Insulin- and thyroid hormone-independent adaptation of myofibrillar proteolysis to glucocorticoids
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Myofibrillar protein breakdown in skeletal muscle progresses through two distinct phases in response to chronic glucocorticoid administration in the rat, i.e., an early phase lasting 4–5 days, during which proteolysis increases followed by a later phase during which proteolysis decreases. The possible involvement of insulin and the iodothyronines in this phenomenon has now been examined. Diabetic, thyroidectomized, and normal rats were treated with corticosteroid for 10–11 days, and at timed intervals muscle proteolysis was evaluated by measuring the release of 3-methyl-L-histidine (3-MH) and tyrosine from the perfused hindquarter as well as the excretion of 3-MH in the urine. Corticosterone (CTC) administration to normal rats increased plasma insulin, whereas plasma 3,5,3'-triiodothyronine responded with an early rise followed by a fall after 4–5 days. However, the biphasic response of myofibrillar proteolysis to chronic glucocorticoid treatment was not abolished in CTC-treated diabetic or thyroidectomized rats. CTC treatment increased release of tyrosine by perfused muscle of diabetic rats but, unlike 3-MH release, did not diminish later. Thus the adaptation of myofibrillar proteolysis to chronic glucocorticoid treatment appears to be independent of insulin and thyroid hormones. However, insulin may play a role in curtailing glucocorticoid-induced breakdown of nonmyofibrillar proteins.Keywords:
Proteolysis
Myofibril
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Myofibrillar protein breakdown in skeletal muscle progresses through two distinct phases in response to chronic glucocorticoid administration in the rat, i.e., an early phase lasting 4–5 days, during which proteolysis increases followed by a later phase during which proteolysis decreases. The possible involvement of insulin and the iodothyronines in this phenomenon has now been examined. Diabetic, thyroidectomized, and normal rats were treated with corticosteroid for 10–11 days, and at timed intervals muscle proteolysis was evaluated by measuring the release of 3-methyl-L-histidine (3-MH) and tyrosine from the perfused hindquarter as well as the excretion of 3-MH in the urine. Corticosterone (CTC) administration to normal rats increased plasma insulin, whereas plasma 3,5,3'-triiodothyronine responded with an early rise followed by a fall after 4–5 days. However, the biphasic response of myofibrillar proteolysis to chronic glucocorticoid treatment was not abolished in CTC-treated diabetic or thyroidectomized rats. CTC treatment increased release of tyrosine by perfused muscle of diabetic rats but, unlike 3-MH release, did not diminish later. Thus the adaptation of myofibrillar proteolysis to chronic glucocorticoid treatment appears to be independent of insulin and thyroid hormones. However, insulin may play a role in curtailing glucocorticoid-induced breakdown of nonmyofibrillar proteins.
Proteolysis
Myofibril
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In order to obtain further information about the stimulatory action of excess iodide on thyroid hormone secretion in thyroxine (T4)-treated rats, experiments were performed in hypophysectomized rats, or rats treated with graded doses of T4 or triiodothyronine (T3).T3 as well as T4 played a permissive role in the production of the iodide effect in normal animals, but T3 was more effective than T4. Excess iodide stimulated thyroid hormone secretion in hypophysectomized animals, this finding being compatible with the hypothesis that, by inhibiting TSH secretion, T3 and T4 produced a condition in which excess iodide stimulated thyroid hormone secretion in intact rats. However, T4 played an additional role in thyroid hormone secretion by acting directly on the thyroid. In hypophysectomized animals, small doses of T4 stimulated thyroid hormone secretion, and this action was additive to that of excess iodide, whereas large doses of T4 were inhibitory and reduced the effectiveness of excess iodide. The stimulatory action on thyroid hormone secretion was specific for iodide and was not shared by other anions. The action of excess iodide was blocked by methimazole. We suggest that excess iodide stimulates thyroid hormone secretion by increasing intrathyroidal concentrations of cyclic AMP in the absence of TSH, and that this increase in cyclic AMP concentration is blocked by methimazole.
Hypophysectomy
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T4, rT3, and T3 kinetic studies have been performed in a T4-substituted female who showed an increased serum T4/T3 ratio and substantially increased rT3 serum levels in the presence of normal serum thyroid hormone binding properties. The kinetic studies were performed to discriminate between T4 transport inhibition into plasma T3-producing tissues and inhibition of extrathyroidal T4 to T3 conversion. The principal findings were that both T4 and rT3 transport were inhibited into the rapid equilibrating pool (REP), which mainly consists of the liver. The plasma T3 production rate was decreased. Despite an elevated serum free T4 level, serum TSH was elevated, pointing to T4 transport inhibition at the level of the thyrotroph as well. Transport of T4 and rT3 was normal to the slowly equilibrating pool, whereas no transport inhibition of T3 was found to either pool. Because T4 into T3 conversion efficiency in the REP (the main source of plasma T3 production) was normal, it was concluded that the lowered T3 production in the subject was caused by transport inhibition of T4 into the liver. Although the occurrence of the syndrome is rare, its significance is of general importance, in that it shows that transport of thyroid hormone may vary at the tissue level. Furthermore, as T3 is the principal biologically active thyroid hormone, regulation of transport of T4 into the REP may play a (patho)physiological role in the ultimate determination of thyroid hormone activity in the tissues.
Reverse triiodothyronine
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Chronic exposure of rats to cold (4 degrees C) leads to thyroid gland hyperactivity as a compensatory mechanism for activating body heat production. There is increased extrathyroidal production of T3 from T4 in parallel to thyroid hormone hypersecretion. Since the 5'-deiodination (5'-D) of T4 can be modulated by thyroid hormones, it has been suggested that the increased thyroid hormone secretion may activate the 5'-D enzymatic pathway leading to increased extrathyroidal T3 production. In an attempt to explore this possibility, T4 to T3 conversion was studied in liver and kidney homogenates of thyroidectomized rats which received T4 (0.5 to 50 micrograms/100 g body weight per day) for 10 days. Tissue homogenates were incubated with T4 (5 micrograms) for 2 h and the T3 generated was measured by RIA as an index of the activity of the 5'-D pathway. A direct relationship between T4 dose and the production of T3 by the homogenate was observed. 5'-D activity was significantly decreased in hypothyroid rats and greatly increased in hyperthyroid rats. Thyroidectomized rats treated with a replacement dose of T4 (1 microgram/100 g body weight/day) were exposed to 4 degrees C for 60 days. Despite the absence of the thyroid gland, increased 5'-D activity was observed in both liver and kidney homogenates compared to both intact and T4-treated thyroidectomized rats maintained at 25 degrees C. We conclude that chronic cold exposure of rats stimulates 5'-D activity which is independent of the concomitant thyroid gland hyperactivity.
Microgram
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Cellular levels of mRNA encoding pro TRH in the rostral paraventricular nucleus are reduced by thyroid hormones.To determine whether this regulatory effect of thyroid hormones requires a functional pituitary gland or, specifically, TSH, we examined the effect of T 3 on proTRH mRNA in hypophysectomized, thyro-parathyroidectomized male rats with or without bovine TSH replacement.Hypophysectomy plus thyro-parathyroidectomy reduced serum T 4 and TSH to undetectable levels in all animals and elevated TRH mRNA in the paraventricular nucleus over that of sham-operated animals.Eleven consecutive daily injections of T 3 significantly reduced TRH mRNA levels in both sham controls and thyro-parathyroidectomized rats.However, 11 daily injections of bovine TSH (1 U/day) failed to alter the effect of T 3 on TRH mRNA levels.These results demonstrate that the regulatory influence of thyroid hormones on the biosynthesis of TRH within the thyrotropic center of the brain is independent of the pituitary gland and of TSH.
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Thyrotropic cell
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Abstract. In newly hatched chicks, TRH administration was followed by increased circulating concentrations of growth hormone (GH), thyroxine (T 4 ) and 3,3',5-triiodothyronine (T 3 ). Little change in the circulating concentration of 3,3',5'-triiodothyronine (rT 3 ) was however observed. The effect of TRH on the circulating concentration of GH was not found in chick embryos at 17 or 19 days of incubation but was observed during pipping. The T 4 response was maximal in newly hatched chicks and present in 17 and 19 days embryos. The magnitude of the T 3 responses increased with age while that of T 4 decreased.
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Abstract. Mice were injected sc with TSH (0.5 U) at 12 h intervals for 5 days. Groups of mice were sacrificed daily to determine serum T 4 and T 3 concentrations, 4 h thyroidal 125 I uptake, distribution of 125 I among thyroidal iodoamino acids, and thyroidal content of T 4 and T 3 . Serum T 4 and T 3 concentrations increased significantly after the initial injection of TSH and gradually decreased thereafter, reaching initial levels on the 3rd and 4th days, respectively. In contrast to serum hormone levels, thyroidal 125 I uptake, incorporation of 125 I into T 4 and T 3 increased significantly on the first day and remained elevated throughout the period of TSH-treatment. Thyroidal T 4 content expressed as μg/mg weight of tissue decreased significantly on the first day and thereafter remained constant. Thyroidal T 3 content did not change significantly throughout the experimental period. The differences between thyroidal synthesis and thyroidal contents of T 4 and T 3 strongly suggest that thyroid hormone secretion is being continuously stimulated. Transient increases in serum T 4 and T 3 concentrations are probably due to a gradual increase in the rate of peripheral degradation of thyroid hormones. These results suggest that TSH-induced refractoriness in thyroidal iodine metabolism does not appear to exist, at least when TSH is given in vivo for 5 days.
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The regulation of growth hormone (GH) cell development by thyroid and glucocorticoid hormones in the fetal rat pituitary gland was examined. Dexamethasone (Dex) treatment of dams induced GH and GH mRNA accumulation in the fetal pituitary gland on day 17 or 18 of gestation when substantial GH expression has not yet occurred in the control fetus. The additional thyroxine injections apparently enhanced the effect of Dex, whereas it exhibited no effect when given alone. The reduction of fetal thyroid hormone level by methimazole suppressed either the Dex induction of GH expression on day 18 or the spontaneous onset of GH expression on day 19 of gestation. The results suggest that 1) thyroid hormone exerts its stimulatory action on fetal GH gene expression only in the presence of glucocorticoid, 2) this synergistic action of these two hormones is evident as early as day 17 of gestation, and 3) rapid maturation of GH cells seen on day 19 in the normal fetus is considered to be induced by concomitant increase in both serum thyroid and glucocorticoid hormone levels.
Endocrine gland
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