Infection decreases fatty acid oxidation and nuclear hormone receptors in the diaphragm

Abstract

there is increasing evidence that decreased ventilatory muscle contraction contributes signifi cantly to this respiratory failure ( 3,4 ). Friman ( 5 ) reported that in humans, the maximal force that a muscle can produce and the endurance capacity of muscle decreases during infections. Moreover, animal models of infection also showed a decrease in the force that the ventilatory muscles can generate, leading to hypercapneic respiratory failure ( 3,4,6 ). Additionally, endotoxin (lipopolysaccharide, LPS) administration, a model of gram-negative sepsis, also impairs ventilatory muscle contractility ( 7-9 ). Similarly, treatment with tumor necrosis factor-alpha (TNF-␣ ), an important cytokine that mediates many of the effects of sepsis and LPS administration, has been shown to also decrease diaphragmatic pressure and contraction ( 10 ). The administration of TNF-␣ antibodies partially blocked the deleterious effects of LPS on diaphragmatic contractility, suggesting that the effects of sepsis and LPS are mediated by cytokines ( 9 ).The mechanisms accounting for the ventilatory muscle failure during sepsis are likely to be multifactorial ( 3, 4 ). In some circumstances, decreased systemic blood pressure could result in insuffi cient muscle blood fl ow resulting in a reduction in the delivery of oxygen and nutrients required for normal muscle function. However, studies have shown that blood fl ow to the ventilatory muscles increases during sepsis, which should compensate for the Abstract Respiratory failure is a major cause of mortality during septic shock and is due in part to decreased ventilatory muscle contraction. Ventilatory muscles have high energy demands; fatty acid (FA) oxidation is an important source of ATP. FA oxidation is regulated by nuclear hormone receptors; studies have shown that the expression of these receptors is decreased in liver, heart, and kidney during sepsis. Here, we demonstrate that lipopolysaccharide ( Respiratory failure is a major cause of morbidity and mortality in patients with septic shock ( 1, 2 ). This respiratory insuffi ciency is usually attributed to lung injury, but Abbreviations: ACC, acetyl CoA carboxylase; ACS, acyl-CoA synthetase; AGPAT, 1-acyl-glycerol-3-phosphate acyltransferase; Atp5g1, ATP synthase, H + transporting, mitochondrial FO complex, subunit c; CBP, CREB binding protein; Cox 5a, cytochrome c oxidase, subunit 5a; CPT-1 ␤ , carnitine palmitoyltransferase beta; ERR ␣ , estrogen-related receptor alpha; FATP-1, FA transport protein 1; GPAT, glycerol-3-phosphate acyltransferase; HK1, hexose kinase 1; HK2, hexose kinase 2; Idh3a, isocitrate dehyrogenase 3 (NAD + ) alpha; LPS, lipopolysaccharide; MCAD, medium chain acyl-CoA dehydrogenase; Nduf58, NADH dehydrogenase (ubiquinone) Fe-S protein 8; PDK4, pyruvate dehydrogenase kinase isoenzyme 4; PGC-1, peroxisome proliferator-activated receptor gamma coactivator-1; SAA, serum amyloid A; SRC1, steroid receptor coactivator-1; TNF-␣ , tumor necrosis factor-alpha; TRAP, thyroid receptor-associated protein.

Functional crosstalk of PGC-1 coactivators and inflammation in skeletal muscle pathophysiology

“…An early study found that LPS, TNF, and IL-1 augment PGC-1 expression resulting in increased oxidative phosphorylation while more recently, sepsis was shown to lower PGC-1 and PGC-1 in skeletal muscle of rats [61,285]. In support of these data, PGC-1 and PGC-1 are also reduced in diaphragm after LPS administration with concomitant decrease in fatty acid oxidation [286]. A more careful examination of the time-course revealed that intraperitoneal injection of LPS induced PGC-1 in skeletal muscle after 2h, but decreased its expression after 24h, suggesting a shortterm up-but a long-term down-regulation [287].…”

Targeted metabolomics for discrimination of systemic inflammatory disorders in critically ill patients

“…Because it has been shown that this effect occurs within 2 h after LPS administration and is sustained for at least 24 h ( 29, 30 ), medium-chain acylcarnitines and phospholipids might be appropriate biomarkers for differentiation of sepsis and noninfectious SIRS in the early stage of the disease. the result of a coordinated, predominantly down-regulation of many proteins taking part in FA transport , FA oxidation (carnitine palmitoyl transferase, medium chain acyl CoA dehydrogenase [MCAD]), and the breakdown of triglycerides (LPL) (17)(18)(19)(20). A well characterized enzyme taking part in FA oxidation that is suppressed in sepsis is MCAD ( 17,19 ).…”

“…the result of a coordinated, predominantly down-regulation of many proteins taking part in FA transport , FA oxidation (carnitine palmitoyl transferase, medium chain acyl CoA dehydrogenase [MCAD]), and the breakdown of triglycerides (LPL) (17)(18)(19)(20). A well characterized enzyme taking part in FA oxidation that is suppressed in sepsis is MCAD ( 17,19 ). This mitochondrial enzyme processes FAs bound to CoA (acyl-CoA) with a chain length of C5-C14.…”

“…In a previous study, we identifi ed a peptide biomarker by proteome analysis that discriminates noninfectious induced SIRS from sepsis, which is being validated in other patient groups ( 15 ). Because SIRS and sepsis are accompanied by severe metabolic alterations (16)(17)(18)(19)(20), we hypothesize that a systematic analysis of the Abstract The occurrence of systemic infl ammatory response syndrome (SIRS) remains a major problem in intensive care units with high morbidity and mortality. The differentiation between noninfectious and infectious etiologies of this disorder is challenging in routine clinical practice.…”

The Role of Altered Lipid Metabolism in Septic Myocardial Dysfunction

“…The increase in VLDL during sepsis, traditionally considered as a reaction mobilizing lipid stores to delivery an increased amount to the immune cells, may also have a protective meaning: the increased level of serum VLDL and of their content in phospholipids can substitute for the HDL in binding and neutralizing LPS [119,120].…”