in skeletal muscle of fetal sheep during late gestation (term 145 ± 2 days) and after manipulation of plasma thyroid hormone concentration. Thyroidectomy at 105–110 days of gestation suppressed muscle GHR and IGF-I gene expression in fetuses studied at 127–130 and 142–145 days. Muscle GHR mRNA abundance remained unchanged with increasing gestational age in intact and thyroidectomized fetuses. In the intact fetuses, a decrease in muscle IGF-I gene expression was observed between 127–130 and 142–145 days, which coincided with the normal prepartum surges in plasma cortisol and triiodothyronine (T3). At 127–130 days, downregulation of muscle IGF-I mRNA abundance was induced prematurely in intact fetuses by an infusion of cortisol for 5 days (2–3 mg · kg−1 · day−1 iv), which increased plasma cortisol and T3 concentrations to values seen near term. However, increasing plasma T3 alone by an infusion of T3 for 5 days (8–12 μg · kg−1 · day−1 iv) in intact fetuses at this age had no effect on GHR or IGF-I gene expression in skeletal muscle. In the thyroidectomized fetuses, no additional change in the low level of muscle IGF-I mRNA abundance was seen with increasing gestational age, but at 127–130 days, IGF-I gene expression was reduced further when plasma cortisol and T3 concentrations were increased by exogenous cortisol infusion. Muscle IGF-II mRNA abundance was not affected by thyroidectomy, gestational age, or exogenous hormone infusion. These findings show, in the sheep fetus, that thyroid hormones may influence the growth and development of skeletal muscle via changes in the local activity of the somatotrophic axis.

Control of hepatic insulin-like growth factor II gene expression by thyroid hormones in fetal sheep near term

1998 ◽  
Vol 275 (1) ◽  
pp. E149-E156 ◽  
Author(s):  
Alison J. Forhead ◽  
Juan Li ◽  
R. Stewart Gilmour ◽  
Abigail L. Fowden
Keyword(s):  
Gene Expression ◽  
Growth Factor ◽  
Thyroid Hormones ◽  
Plasma Cortisol ◽  
Plasma Concentrations ◽  
Mrna Abundance ◽  
Mrna Levels ◽  
Insulin Like Growth Factor ◽  
Fetal Sheep ◽  
Fetal Plasma

The effects of thyroid hormones on hepatic insulin-like growth factor (IGF) II gene expression and their interaction with cortisol in the ontogenic control of this gene were investigated in fetal sheep during late gestation (term 145 ± 2 days) and after experimental manipulation of fetal plasma hormone concentrations. In intact fetuses, a significant decrease in hepatic IGF-II mRNA abundance was observed between 127–130 and 142–145 days of gestation, which coincided with the normal prepartum rise in plasma cortisol and triiodothyronine (T3) concentrations. This ontogenic decline in hepatic IGF-II gene expression was abolished in fetuses in which the prepartum rise in plasma T3, but not cortisol, was prevented by fetal thyroidectomy. At 127–130 days, downregulation of hepatic IGF-II mRNA abundance was induced prematurely in intact fetuses by an infusion of cortisol for 5 days (2–3 mg ⋅ kg−1 ⋅ day−1iv). Plasma concentrations of cortisol and T3 in the cortisol-infused intact fetuses were increased to values seen close to term. Similar findings were observed in thyroidectomized fetuses, in which, despite thyroidectomy, cortisol infusion significantly increased plasma T3 concentrations and caused a premature decrease in hepatic IGF-II mRNA levels. However, in intact fetuses at 127–130 days, the increasing of T3 concentrations alone by exogenous T3 infusion (8–12 μg ⋅ kg−1 ⋅ day−1iv for 5 days) had no effect on hepatic IGF-II mRNA levels. Overall, a decrease in hepatic IGF-II mRNA abundance was only observed in fetuses in which there were concurrent increases in plasma cortisol and T3 concentrations. When observations from all fetuses were considered, irrespective of gestational age or treatment, hepatic IGF-II mRNA levels were negatively correlated with plasma cortisol and T3 but not thyroxine concentrations. Partial correlation analysis of hepatic IGF-II, cortisol, and T3 values showed that the plasma concentration of cortisol in the fetus had the predominant effect on hepatic IGF-II mRNA abundance. These findings show that T3 may mediate, in part, the maturational effects of cortisol on hepatic IGF-II gene expression but that it is ineffective without a concomitant rise in fetal plasma cortisol. Hence, increased concentrations of both cortisol and T3 appear necessary to induce downregulation of hepatic IGF-II mRNA abundance in fetal sheep close to term.

scholarly journals Effects of thyroid hormones on pulmonary and renal angiotensin-converting enzyme concentrations in fetal sheep near term

2002 ◽  
Vol 173 (1) ◽  
pp. 143-150 ◽  
Author(s):  
AJ Forhead ◽  
AL Fowden
Keyword(s):  
Angiotensin Converting Enzyme ◽  
Thyroid Hormones ◽  
Plasma Cortisol ◽  
Experimental Manipulation ◽  
Late Gestation ◽  
Converting Enzyme ◽  
Fetal Sheep ◽  
Near Term ◽  
Sheep Fetus

In the sheep fetus, pulmonary and renal concentrations of angiotensin-converting enzyme (ACE) increase towards term in parallel with the prepartum surges in plasma cortisol and tri-iodothyronine (T(3)). The ontogenic change in pulmonary ACE has been shown to be induced, at least in part, by cortisol but the role of the thyroid hormones is unknown. Therefore, this study investigated the effects of thyroid hormones on tissue ACE concentration in fetal sheep during late gestation. Pulmonary and renal ACE concentrations were measured in sheep fetuses after experimental manipulation of thyroid hormone status by fetal thyroidectomy and exogenous hormone infusion. In intact fetuses, pulmonary and renal ACE concentrations increased between 127-132 and 142-145 days of gestation (term 145 +/- 2 days), coincident with the prepartum rises in plasma cortisol and T(3). The ontogenic increment in pulmonary ACE concentration was abolished when the prepartum surge in T(3), but not cortisol, was prevented by fetal thyroidectomy. At 143-145 days, ACE concentration in the lungs and kidneys of the thyroidectomised fetuses were both lower than those in the intact fetuses. In intact fetuses at 127-132 days, pulmonary ACE was upregulated by intravenous infusions of either cortisol (2-3 mg/kg per day) or T(3) (8-12 microg/kg per day) for 5 days. Renal ACE was unaffected by cortisol or T(3) infusion. Therefore, thyroid hormones have an important role in the developmental control of pulmonary and renal ACE concentration in the sheep fetus towards term. In addition, the prepartum rise in plasma T(3) appears to mediate, in part, the maturational effect of cortisol on pulmonary ACE concentration.

Intravenous infusion of insulin-like growth factor I in fetal sheep reduces hepatic IGF-I and IGF-II mRNAs

1996 ◽  
Vol 271 (6) ◽  
pp. R1632-R1637 ◽  
Author(s):  
K. L. Kind ◽  
J. A. Owens ◽  
F. Lok ◽  
J. S. Robinson ◽  
K. J. Quinn ◽  
...  
Keyword(s):  
Gene Expression ◽  
Skeletal Muscle ◽  
Growth Factor ◽  
Intravenous Infusion ◽  
Feedback Inhibition ◽  
Fetal Liver ◽  
Plasma Concentrations ◽  
Insulin Like Growth Factor ◽  
Fetal Sheep ◽  
Igf I

Liver contains the highest concentrations of insulin-like growth factor (IGF) I mRNA in adult rats and sheep and is a major source of circulating IGF-I. In rats, inhibition of hepatic IGF-I production by exogenous IGF-I has been reported. In fetal sheep, skeletal muscle and liver are major sites of IGF-I synthesis and potential sources of circulating IGF-I. To determine whether feedback inhibition of IGF gene expression in fetal liver or muscle by IGF-I occurs, IGF-I and IGF-II mRNAs were measured in these tissues after intravenous infusion of recombinant human IGF-I into fetal sheep. Infusion of IGF-I (26 +/- 4 micrograms.h-1.kg-1; n = 6) or saline (n = 6) commenced on day 120 of pregnancy (term = 150 days) and continued for 10 days. Plasma concentrations of IGF-I were threefold higher in infused fetuses at 130 days of gestation (P < 0.0003), whereas those of IGF-II were unchanged. IGF-I infusion reduced the relative abundance of IGF-I mRNA (P < 0.0002) and IGF-II mRNA (P < 0.01) in fetal liver by approximately 50% but did not alter IGF-I or IGF-II mRNA in skeletal muscle. These results indicate that IGF-I inhibits the expression of both IGF-I and IGF-II genes in fetal liver and that IGF gene expression in fetal liver and muscle is differentially regulated by IGF-I.

scholarly journals Ontogeny and Effects of Hypothalamic Pituitary Disconnection on Formation of Inositol Trisphosphate in Fetal Sheep Pituitary Cells

Endocrinology ◽  
2007 ◽  
Vol 148 (3) ◽  
pp. 1440-1444 ◽  
Author(s):  
Luke C. Carey ◽  
Stephen B. Tatter ◽  
James C. Rose
Keyword(s):  
Gestational Age ◽  
Plasma Cortisol ◽  
Inositol Trisphosphate ◽  
Second Messenger ◽  
Late Gestation ◽  
Pituitary Cells ◽  
Fetal Sheep ◽  
The Impact ◽  
Pituitary Adrenal Axis ◽  
Sheep Fetus

In late gestation fetal sheep, the pituitary becomes increasingly responsive to stimulation by arginine vasopressin (AVP). This change appears to be one important factor mediating the plasma cortisol surge, a critical developmental event. It is not known precisely why pituitary corticotropes become more responsive at this time. In this study we examined the possibility that changes in second messenger generation [inositol trisphosphate (IP3)] are responsible. Two studies were undertaken. The first was an ontogeny study, where pituitaries were isolated from 100-, 120-, and 140-d gestational age (dGA) fetal sheep. Cells were cultured, stimulated with AVP, and the formation of IP3 assessed. The amount of IP3 generated increased with gestational age (percent increases from unstimulated controls were 4.6, 11.5, and 21.5 for 100, 120, and 140 dGA, respectively), with significant differences between the 140-dGA group and both earlier groups apparent. The second study examined the impact of 120-dGA hypothalamo-pituitary disconnection (HPD), which prevents corticotrope maturation, on responsiveness of pituitary cells isolated from 140-dGA fetuses. Cells were stimulated with AVP, and the formation of IP3 and secretion of ACTH were assessed. Significantly less IP3 was formed, and ACTH secreted in cells from HPD compared with control fetuses (IP3 and ACTH levels were 50% and 35% lower, respectively). Results from the HPD study demonstrate that the ontogenic changes in IP3 after AVP require an intact hypothalamic-pituitary-adrenal axis. These findings suggest that heightened second messenger generation may be a key reason for increased ACTH secretory responsiveness to AVP in the late gestation sheep fetus.

scholarly journals Functional deficits and insulin-like growth factor-I gene expression following tourniquet-induced injury of skeletal muscle in young and old rats

2008 ◽  
Vol 105 (4) ◽  
pp. 1274-1281 ◽  
Author(s):  
David W. Hammers ◽  
Edward K. Merritt ◽  
Wayne Matheny ◽  
Martin L. Adamo ◽  
Thomas J. Walters ◽  
...  
Keyword(s):  
Gene Expression ◽  
Skeletal Muscle ◽  
Intracellular Signaling ◽  
Ischemia Reperfusion ◽  
Force Production ◽  
Histological Evaluation ◽  
Igf I ◽  
Old Rats ◽  
I Gene ◽  
Recovery Groups

This study investigated the effect of age on recovery of skeletal muscle from an ischemia-reperfusion (I/R)-induced injury. Young (6 mo old) and old (24–27 mo old) Sprague-Dawley rats underwent a 2-h bout of hindlimb ischemia induced by a pneumatic tourniquet (TK). The TK was released to allow reperfusion of the affected limb, and animals were divided into 7- and 14-day recovery groups. Maximum plantar flexor force production was assessed in both 7- and 14-day recovery groups of both ages, followed by histological evaluation. Subsequent analysis of IGF-I gene expression and intracellular signaling in 7-day recovery muscles was performed by RT-PCR and Western blotting, respectively. Old rats had significantly greater deficits in force production and exhibited more evidence of histological pathology than young at both 7 and 14 days postinjury. In addition, old rats demonstrated an attenuated upregulation of IGF-I mRNA and induction of proanabolic signaling compared with young in response to injury. We conclude that aged skeletal muscle exhibits more damage and/or defective regeneration following I/R and identify an age-associated decrease in local IGF-I responsiveness as a potential mechanism for this phenomenon.

scholarly journals Maternal nutrition alters the expression of insulin-like growth factors in fetal sheep liver and skeletal muscle

2000 ◽  
Vol 167 (3) ◽  
pp. 429-437 ◽  
Author(s):  
JM Brameld ◽  
A Mostyn ◽  
J Dandrea ◽  
TJ Stephenson ◽  
JM Dawson ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Growth Hormone Receptor ◽  
Maternal Nutrition ◽  
Fetal Liver ◽  
Mrna Abundance ◽  
Nutrient Restriction ◽  
Fetal Sheep ◽  
Gestation Age ◽  
Igf I ◽  
Metabolisable Energy

We investigated the influence of maternal dietary restriction between days 28 and 80 of gestation followed by re-feeding to the intake of well-fed ewes up to 140 days of gestation (term is 147 days) in sheep, on expression of mRNA for insulin-like growth factor (IGF)-I, IGF-II and growth hormone receptor (GHR) in fetal liver and skeletal muscle. Singleton bearing ewes either consumed 3.2-3.8 MJ/day of metabolisable energy (ME) (i.e. nutrient restricted - approximately 60% of ME requirements, taking into account requirements for both ewe maintenance and growth of the conceptus) or 8.7-9.9 MJ/day (i.e. well fed - approximately 150% of ME requirements) between days 28 and 80 of gestation. All ewes were then well fed (150% of ME requirements) up to day 140 of gestation and consumed 8-10.9 MJ/day. At days 80 and 140 of gestation, five ewes were sampled from each group and fetal tissues taken. There was no difference in fetal body weight or liver weights between groups at either sampling date, or skeletal muscle (quadriceps) weight at 140 days. IGF-I mRNA abundance was lower in livers of nutrient-restricted fetuses at day 80 of gestation (nutrient restricted 2.35; well fed 3.70 arbitrary units), but was higher than well-fed fetuses at day 140 of gestation, after 60 days of re-feeding (restricted/re-fed 4.27; well fed 2.83;s.e.d. 0.98 arbitrary units, P=0.061 for dietxage interaction). IGF-II mRNA abundance was consistently higher in livers of nutrient-restricted fetuses (80 days: nutrient restricted 7.78; well fed 5.91; 140 days: restricted/re-fed 7.23; well fed 6.01;s.e.d. 1.09 arbitrary units, P=0.061 for diet). Nutrient restriction had no effect on hepatic GHR mRNA abundance, but re-feeding of previously nutrient-restricted fetuses increased GHR mRNA compared with continuously well-fed fetuses (80 days: nutrient restricted 70.6; well fed 75.1; 140 days: restricted/re-fed 115.7; well fed 89.4;s.e.d. 10.13 arbitrary units, P=0.047 for dietxage interaction). In fetal skeletal muscle, IGF-I mRNA abundance was not influenced by maternal nutrition and decreased with gestation age (P<0.01). IGF-II mRNA abundance was higher in skeletal muscle of nutrient-restricted fetuses compared with well-fed fetuses at day 80 of gestation (nutrient restricted 16.72; well fed 10.53 arbitrary units), but was lower than well-fed fetuses after 60 days of re-feeding (restricted/re-fed 7.77; well fed 13.72;s.e.d. 1.98 arbitrary units, P<0.001 for dietxage interaction). There was no effect of maternal nutrition or gestation age on fetal skeletal muscle GHR expression. In conclusion, maternal nutrient restriction in early to mid gestation with re-feeding thereafter results in alterations in hepatic and skeletal muscle expression of IGF-I, IGF-II and/or GHR in the fetus which may subsequently relate to altered organ and tissue function.

Developmental regulation of preproenkephalin (PENK) gene expression in the adrenal gland of the ovine fetus and newborn lamb: effects of hypoxemia and exogenous cortisol infusion

1997 ◽  
Vol 155 (1) ◽  
pp. 143-149 ◽  
Author(s):  
M Fraser ◽  
SG Matthews ◽  
G Braems ◽  
T Jeffray ◽  
Keyword(s):  
Gene Expression ◽  
Adrenal Gland ◽  
Plasma Cortisol ◽  
Late Gestation ◽  
Mrna Levels ◽  
Fetal Sheep ◽  
Adult Sheep ◽  
Organ Systems ◽  
Response To Stress ◽  
In Pregnancy

Development of the fetal adrenal gland is crucial not only for maturation of several fetal organ systems and the initiation of parturition, but also for the development of the fetal response to stress. The enkephalin-related peptides are present in the chromaffin cells of the fetal adrenal medulla and are secreted in response to stress and with sympathetic stimulation. However, changes in expression of preproenkephalin (PENK) with gestation and in response to stress have not been studied in detail. Therefore we examined the developmental pattern of PENK gene expression in the adrenal gland of fetal and newborn lambs, and of adult sheep. We also determined whether levels of PENK mRNA in the fetal adrenal gland changed in response to exogenous glucocorticoids in late gestation, or in response to hypoxemia. Adrenal glands were removed from fetal sheep, lambs and adult sheep at different stages of development for measurement of PENK mRNA. Cortisol was infused (5 micrograms/min) for 12, 24 or 96 h beginning on day 124-129 of gestation. Moderate hypoxemia was induced for 48 h beginning on day 126-130, or at day 134-136 of gestation, by lowering the maternal fractional inspired oxygen. At the end of the treatment periods, the ewes and fetuses were euthanized. Adrenal PENK mRNA were measured by Northern blot analysis. PENK mRNA levels in fetal adrenals were significantly higher (P < 0.05) on days 140-141 of gestation than earlier in pregnancy, and then decreased significantly with the onset of parturition (days 142-146). After cortisol infusion to the fetus for 96 h there was a significant reduction in adrenal PENK mRNA levels. Hypoxemia resulted in a significant increase in PENK mRNA levels in fetuses at day 126-130 of gestation, but not at the later time in pregnancy when endogenous plasma cortisol concentrations were higher. We conclude that there is a decrease in levels of PENK mRNA in the fetal adrenal gland before parturition at the time of the endogenous prepartum rise in plasma cortisol. Hypoxemia led to an elevation of PENK mRNA levels in fetuses at less than 130 days, but after that time, when the basal and stimulated cortisol responses had risen, there was no significant effect of hypoxemia on PENK mRNA. Cortisol infusion to the fetus at this stage of pregnancy resulted in a decrease in adrenal PENK mRNA levels. We suggest that cortisol may play an important role in the regulation of fetal adrenal PENK mRNA levels and enkephalin synthesis by the adrenal gland of the fetal sheep.

scholarly journals Control of ovine hepatic growth hormone receptor and insulin-like growth factor I by thyroid hormones in utero

2000 ◽  
Vol 278 (6) ◽  
pp. E1166-E1174 ◽  
Author(s):  
A. J. Forhead ◽  
J. Li ◽  
J. C. Saunders ◽  
M. J. Dauncey ◽  
R. S. Gilmour ◽  
...  
Keyword(s):  
Gene Expression ◽  
Growth Hormone ◽  
Growth Factor ◽  
Thyroid Hormones ◽  
Hormone Receptor ◽  
Growth Hormone Receptor ◽  
Insulin Like Growth Factor ◽  
Factor I ◽  
Igf I ◽  
I Gene

By use of RNase protection assays, hepatic growth hormone receptor (GHR) and insulin-like growth factor I (IGF-I) mRNA abundances were measured in sheep fetuses after experimental manipulation of fetal plasma thyroid hormone concentrations by fetal thyroidectomy (TX) and exogenous infusion of triiodothyronine (T3) and cortisol. TX abolished the normal prepartum rise in hepatic GHR abundance but had little effect on hepatic GHR gene expression at 127–130 days (term 145 ± 2 days). By contrast, it upregulated basal IGF-I expression in immature fetal liver by increasing both Class 1 and Class 2 transcript abundance but had no further effects on IGF-I gene mRNA levels at 142–145 days. Raising plasma T3 to prepartum values by exogenous infusion of either T3 or cortisol into immature intact fetuses prematurely raised hepatic GHR and IGF-I mRNA abundances to values similar to those seen in intact fetuses at 142–145 days. In TX fetuses, cortisol infusion increased hepatic GHR mRNA but not total IGF-I mRNA abundance at 127–130 days. These findings show that thyroid hormones have an important role in the regulation of hepatic GHR and IGF-I gene expression in fetal sheep during late gestation and suggest that T3 mediates the maturational effects of cortisol on the hepatic somatotropic axis close to term.

scholarly journals Developmental Control of Iodothyronine Deiodinases by Cortisol in the Ovine Fetus and Placenta Near Term

Endocrinology ◽  
2006 ◽  
Vol 147 (12) ◽  
pp. 5988-5994 ◽  
Author(s):  
Alison J. Forhead ◽  
Katrina Curtis ◽  
Ellen Kaptein ◽  
Theo J. Visser ◽  
Abigail L. Fowden
Keyword(s):  
Adipose Tissue ◽  
Thyroid Hormones ◽  
Plasma Cortisol ◽  
Late Gestation ◽  
Fetal Sheep ◽  
Perirenal Adipose Tissue ◽  
Deiodinase Activity ◽  
Serum T4 ◽  
Ovine Fetus ◽  
Near Term

Preterm infants have low serum T4 and T3 levels, which may partly explain the immaturity of their tissues. Deiodinase enzymes are important in determining the bioavailability of thyroid hormones: deiodinases D1 and D2 convert T4 to T3, whereas deiodinase D3 inactivates T3 and produces rT3 from T4. In human and ovine fetuses, plasma T3 rises near term in association with the prepartum cortisol surge. This study investigated the developmental effects of cortisol and T3 on tissue deiodinases and plasma thyroid hormones in fetal sheep during late gestation. Plasma cortisol and T3 concentrations in utero were manipulated by exogenous hormone infusion and fetal adrenalectomy. Between 130 and 144 d of gestation (term 145 ± 2 d), maturational increments in plasma cortisol and T3, and D1 (hepatic, renal, perirenal adipose tissue) and D3 (cerebral), and decrements in renal and placental D3 activities were abolished by fetal adrenalectomy. Between 125 and 130 d, iv cortisol infusion raised hepatic, renal, and perirenal adipose tissue D1 and reduced renal and placental D3 activities. Infusion with T3 alone increased hepatic D1 and decreased renal D3 activities. Therefore, in the sheep fetus, the prepartum cortisol surge induces tissue-specific changes in deiodinase activity that, by promoting production and suppressing clearance of T3, may be responsible for the rise in plasma T3 concentration near term. Some of the maturational effects of cortisol on deiodinase activity may be mediated by T3.

Effect of rhIGF-I infusion on whole fetal and fetal skeletal muscle protein metabolism in sheep

1998 ◽  
Vol 275 (6) ◽  
pp. E1082-E1091 ◽  
Author(s):  
David W. Boyle ◽  
Scott C. Denne ◽  
Helen Moorehead ◽  
Wei-Hua Lee ◽  
Ronald R. Bowsher ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Protein Metabolism ◽  
Muscle Protein ◽  
External Iliac Artery ◽  
Late Gestation ◽  
Whole Body ◽  
Skeletal Muscle Protein ◽  
Fetal Sheep ◽  
Igf I ◽  
Body Level

Insulin-like growth factor I (IGF-I) has been shown to have significant anabolic effects in the regulation of fetal protein metabolism. To investigate the tissue-specific effects of IGF-I on fetal skeletal muscle metabolism, we infused recombinant human (rh) IGF-I directly into the hindlimb of nine chronically catheterized, late-gestation fetal sheep. Substrate balance and amino acid kinetics were measured across the hindlimb and were compared with the effects at the whole body level before and during a 3-h infusion of rhIGF-I into the external iliac artery at 150 μg/h. Infusion of rhIGF-I resulted in increases in IGF-I concentrations by 2- to 5.75-fold in the ipsilateral iliac vein and by nearly 3-fold in the abdominal aorta. In the study limb, IGF-I had no effect on protein synthesis (phenylalanine rate of disposal 0.88 ± 0.13 before vs. 0.73 ± 0.19 μmol/min during IGF-I) or breakdown (phenylalanine rate of appearance 0.67 ± 0.13 before vs. 0.60 ± 0.17 μmol/min during IGF-I) and did not alter net phenylalanine balance. IGF-I also did not affect hindlimb oxygen or glucose uptake. In contrast, at the whole body level, the rate of appearance of leucine, indicative of fetal protein breakdown, decreased during IGF-I infusion (rate of appearance of leucine 41.1 ± 3.3 to 37.6 ± 2.7 μmol/min) as did fetal leucine oxidation (8.4 ± 0.8 to 6.8 ± 0.6 μmol/min). There was no change in the umbilical uptake of leucine, and although not statistically significant, fetal leucine accretion increased 2.4-fold. These results provide further evidence that IGF-I promotes fetal protein accretion; however, its site of action is in tissues other than skeletal muscle.

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