• Madlyn I Frisard, Yaru Wu, Ryan P McMillan, Kevin A Voelker, Kristin A Wahlberg, Angela S Anderson, Nabil Boutagy, Kyle Resendes, Eric Ravussin, and Matthew W Hulver.
• Department of Human Nutrition, Foods, and Exercise, Virginia Tech, Blacksburg, VA, USA, 24060; The Metabolic Phenotyping Core at Virginia Tech, Blacksburg, VA, USA, 24060; Fralin Translational Obesity Research Center, Virginia Tech, Blacksburg, VA. USA, 24060.
• Metab. Clin. Exp. 2015 Mar 1;64(3):416-27.

ObjectiveWe have previously demonstrated that activation of toll-like receptor 4 (TLR4) in skeletal muscle results in an increased reliance on glucose as an energy source and a concomitant decrease in fatty acid oxidation under basal conditions. Herein, we examined the effects of lipopolysaccharide (LPS), the primary ligand for TLR4, on mitochondrial oxygen consumption in skeletal muscle cell culture and mitochondria isolated from rodent skeletal muscle.Materials/MethodsSkeletal muscle cell cultures were exposed to LPS and oxygen consumption was assessed using a Seahorse Bioscience extracellular flux analyzer. Mice were also exposed to LPS and oxygen consumption was assessed in mitochondria isolated from skeletal muscle.ResultsAcute LPS exposure resulted in significant reductions in Carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone (FCCP)-stimulated maximal respiration (state 3u) and increased oligomycin induced state 4 (state 4O) respiration in C2C12 and human primary myotubes. These findings were observed in conjunction with increased mRNA of uncoupling protein 3 (UCP3), superoxide dismutase 2 (SOD2), and pyruvate dehydrogenase activity. The LPS-mediated changes in substrate oxidation and maximal mitochondrial respiration were prevented in the presence of the antioxidants N-acetylcysteine and catalase, suggesting a potential role of reactive oxygen species in mediating these effects. Mitochondria isolated from red gastrocnemius and quadriceps femoris muscle from mice injected with LPS also demonstrated reduced respiratory control ratio (RCR), and ADP- and FCCP-stimulated respiration.ConclusionLPS exposure in skeletal muscle alters mitochondrial oxygen consumption and substrate preference, which is absent when antioxidants are present.Copyright © 2015 Elsevier Inc. All rights reserved.

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