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

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.

PDK4 drives metabolic alterations and muscle atrophy in cancer cachexia

“…Others have previously shown elevated PDK4 expression concurrently with the depletion of muscle mass; however, no mechanistic data have been presented thus far. Indeed, PDK4 was found elevated in muscle along with the onset of experimental cancer, starvation, diabetes, sepsis, or amyotrophic lateral sclerosis in animal models (19)(20)(21)(22)(23)(24)(25)(26). Moreover, PDK4 hyperexpression in cardiac muscle was shown to exacerbate the cardiomyopathy induced by abnormal activation of the calcineurin pathway in response to stress conditions, although its overexpression per se was not sufficient to cause changes in heart size (43).…”

“…PDK4 was found elevated in skeletal muscle in animal models for the study of cancer, starvation, diabetes, sepsis, or amyotrophic lateral sclerosis (19)(20)(21)(22)(23)(24)(25), whereas its pharmacologic inhibition in mice was reported to improve statin-mediated myopathies (26), reduce endotoxaemiainduced muscle protein (24), and attenuate the loss of body weight and fat mass in the presence of a tumor (25). PDK4 has been reported as a key target gene of Forkhead box protein O (FOXO)1, peroxisome proliferator-activated receptor (PPAR)d or PPARa in response to the signaling mediated by insulin, elevated free fatty acids, or starvation (20,(27)(28)(29).…”

Effects of Single 48 H Fasting on Soleus Muscle Mass and Contractile Properties in Old and Young Mice

“…Food deprivation for prolonged period of time promotes protein breakdown and inhibits protein synthesis (Jagoe, Lecker, Gomes, & Goldberg, 2002). Fasting leads to an increase in plasma levels of glucocorticoids and catabolic cytokines (Crossland, Constantin-Teodosiu, Gardiner, & Greenhaff, 2017). As a consequence, there is up-regulation of muscle E3 ubiquitin ligases, MuRF-1 and atrogin-1, which in turn promote proteasome-mediated protein degradation in skeletal muscle (Egerman & Glass, 2014).…”

The impact of immobilisation and inflammation on the regulation of muscle mass and insulin resistance: different routes to similar end‐points

“…), not least because divergent in vivo pharmacological approaches that reduce muscle inflammation blunt the dysregulation of muscle carbohydrate metabolism (Crossland et al . , ).…”

“…Furthermore, strategies aimed at blunting the muscle cytokine response to inflammation in vivo in an animal model of clinical sepsis have been shown to dampen the dysregulation of Akt/FOXO signalling and the abundance of downstream mRNA targets, whilst concomitantly preventing muscle protein loss and the impairment of pyruvate dehydrogenase complex activation and carbohydrate oxidation (Crossland et al . , ). Collectively, these findings, along with other reports of dysregulation of Akt signalling in the catabolic, insulin resistant state (Wang et al .…”