Temporal changes in the involvement of pyruvate dehydrogenase complex in muscle lactate accumulation during lipopolysaccharide infusion in rats

N. Alamdari, D. Constantin-Teodosiu, Andrew Murton, S. M. Gardiner, T. Bennett, R. Layfield, P. L. Greenhaff

Research output: Contribution to journalArticle

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Abstract

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-α 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. Journal compilation

Original languageEnglish (US)
Pages (from-to)1767-1775
Number of pages9
JournalJournal of Physiology
Volume586
Issue number6
DOIs
StatePublished - Mar 15 2008
Externally publishedYes

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Pyruvate Dehydrogenase Complex
Lipopolysaccharides
Lactic Acid
Muscles
Adenosine Triphosphate
Acetylcarnitine
Messenger RNA
Phosphocreatine
Pyruvic Acid
Isoenzymes
Sprague Dawley Rats
Interleukin-6
Sepsis
Up-Regulation
Tumor Necrosis Factor-alpha
Cytokines
Oxygen

ASJC Scopus subject areas

  • Physiology

Cite this

Temporal changes in the involvement of pyruvate dehydrogenase complex in muscle lactate accumulation during lipopolysaccharide infusion in rats. / Alamdari, N.; Constantin-Teodosiu, D.; Murton, Andrew; Gardiner, S. M.; Bennett, T.; Layfield, R.; Greenhaff, P. L.

In: Journal of Physiology, Vol. 586, No. 6, 15.03.2008, p. 1767-1775.

Research output: Contribution to journalArticle

Alamdari, N. ; Constantin-Teodosiu, D. ; Murton, Andrew ; Gardiner, S. M. ; Bennett, T. ; Layfield, R. ; Greenhaff, P. L. / Temporal changes in the involvement of pyruvate dehydrogenase complex in muscle lactate accumulation during lipopolysaccharide infusion in rats. In: Journal of Physiology. 2008 ; Vol. 586, No. 6. pp. 1767-1775.
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