Fate of Adrenal Ascorbic Acid: Relationship to Corticosteroid Secretion1

Slusher, Margaret A.; Roberts, Sidney

doi:10.1210/endo-61-1-98

Cited by 47 publications

(23 citation statements)

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“…For glucocorticoid responses, MIRKO and control (lox/lox) mice were injected with Dex (20 μg/kg/d) for 8 days. This dose was calculated based on the endogenous secretion rate present in stressed rodents as described by Slusher and Roberts and does not cause muscle protein abnormalities in adrenalectomized rodents (1,39). Gastrocnemius muscles were removed from anesthetized mice, immediately frozen in liquid nitrogen, and stored at -80°C.…”

Section: Methodsmentioning

confidence: 99%

Endogenous glucocorticoids and impaired insulin signaling are both required to stimulate muscle wasting under pathophysiological conditions in mice

Hu¹,

Wang²,

Lee³

et al. 2009

J. Clin. Invest.

136

183

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Muscle wasting is associated with a number of pathophysiologic conditions, including metabolic acidosis, diabetes, sepsis, and high angiotensin II levels. Under these conditions, activation of muscle protein degradation requires endogenous glucocorticoids. As the mechanism(s) underlying this dependence on glucocorticoids have not been identified, we analyzed the effects of glucocorticoids on muscle wasting in a mouse model of acute diabetes. Adrenalectomized, acutely diabetic mice given a physiologic dose of glucocorticoids exhibited decreased IRS-1-associated PI3K activity in muscle and progressive muscle atrophy. These responses were related to increased association of PI3K with the glucocorticoid receptor (GR). In mice with muscle-specific GR deletion (referred to as MGRKO mice), acute diabetes minimally suppressed IRS-1-associated PI3K activity in muscle and did not cause muscle atrophy. However, when a physiologic dose of glucocorticoids was given to mice with muscle-specific IR deletion, muscle protein degradation was accelerated. Fluorescence resonance energy transfer and an in vitro competition assay revealed that activated GRs competed for PI3K, reducing its association with IRS-1. Reexpression of WT GRs or those with a mutation in the nuclear localization signal in the muscle of MGRKO mice indicated that competition for PI3K was a prominent mechanism underlying reduced IRS-1-associated PI3K activity. This nongenomic influence of the GR contributes to activation of muscle protein degradation. We therefore conclude that stimulation of muscle proteolysis requires 2 events, increased glucocorticoid levels and impaired insulin signaling.

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Section: Methodsmentioning

confidence: 99%

Endogenous glucocorticoids and impaired insulin signaling are both required to stimulate muscle wasting under pathophysiological conditions in mice

Hu¹,

Wang²,

Lee³

et al. 2009

J. Clin. Invest.

136

183

View full text Add to dashboard Cite

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“…The low dose of dexamethasone for group B rats was based on the endogenous secretory rate of corticosterone in rats (21,22), assuming a relative dexamethasone to corticosterone potency ratio of 265:1 (23). The dose for group C rats was chosen to correspond to the plasma corticosterone levels ofstressed rats (17,22).…”

Section: Methodsmentioning

confidence: 99%

Metabolic acidosis stimulates protein degradation in rat muscle by a glucocorticoid-dependent mechanism.

May¹,

Kelly²,

Mitch³

1986

J. Clin. Invest.

348

221

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Metabolic acidosis is associated with enhanced renal ammoniagenesis which is regulated, in part, by glucocorticoids. The interaction between glucocorticoids and chronic metabolic acidosis on nitrogen utilization and muscle protein metabolism is unknown. In rats pair-fed by gavage, we found that chronic acidosis stunted growth and caused a 43% increase in urinary nitrogen and an 87% increase in urinary corticosterone. Net protein degradation in incubated epitrochlearis muscles from chronically acidotic rats was stimulated at all concentrations of insulin from o to 104 MU/ml. This effect of acidosis persisted despite supplementation of the media with amino acids with or without insulin, indomethacin, and inhibitors of lysosomal thiol cathepsins. Acidosis did not change protein synthesis; hence, the increase in net protein degradation was caused by stimulation of proteolysis. Acidosis did not increase glutamine production in muscle. The protein catabolic effect of acidosis required glucocorticoids; protein degradation was stimulated in muscle of acidotic, adrenalectomized rats only if they were treated with dexamethasone. Moreover, when nonacidotic animals were given 3 isg/100 g of body weight dexamethasone twice a day, muscle protein degradation was increased if the muscles were simply incubated in acidified media. We conclude that chronic metabolic acidosis depresses nitrogen utilization and increases glucocorticoid production. The combination of increased glucocorticoids and acidosis stimulates muscle proteolysis but does not affect protein synthesis. These changes in muscle protein metabolism may play a role in the defense against acidosis by providing amino acid nitrogen to support the glutamine production necessary for renal ammoniagenesis.

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“…Montanari et al observed that an increase of plasma corticosterone did not always accompany a reduction of adrenal ascorbic acid (12). This finding casts doubt on the value of adrenal ascorbic acid deter mination as an index of ACTH secretion (12,13). So morphine does not seem to in hibit the CC14-induced pituitary-adrenal activation, and this result might agree with the observation of Rerup (14).…”

Section: Discussionmentioning

confidence: 88%

The Effect of Carbon Tetrachloride on Plasma Corticosterone Level

Furukawa¹

1966

Japanese Journal of Pharmacology

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Fate of Adrenal Ascorbic Acid: Relationship to Corticosteroid Secretion1

Cited by 47 publications

References 0 publications

Endogenous glucocorticoids and impaired insulin signaling are both required to stimulate muscle wasting under pathophysiological conditions in mice

Endogenous glucocorticoids and impaired insulin signaling are both required to stimulate muscle wasting under pathophysiological conditions in mice

Metabolic acidosis stimulates protein degradation in rat muscle by a glucocorticoid-dependent mechanism.

The Effect of Carbon Tetrachloride on Plasma Corticosterone Level

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