Modulation of muscle protein synthesis by insulin is maintained during neonatal endotoxemia

Abstract

motes insulin resistance and reduces protein synthesis in skeletal muscle of adults. The effect of sepsis on insulin-stimulated muscle protein synthesis has not been determined in neonates, a highly anabolic population that is uniquely sensitive to insulin. Overnight fasted neonatal pigs were infused for 8 h with endotoxin [lipopolysaccharide (LPS), 0 and 10 g ⅐ kg Ϫ1 ⅐ h Ϫ1 ]. Glucose and amino acids were maintained at fasting levels, insulin was clamped at either fasting or fed (2 or 10 U/ml) levels, and fractional protein synthesis rates were determined at the end of the infusion. LPS infusion induced a septic-like state, as indicated by a sustained elevation in body temperature, heart rate, and cortisol. At fasting insulin levels, LPS reduced fractional protein synthesis rates in gastrocnemius muscle (Ϫ26%) but had no effect on the masseter and heart. By contrast, LPS stimulated liver protein synthesis (ϩ28%). Increasing insulin to fed levels accelerated protein synthesis rates in gastrocnemius (controls by ϩ38%, LPS by ϩ60%), masseter (controls by ϩ50%, LPS by ϩ43%), heart (controls by ϩ34%, LPS by ϩ40%), and diaphragm (controls by ϩ54%, LPS by ϩ29%), and the response to insulin was similar in LPS and controls. Insulin did not alter protein synthesis in liver, kidney, or jejunum in either group. These findings suggest that acute endotoxemia lowers basal fasting muscle protein synthesis in neonates but does not alter the response of protein synthesis to insulin. growth; amino acids; protein metabolism; insulin resistance; sepsis BACTERIAL ENDOTOXIN [lipopolysaccharide (LPS)] elicits a systemic inflammatory response that has profound consequences on human metabolic homeostasis (1, 45). The physiological response to LPS mimics the metabolic processes triggered by the generalized immune response observed during sepsis, such as insulin resistance for glucose and amino acid metabolism (1,39,46) and the profound reduction of muscle protein synthesis in adult animals (26,29). Hormones and acute-phase reactants that exert and regulate the stress response during sepsis, such as tumor necrosis factor-␣ (TNF-␣), cortisol, insulin, and insulin-like growth factor I (17,44,45), affect the metabolic homeostasis in the normal host, and LPS has been recognized as a potent stimulus that elicits this innate immune response (17,18,44,49).

Amino acids augment muscle protein synthesis in neonatal pigs during acute endotoxemia by stimulating mTOR-dependent translation initiation

“…1). Following previously described techniques, the average basal concentrations of whole blood glucose and plasma branched-chain amino acids (BCAA) were obtained (47). Real-time plasma BCAA concentrations were determined by rapid enzymatic kinetic assay (2) to establish the average basal concentration of BCAA to be used in the subsequent clamp procedure (Fig.…”

“…Whole blood glucose, plasma insulin, and total BCAA concentrations were determined as previously described (2,14,47). Whole body net glucose disposal rates (mg glucose ⅐ kg Ϫ1 ⅐ min Ϫ1 ) and whole body net amino acid disposal rates (mmol ⅐ kg Ϫ1 ⅐ h Ϫ1 ) were determined from the infusion rates of dextrose and amino acid solution needed to maintain baseline fasting levels of blood glucose and plasma amino acids, respectively.…”

“…In LPSinfused neonatal pigs, the response of muscle protein synthesis to insulin stimulation is maintained largely independently of amino acid stimulation and despite persistent suppression of translation initiation (45)(46)(47), suggesting that insulin accelerates protein synthesis in muscle through an mTOR-independent process (46,47). Our previous studies in LPS-infused neonatal pigs suggest that the response of muscle protein synthesis to insulin may be mediated by the elongation step in peptide formation (46).…”

“…Our previous studies in LPS-infused neonatal pigs suggest that the response of muscle protein synthesis to insulin may be mediated by the elongation step in peptide formation (46). Conversely, LPS stimulates protein synthesis by enhancing translation initiation in the liver, and insulin does not affect this response (46,47).…”

Lipopolysaccharide-induced cytokine expression pattern in peripheral blood mononuclear cells in childhood obesity

“…The LPS-induced immune response during sepsis profoundly reduces the synthesis of muscle protein in adult animals (32). Septicemia or acute bacterial intoxication may downregulate gene expression involved in protein synthesis (33). A decreased level of total protein in the obese children may underlie the increased risk of infection, and infection may result in an even greater decrease in muscle.…”