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

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.

Peroxisome proliferator-activated receptor γ agonism attenuates endotoxaemia-induced muscle protein loss and lactate accumulation in rats

“…Furthermore, we have strongly implicated the dysregulation of AKT/FOXO signalling in these events [15]. The up-regulation of muscle PDK4 mRNA observed with Con/LPS treatment in the present study ( Figure 2H), along with the increase in muscle lactate accumulation (Figure 4), is entirely consistent with our previous observations [7,15]. Moreover, we have also reported that blunting the cytokine response to LPS using low-dose Dex offset the dysregulation of Akt signalling, and normalized muscle PDK4 mRNA and protein expression, PDC activity and lactate accumulation [16].…”

“…We have previously demonstrated a cytokine-linked increase in PDK4 mRNA and protein expression, coupled to the inhibition of PDC activity and stimulation of lactate accumulation in muscle during LPS-induced endotoxaemia in this rodent model [7,15]. Furthermore, we have strongly implicated the dysregulation of AKT/FOXO signalling in these events [15].…”

“…The rapid and marked loss of skeletal muscle mass during sepsis is thought to, in part, reflect the activation of several pathways important in muscle protein breakdown, including ubiquitin-proteasome pathway (UPP)-, calpain-and lysosome-dependent proteolytic pathways [1][2][3][4]. Sepsis also results in the inhibition of muscle carbohydrate oxidation, not least by increasing muscle pyruvate dehydrogenase kinase 4 (PDK4) abundance, which inhibits pyruvate dehydrogenase complex (PDC) activation [5][6][7], thereby decreasing PDC flux and increasing muscle lactate accumulation. Importantly, it has been demonstrated that pro-inflammatory cytokines, and in particular tumour necrosis factor-α (TNF-α), play a major role in the aetiology of muscle atrophy [8] and dysregulation of muscle carbohydrate metabolism [9].…”

Pyruvate Dehydrogenase Activity is Decreased in the Peripheral Blood Mononuclear Cells of Patients with Sepsis: A Prospective Observational Trial

“…Rodent studies have demonstrated that sepsis causes a reduction in the activity and quantity of PDH, which has, in turn, been associated with increased levels of lactate (6)(7)(8). However, no study has measured PDH activity and quantity during sepsis in humans.…”

The Role of Altered Lipid Metabolism in Septic Myocardial Dysfunction

“…In a physiological environment rich in oxygen but also in pathophysiological conditions (like diet rich in lipids, starvation or diabetes) the heart can utilize all metabolites but it prefers FFA oxidation, from which it gets 60-90% of the necessary energy, obtaining the remaining part from the oxidation of glucose and ketone bodies [39]. The myocardiocyte gets FFA mainly taking up tryglicerides (TG)-rich lipoproteins (LP) (chylomicrons and very low-density lipoprotein, VLDL) through the endothelial lipoprotein lipase (LPL), enzyme present in the capillary endothelium and bound to it through a proteoglycan, the Glycosylphosphatidyl-inositol high density lipoprotein-binding protein 1 (GPIHBP1), which anchors LPL to endothelium and serves as a bridge allowing LP uptake [40].…”