Sepsis upregulates the gene expression of multiple ubiquitin ligases in skeletal muscle

Wray, Curtis J.; Mammen, Joshua M.V.; Hershko, Dan; Hasselgren, Per Olof

doi:10.1016/s1357-2725(02)00341-2

Cited by 199 publications

(195 citation statements)

References 19 publications

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“…Since increased activity of the UPP is thought to significantly contribute to muscle protein loss during sepsis [1,35,36], the greater mRNA expression of MAFbx and MuRF1 and activity of the 20S proteasome observed with Con/LPS treatment in the present study ( Figures 2E, 2F and 5A), as seen previously with this model [15,16], clearly point to increased UPP activity being, at least partly, responsible for the reduced muscle protein:DNA ratio observed in these animals. More importantly, however, Rosi treatment significantly dampened the LPS-induced increases in muscle MuRF1 mRNA ( Figure 2F), tended to reduce the increase in MAFbx mRNA ( Figure 2E) and significantly diminished muscle 20S proteasome activity ( Figure 5A).…”

Section: Discussionsupporting

confidence: 87%

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

et al. 2017

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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.

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Section: Discussionsupporting

confidence: 87%

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

et al. 2017

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“…On the other hand, PTX and PTX ϩ FRT did not even restore normal levels of atrogin-1 in the skeletal muscle of AH-130 hosts. This is quite an unexpected finding, given that several reports in the literature have shown that recovery of muscle mass in different experimental models of atrophy is paralleled by normalization of atrogin-1 expression (48,54,62). However, this result, as well as our other observation that muscle wasting in day 4 tumor hosts is not associated with increased expression of atrogin-1, suggests that changes of muscle mass and atrogin-1 mRNA levels are not necessarily tightly coupled.…”

Section: Discussionsupporting

confidence: 51%

IGF-1 is downregulated in experimental cancer cachexia

Costelli

Muscaritoli²,

Bossola³

et al. 2006

American Journal of Physiology-Regulatory, Integrative and Comp

157

127

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Cancer cachexia is characterized by skeletal muscle wasting that is mainly supported by hypercatabolism. Muscle atrophy has been suggested to depend on impaired IGF-1 signal transduction pathway. The present study has been aimed at investigating the IGF-1 system in rats bearing the AH-130 hepatoma, a well-characterized model of cachexia. IGF-1 mRNA expression in the gastrocnemius of tumor hosts progressively decreases to ϳ50% of controls. By contrast, both IGF-1 receptor and insulin receptor mRNA levels increase in day 7 AH-130 hosts. IGF-1 and insulin circulating levels, as well as IGF-1 expression in the liver, are reduced. Muscle wasting in the AH-130 bearers is associated with hyperactivation of the ubiquitin-proteasome system. Consistently, the mRNA levels of ubiquitin and of the ubiquitin ligases atrogin-1 and MuRF1 are significantly increased in the gastrocnemius of day 7 AH-130 hosts. Exogenous IGF-1 administered to tumor bearers does not prevent cachexia. IGF-1 mRNA levels also have been evaluated in the gastrocnemius of AH-130 hosts treated with pentoxifylline, an inhibitor of TNF-␣ synthesis, alone or combined with formoterol, a ␤2-adrenergic agonist. Both treatments partially correct muscle atrophy without modifying IGF-1 and atrogin-1 mRNA levels, whereas MuRF1 hyperexpression is reduced by the combination of pentoxifylline with formoterol. These results demonstrate for the first time that the IGF-1 system is downregulated in cancer cachexia, although the underlying mechanism remains unknown. Moreover, no simple relation linking IGF-1 and/or atrogin-1 mRNA levels and muscle atrophy could be observed in these experimental conditions. Further studies are thus needed to clarify both issues.

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“…During muscle atrophy, including that induced by fasting [19][20][21][22], the expression of MuRF-1 and MAFbx have been reported to be increased. MuRF-1 ubiquitinates myofibrillar and cytoskeleton proteins and metabolic enzymes in preparation for their subsequent breakdown in the proteasome [57][58][59][60].…”

Section: Effects Of Alfacalcidol and Muscle Fibre Atrophymentioning

confidence: 99%

“…Elevated levels of interleukin 6 (IL-6) may also reduce food intake [17] and contribute to muscle wasting via abolishing the normally anabolic effect of insulin-like growth factor 1 (IGF-1) [18]. The muscle breakdown may be realised by an increased expression of the muscle specific ubiquitin ligases, MAFbx and MuRF-1, that play an important role in protein breakdown, as observed during undernutrition [19][20][21][22] and systemic inflammation [23]. It is thus possible that undernutrition and inflammation may induce the expression of the muscle specific E3 ubiquitin ligases and thereby contribute to the loss of body and muscle mass during alfacalcidol supplementation.…”

Section: Introductionmentioning

confidence: 99%

Effects of alfacalcidol on circulating cytokines and growth factors in rat skeletal muscle

et al. 2011

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Supra-physiological levels of vitamin D induce skeletal muscle atrophy, which may be particularly detrimental in already sarcopaenic elderly. Neither the cause nor whether the atrophy is fibre type specific are known. To obtain supraphysiological levels of circulating vitamin D (1,25(OH) 2 D 3 ) 27.5-month-old female Fischer 344 9 Brown Norway F1 rats were orally treated for 6 weeks with vehicle or the vitamin D analogue alfacalcidol. Alfacalcidol treatment induced a 22% decrease in body mass and 17% muscle atrophy. Fibre atrophy was restricted to type IIb fibres in the low-oxidative part of the gastrocnemius medialis only (-22%; P \ 0.05). There was a concomitant 1.6-fold increase in mRNA expression of the ubiquitin ligase MuRF-1 (P \ 0.001), whereas those of insulin-like growth factor 1 and myostatin were not affected. Circulating IL-6 was unaltered, but leptin and adiponectin were decreased (-39%) and increased (64%), respectively. The treated rats also exhibited a reduced food intake. In conclusion, supraphysiological levels of circulating 1,25(OH) 2 D 3 cause preferential atrophy of type IIb fibres, which is associated with an increased expression of MuRF-1 without evidence of systemic inflammation. The atrophy and loss of body mass in the presence of supra-physiological levels of vitamin D are primarily due to a reduced food intake.

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Sepsis upregulates the gene expression of multiple ubiquitin ligases in skeletal muscle

Cited by 199 publications

References 19 publications

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

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

IGF-1 is downregulated in experimental cancer cachexia

Effects of alfacalcidol on circulating cytokines and growth factors in rat skeletal muscle

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