Glucocorticoids and acidosis stimulate protein and amino acid catabolism in vivo

Abstract

We have shown that chronic metabolic acidosis in awake rats accelerates whole body protein turnover using stochastic modeling and a continuous infusion of L-[1-13C] leucine. To delineate the role that glucocorticoids play in mediating these catabolic responses, we measured protein turnover in awake, chronically catheterized, adrenalectomized rats in the presence or absence of glucocorticoids and/or a NH4Cl feeding regimen which induced chronic metabolic acidosis. In adrenalectomized rats receiving no glucocorticoids there was no statistical difference in amino acid oxidation, protein degradation or synthesis whether or not the rats had acidosis. In contrast, chronically acidotic, adrenalectomized rats receiving glucocorticoids demonstrated accelerated whole body protein turnover with a 84% increase in amino acid oxidation and a 26% increase in protein degradation, compared to rats not receiving glucocorticoids or those given the same dose of glucocorticoids but without acidosis. We conclude that metabolic acidosis accelerates amino acid oxidation and protein degradation in vivo, and that glucocorticoids are necessary but not sufficient to mediate the catabolic effects of metabolic acidosis.

Glucocorticoids enhance acid activation of the Na+/H+ exchanger 3 (NHE3)

“…Adrenalectomy inhibited this effect of acidosis, but provision of low or high doses of dexamethasone to adrenalectomized rats once again allowed acidosis to stimulate protein degradation (4). Similar results were found for acidosis-stimulated muscle leucine oxidation (18), and for acidosis-induced increases in the abundance of mRNAs encoding polyubiquitin and the C2 and C9 subunits of the 26S proteosome (19), all of which contribute to acidosis-induced protein breakdown. Similarly, in cultured BC 3 H1 cells maintained in 1% serum, increased protein degradation was not seen with media acidification or dexamethasone alone, but was seen with media acidification and dexamethasone together (20).…”

Dialysis Modality and Correction of Uremic Metabolic Acidosis

“…In our cohort, the likelihood of significant hyperkalemia increased with decrease in serum bicarbonate. Acidosis also induces protein energy wasting through increased protein catabolism, decreased protein synthesis, and increased insulin resistance (1)(2)(3)(4). Other potential mechanisms include systemic inflammation and a more rapid loss of residual renal function (11)(12)(13)(31)(32)(33)(34)(35).…”

“…In patients with CKD, uncorrected metabolic acidosis leads to clinically significant consequences like protein energy wasting and bone disease, and in hemodialysis (HD) patients, it is associated with higher death risk (1)(2)(3)(4)(5)(6)(7). Clinical trials have shown that correction of metabolic acidosis results in improvements in protein energy wasting and reduction of hospitalizations of peritoneal dialysis (PD) patients (8,9).…”

Inhibition of PI3-kinase signaling by glucocorticoids results in increased branched-chain amino acid degradation in renal epithelial cells

“…Feeding CRF rats a high-protein diet did not raise the plasma concentrations of these essential amino acids, suggesting that overriding conditions (i.e., acidosis or a hormonal imbalance) accelerated their degradation (25). We and others have identified glucocorticoids as a physiological signal that increases branched-chain ketoacid dehydrogenase (BCKD) activity in muscle of adrenalectomized rats (1,14,21,28) and in LLC-PK 1 renal epithelial cells that had been stably transfected to express glucocorticoid receptors [LLC-PK1-GR101 cells (35)]. The BCKD enzyme complex is responsible for the irreversible degradation of BCAAs.…”