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Lipopolysaccharide‐mediated inhibition of pyruvate dehydrogenase activity in rat extensor digitorum longus muscle
Author(s) -
Alamdari Nima,
Murton Andrew J,
ConstantinTeodosiu Dumitru,
Gardiner Sheila M,
Bennett Terence,
Layfield Robert,
Greenhaff Paul L
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a816
Subject(s) - medicine , endocrinology , acidosis , lactate dehydrogenase , lactic dehydrogenase , lactic acidosis , chemistry , sepsis , lipopolysaccharide , saline , insulin resistance , lactic acid , insulin , biology , enzyme , biochemistry , bacteria , genetics
Sepsis is known to induce muscle insulin resistance and lactic acidosis (1). The present study examined whether a lipopolysaccharide (LPS)‐mediated impairment of pyruvate dehydrogenase complex (PDC) activity could explain these observations. Conscious, male, Sprague‐Dawley rats were infused i.v. with either saline (0.4 ml h −1 ) or LPS (150 μg kg −1 h −1 ) for 2h, 6h or 24h (n = 6–8 in each group). At each time point, the extensor digitorum longus (EDL) muscle was rapidly removed, snap‐frozen and used to determine muscle PDC activity and lactate content. Muscle PDC activity was no different between groups at 2h and 6h but was lower after 24h of LPS infusion compared to control (0.08 ± 0.01 vs 0.22 ± 0.03 mmol min −1 (kg wm) −1 , respectively; P<0.01). Muscle lactate content was elevated above control after 2h (12.1 ± 1.4 vs 6.6 ± 1.7 mmol (kg dm) −1 , P<0.05) and 6h (9.3 ± 1.4 vs 5.0 ± 1.06 mmol (kg dm) −1 , P<0.05), but not after 24h of LPS infusion. These data are consistent with our previous observations that sepsis can rapidly up‐regulate pyruvate dehydrogenase kinase transcription (2), and point to an LPS‐mediated inhibition of muscle PDC being directly responsible for lactic acidosis and insulin resistance observed in sepsis. This work was supported by the Medical Research Council, U.K.