O107 Endotoxaemia rapidly impacts on skeletal muscle mrna expression under conditions of controlled nutrient availability in humans

Abstract

Abstract Introduction Inflammation induces changes in muscle protein turnover and mass and dampens insulin stimulated glucose disposal and oxidation. Limited information is available regarding the molecular regulation of these events. We determined the acute effects of lipopolysaccharide (LPS) infusion on targeted muscle mRNA expression. Methods Seven healthy, males (age 21.9±0.6 yrs, BMI 23.4±1.2 kg.m-2) participated in this ethically approved randomised crossover design study. On 2 occasions separated by >2 weeks, subjects underwent a 4h hyperinsulinaemic euglycaemic clamp combined with a primed mixed amino-acid (6 g.h-1; to create a ‘fed-state’) infusion, immediately following bolus saline (control) or LPS (4 ng.kg-1) infusion. Vastus lateralis muscle biopsies were obtained at baseline, 120 and 240 min. Muscle mRNA expression was measured (191 targets deemed to be representative of insulin sensitivity, carbohydrate and fat metabolism, inflammation, and protein turnover) using microfluidics TaqMan array cards. Results Plasma [TNF alpha] was markedly elevated above control following 60 min of LPS infusion (P<0.05) and remained elevated. Following gene filtering (>1.5 fold change in muscle mRNA expression from baseline, P<0.05), Ingenuity Pathway Analysis identified several metabolic functions significantly altered from baseline after 120 and 240 min in control. The magnitude of change in each metabolic function (-log p value) and the size of each gene network was substantially greater after LPS. Conclusion Muscle mRNAs respond rapidly to insulin and amino acid infusion in humans, but the magnitude of response was greater in the presence of LPS and may underpin changes in muscle protein and fuel metabolism seen under these conditions. Take-home message Endotoxaemia acts rapidly (within 2 to 4 hours) to alter the expression levels of muscle mRNAs known to be intimately involved in the molecular regulation of muscle mass, insulin resistance and fuel oxidation in human volunteers under controlled conditions of insulin and nutrient availability. This may play a role in the changes in muscle metabolism seen under such conditions.