Abstract
The peroxisome proliferator-activated receptor γ (PPARγ) agonist rosiglitazone (Rosi) appears to provide protection against organ dysfunction during endotoxaemia. We examined the potential benefits of Rosi on skeletal muscle protein maintenance and carbohydrate metabolism during lipopolysaccharide (LPS)-induced endotoxaemia. Sprague-Dawley rats were fed either standard chow (control) or standard chow containing Rosi (8.5 ± 0.1 mg·kg-1·day-1) for 2 weeks before and during 24 h continuous intravenous infusion of LPS (15 μg·kg-1·h-1) or saline. Rosi blunted LPS-induced increases in muscle tumour necrosis factor-α (TNF-α) and interleukin-6 (IL-6) mRNA by 70% (P<0.05) and 64% (P<0.01) respectively. Furthermore, Rosi suppressed the LPS-induced reduction in phosphorylated AKT and phosphorylated Forkhead box O (FOXO) 1 protein, as well as the up-regulation of muscle RING finger 1 (MuRF1; P<0.01) mRNA and the LPS-induced increase in 20S proteasome activity (P<0.05). Accordingly, LPS reduced the muscle protein:DNA ratio (∼30%, P<0.001), which Rosi offset. Increased muscle pyruvate dehydrogenase kinase 4 (PDK4) mRNA (P<0.001) and muscle lactate accumulation (P<0.001) during endotoxaemia were suppressed by Rosi. Thus, pre-treatment with Rosi reduced muscle cytokine accumulation and blunted muscle protein loss and lactate accumulation during endotoxaemia, and at least in part by reducing activation of molecular events known to increase muscle protein breakdown and mitochondrial pyruvate use.
Highlights
Skeletal muscle wasting and the development of muscle lactic acidosis and insulin resistance are important clinical consequences of sepsis, and if sustained, can have a detrimental impact on patient recovery and survival
We proposed Rosi administration would blunt the induction of muscle protein loss and dysregulation of oxidative carbohydrate use that we have previously observed in skeletal muscle during endotoxaemia [15]
Compared with Con diet plus saline-infusion (Con/Sal), muscle alkaline-soluble protein and the protein:DNA ratio were ∼30% lower in Con plus LPS-treated (Con/LPS) animals, indicating that LPS infusion exerted a significant catabolic effect on extensor digitorum longus (EDL) muscle
Summary
Skeletal muscle wasting and the development of muscle lactic acidosis and insulin resistance are important clinical consequences of sepsis, and if sustained, can have a detrimental impact on patient recovery and survival. 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]. Suppressing the production of pro-inflammatory cytokines during sepsis may prove beneficial in reducing the loss of muscle mass, maintaining carbohydrate oxidation and reducing lactic acidosis associated with this condition.
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