Down Regulation of Pyruvate Dehydrogenase Complex in Skeletal Muscle during Sepsis: Implications for Sepsis-Induced Hyperlactatemia

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Abstract

Sepsis shifts the dynamic metabolic interactions involved in the regulation of inter-organ substrate fluxes, and ultimately results in derangements in the plasma concentrations of metabolites. One manifestation of the septic process is the development of hyperlactatemia in the absence of overt signs of hypoperfusion. Lactate is the end-product of glycolysis. Consequently, changes in lactate concentrations during sepsis may reflect altered regulation of glucose metabolism. In skeletal muscle, the PDH complex is the link between the glycolytic pathway and oxidative tricarboxylic acid cycle activity in the metabolism of glucose. In sepsis, production of pyruvate via glycolysis is accelerated in skeletal muscle. Because the proportion of the PDH complex in the active, nonphosphorylated form is diminished during sepsis, pyruvate is preferentially converted to lactate, and subsequently released into the circulation. The inhibition of PDH activity resides in a stimulation of the PDH kinase during sepsis. Although the factors responsible for lactate metabolism dyshomeostasis are unknown, evidence suggests that TNF functions as a proximal mediator.

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