Burn injury impairs insulin-stimulated Akt/PKB activation in skeletal muscle

Abstract

The molecular bases underlying burn-or critical illness-induced insulin resistance still remain unclarified. Muscle protein catabolism is a ubiquitous feature of critical illness. Akt/PKB plays a central role in the metabolic actions of insulin and is a pivotal regulator of hypertrophy and atrophy of skeletal muscle. We therefore examined the effects of burn injury on insulin-stimulated Akt/PKB activation in skeletal muscle. Insulin-stimulated phosphorylation of Akt/PKB was significantly attenuated in burned compared with sham-burned rats. Insulin-stimulated Akt/PKB kinase activity, as judged by immune complex kinase assay and phosphorylation status of the endogenous substrate of Akt/PKB, glycogen synthase kinase-3␤ (GSK-3␤), was significantly impaired in burned rats. Furthermore, insulin consistently failed to increase the phosphorylation of p70 S6 kinase, another downstream effector of Akt/PKB, in rats with burn injury, whereas phosphorylation of p70 S6 kinase was increased by insulin in controls. The protein expression of Akt/PKB, GSK-3␤, and p70 S6 kinase was unaltered by burn injury. However, insulin-stimulated activation of ERK, a signaling pathway parallel to Akt/PKB, was not affected by burn injury. These results demonstrate that burn injury impairs insulin-stimulated Akt/PKB activation in skeletal muscle and suggest that attenuated Akt/PKB activation may be involved in deranged metabolism and muscle wasting observed after burn injury.protein kinase B; glycogen synthase kinase-3␤; insulin resistance FUNCTIONAL AND METABOLIC ABERRATIONS associated with critical illness such as burn injury include hypermetabolic response, increased protein catabolism, insulin resistance, and muscle wasting. Muscle wasting in critically ill patients leads to muscle weakness, resulting in hypoventilation, difficulties in weaning off respirators, decreased mobilization, prolonged rehabilitation and hospitalization, and even death (2, 3, 4, 6). Insulin resistance is a well-known phenomenon of critical illness and has long been considered to play a cardinal role in the derangements of metabolism and muscle wasting. Binding of insulin to its receptor results in activation of insulin receptor (IR) tyrosine kinase, which in turn phosphorylates the IR substrates (IRSs). Phosphorylation at the tyrosine residues of IRS-1 and IRS-2 transduces signal from IR to phosphatidylinositol 3-kinase (PI3K) (1, 4).A Ser/Thr protein kinase, Akt/PKB, is a major downstream effector of the IR-IRS-PI3K pathway. Akt/PKB is activated by phosphorylation of Thr 308 and Ser 473 residues of the kinase (8, 46, 52). The phosphorylation of Akt/PKB is dependent on phosphatidylinositol 3,4,5-triphosphate, a product of PI3K. Akt/PKB drives a major portion of the PI3K-mediated metabolic actions of insulin. Akt/PKB is required for insulinstimulated glucose uptake and glycogen synthesis (53). Akt/ PKB also promotes protein synthesis via activation of the mTOR-p70 S6 kinase pathway (19). Glycogen synthase kinase-3␤ (GSK-3␤), a negative regulator of glycogen synthase...

Reduced rate of adenosine triphosphate synthesis by in vivo 31P nuclear magnetic resonance spectroscopy and downregulation of PGC-1β in distal skeletal muscle following burn

“…In addition, Akt would normally contribute to protein synthesis via mTOR, but attenuation of Akt leads to inhibition of protein synthesis and cachexia (29). These findings, together with recent published reports (14,28,30), suggest that these two mechanisms, which may involve an increase in FoxO3 expression, may account for muscle wasting and cachexia observed in burned patients (Fig. 6).…”

“…The expression profile of Irs1, which was significantly reduced by 3 days and increased thereafter, may Also, it does not inhibit translational activity of FoxO3, which normally suppresses atrogen expression and proteolysis, leading to muscle atrophy or 'cachexia'. In addition, the insulin-stimulated phosphorylation of AKT/PKB is significantly attenuated (28). Thus, AKT does not phosphorylate FoxO and, via mTOR, does not contribute to protein synthesis, which also results in 'cachexia'.…”

“…If this is the case, then PGC-1ß could contribute to the insulin resistance caused by burn. A different pathway through attenuation of Akt has been also proposed (28). In burn, the phosphorylation of Akt is inhibited and thus Akt does not phosphorylate FoxO1, 3, and 4, which would normally suppress atrogen expression and proteolysis.…”

Acute, Muscle-Type Specific Insulin Resistance Following Injury

“…Hyperinsulinemia can occur following severe injury. However, there appears to be variability depending upon the model used and the time point selected (6,9,25,26). No change or decreases in insulin levels are common early following injury during the "ebb" phase of the injury (27,28).…”

Propranolol Improves Impaired Hepatic Phosphatidylinositol 3-Kinase/Akt Signaling after Burn Injury

“…Burn injury is associated with impaired PI3K/Akt signaling in both the liver (6) and muscle (20,21). Given that prolonged β adrenergic receptor stimulation in cardiomyocytes inhibited insulin receptor signaling (22), we hypothesized that β adrenergic receptor blockade might improve insulin receptor signaling.…”