Administration of endotoxin, tumor necrosis factor, or interleukin 1 to rats activates skeletal muscle branched-chain alpha-keto acid dehydrogenase.

Abstract

Protein catabolic states (i.e., sepsis and trauma) are thought to be associated with accelerated oxidation of branched-chain amino acids (BCAA). Branched-chain a-keto acid dehydrogenase (BCKAD), the rate-limiting enzyme for BCAA oxidation by muscle, is regulated by phosphorylation/dephosphorylation. Skeletal muscle BCKAD was only 2-4% active in control rats. Intravenous injection of Salmonella enteritidis endotoxin (0.25-10 mg/kg) did not change total BCKAI) activity, but increased the percent active enzyme in muscle three-to fourfold in 4-6 h. Identical results were observed in adrenalectomized rats pretreated with one dose of a-methylprednisolone (2.5 mg/kg i.p.) 30-60 min before saline or endotoxin injection, indicating that endotoxin's effect was not mediated by hypersecretion of adrenal hormones. Cortisone pretreatment of normal rats (100 mg/kg per d) for 2 d prevented endotoxin-induced activation of muscle BCKAD, suggesting that endogenous secretion products mediated BCKAD activation by endotoxin. Human recombinant tumor necrosis factor-a and/or IL-1ft or a (50 jig/kg) increased muscle BCKAD activation two-to fourfold in normal rats 4-6 h after intravenous injection. We conclude that cytokine-mediated activation of muscle BCKAD may contribute to accelerated BCAA oxidation in

Inflammatory and Atherosclerotic Interactions in the Depleted Uremic Patient

“…It has also been documented that high levels of pro-inflammatory cytokines may cause muscle wasting by stimulating protein catabolism via the ubiquitin proteosome pathway [58] and by reducing albumin synthesis and inhibiting appetite [51]. Moreover, cytokines and endotoxins may induce net catabolism of muscle protein by stimulating branched-chain ketoacid dehydrogenase, which leads to greater oxidation of branched-chain amino acids [59]. Finally, cytokines may contribute to wasting by decreasing gastric motility and/or by modifying gastric acid secretion [52].…”

Protein degradation and increased mRNAs encoding proteins of the ubiquitin-proteasome proteolytic pathway in BC3H1 myocytes require an interaction between glucocorticoids and acidification.

“…Interpretation of these results is complicated because other factors that could regulate protein turnover and gene expression, including insulin (11), prostaglandins (12), and cytokines (13)(14)(15)(16), could change in adrenalectomized rats.…”

Effect of intradialytic parenteral nutrition in patients with malnutrition–inflammation complex syndrome on body weight, inflammation, serum lipids and adipocytokines: results from a pilot study

“…As shown by a recent investigation, serum albumin does respond to IDPN in some malnourished HD patients (Avery-Lynch, 2006). On the other hand, albumin levels were found to be low even in apparently well nourished HD patients (Nawabi et al, 1990). This suggests that serum albumin might be an unreliable nutritional marker in dialysis patients (Steinman, 2000;Santos et al, 2003).…”

“…IL-6, a significant proatherogenic cytokine, may contribute to the development of atherosclerosis through various metabolic, endothelial and coagulant mechanisms (Yudkin et al, 2000). TNF-a may induce net catabolism of muscle protein by stimulating branched-chain ketoacid dehydrogenase, which leads to greater oxidation of branched-chain amino acids (Nawabi et al, 1990). Moreover, TNF-a has been shown to downregulate apolipoprotein E secretion, promote in vitro calcification of vascular cells, cause endothelial dysfunction and insulin resistance (Bhagat and Vallance, 1997;Moller, 2000;Tintut et al, 2000).…”