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This Article Full Text Full Text (PDF) All Versions of this Article: 586/6/1767    most recent jphysiol.2007.149625v1 Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Alamdari, N. Articles by Greenhaff, P. L. PubMed PubMed Citation Articles by Alamdari, N. Articles by Greenhaff, P. L. Related Collections Integrative

¹ Centre for Integrated Systems Biology and Medicine, School of Biomedical Sciences, University of Nottingham, UK

A characteristic manifestation of sepsis is muscle lactate accumulation. This study examined any putative (causative) association between pyruvate dehydrogenase complex (PDC) inhibition and lactate accumulation in the extensor digitorum longus (EDL) muscle of rats infused with lipopolysaccharide (LPS), and explored the involvement of increased transcription of muscle-specific pyruvate dehydrogenase kinase (PDK) isoenzymes. Conscious, male Sprague–Dawley rats were infused I.V. with saline (0.4 ml h^–1, control) or LPS (150 µg kg^–1 h^–1) for 2 h, 6 h or 24 h (n = 6–8). Muscle lactate concentration was elevated after 2, 6 and 24 h LPS infusion. Muscle PDC activity was the same at 2 h and 6 h, but was 65% lower after 24 h of LPS infusion (P < 0.01), when there was a 47% decrease in acetylcarnitine concentration (P < 0.05), and a 24-fold increase in PDK4 mRNA expression (P < 0.001). These changes were preceded by marked increases in tumour necrosis factor- and interleukin-6 mRNA expression at 2 h. The findings indicate that the early (2 and 6 h) elevation in muscle lactate concentration during LPS infusion was not attributable to limited muscle oxygen availability or ATP production (evidenced by unchanged ATP and phosphocreatine (PCr) concentrations) or to PDC inhibition, whereas after 24 h, muscle lactate accumulation appears to have resulted from PDC activation status limiting pyruvate flux, most probably due to cytokine-mediated up-regulation of PDK4 transcription.

(Received 22 December 2007; accepted after revision 22 January 2008; first published online 24 January 2008)
Corresponding author N. Alamdari: Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA. Email: nalamdar{at}bidmc.harvard.edu