Sepsis increases the expression and activity of the transcription factor Forkhead Box O 1 (FOXO1) in skeletal muscle by a glucocorticoid-dependent mechanism

Smith, Ira J.; Alamdari, Nima; O’Neal, Patrick; Gonnella, Patricia; Aversa, Zaira; Hasselgren, Per-Olof

doi:10.1016/j.biocel.2010.01.006

Cited by 73 publications

(101 citation statements)

References 57 publications

(149 reference statements)

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“…This finding is in agreement with previous reports that suggested that both cecal ligation and puncture (CLP)-and lipopolysaccharide (LPS)-induced sepsis models are associated with increased skeletal muscle FOXO-1 mRNA 43,44 and protein levels. 45 Conversely, we noted that peritonitis was associated with diminished ratio of Akt and FOXO-1 phosphorylated (active)/total protein and that this ratio that appeared to be attenuated with the treatment (Figure 5A and B). These data are consistent with the possibility that the CeO 2 nanoparticle intervention might function to diminish the degree of sepsis-induced muscle breakdown.…”

Section: Ceo 2 Nanoparticle Treatment Improves Protein Degradation/ Smentioning

confidence: 82%

Cerium oxide nanoparticle treatment ameliorates peritonitis-induced diaphragm dysfunction

Asano¹,

Arvapalli²,

Manne³

et al. 2015

IJN

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The severe inflammation observed during sepsis is thought to cause diaphragm dysfunction, which is associated with poor patient prognosis. Cerium oxide (CeO 2 ) nanoparticles have been posited to exhibit anti-inflammatory and antioxidative activities suggesting that these particles may be of potential use for the treatment of inflammatory disorders. To investigate this possibility, Sprague Dawley rats were randomly assigned to the following groups: sham control, CeO 2 nanoparticle treatment only (0.5 mg/kg iv), sepsis, and sepsis+CeO 2 nanoparticles. Sepsis was induced by the introduction of cecal material (600 mg/kg) directly into the peritoneal cavity. Nanoparticle treatment decreased sepsis-associated impairments in diaphragmatic contractile ( P o ) function (sham: 25.6±1.6 N/cm 2 vs CeO 2 : 23.4±0.8 N/cm 2 vs Sep: 15.9±1.0 N/cm 2 vs Sep+CeO 2 : 20.0±1.0 N/cm 2 , P <0.05). These improvements in diaphragm contractile function were accompanied by a normalization of protein translation signaling (Akt, FOXO-1, and 4EBP1), diminished proteolysis (caspase 8 and ubiquitin levels), and decreased inflammatory signaling (Stat3 and iNOS). Histological analysis suggested that nanoparticle treatment was associated with diminished sarcolemma damage and diminished inflammatory cell infiltration. These data indicate CeO 2 nanoparticles may improve diaphragmatic function in the septic laboratory rat.

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Section: Ceo 2 Nanoparticle Treatment Improves Protein Degradation/ Smentioning

confidence: 82%

Cerium oxide nanoparticle treatment ameliorates peritonitis-induced diaphragm dysfunction

Asano¹,

Arvapalli²,

Manne³

et al. 2015

IJN

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“…However, it is well recognized that muscle wasting accompanying sepsis is, in part, due to an elevated rate of protein degradation (49,50,58,59). Data surrounding alterations in muscle protein breakdown in BCATm KO mice are limited and difficult to interpret.…”

Section: Discussionmentioning

confidence: 99%

“…This sepsis-induced muscle atrophy is generally acknowledged to increase morbidity and mortality, as well as slow rehabilitation of this patient population. To date, some therapeutic modalities directed at inhibiting excessive cytokine or glucocorticoid action, or enhancing anabolic hormone availability, have been successfully employed to prevent or minimize muscle wasting in animal models (28,31,41,49,58,59). However, equivocal data have been reported in studies providing metabolic support to critically ill patients using BCAA in general or leucine in particular (5).…”

Section: Perspectives and Significancementioning

confidence: 99%

BCATm deficiency ameliorates endotoxin-induced decrease in muscle protein synthesis and improves survival in septic mice

Lang

Lynch

Vary

2010

American Journal of Physiology-Regulatory, Integrative and Comp

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Lang CH, Lynch CJ, Vary TC. BCATm deficiency ameliorates endotoxin-induced decrease in muscle protein synthesis and improves survival in septic mice. Am J Physiol Regul Integr Comp Physiol 299: R935-R944, 2010. First published July 16, 2010 doi:10.1152/ajpregu.00297.2010 and sepsis decrease mammalian target of rapamycin (mTOR) activity in skeletal muscle, thereby reducing protein synthesis. Our study tests the hypothesis that inhibition of branched-chain amino acid (BCAA) catabolism, which elevates circulating BCAA and stimulates mTOR, will blunt the LPS-induced decrease in muscle protein synthesis. Wildtype (WT) and mitochondrial branched-chain aminotransferase (BCATm) knockout mice were studied 4 h after Escherichia coli LPS or saline. Basal skeletal muscle protein synthesis was increased in knockout mice compared with WT, and this change was associated with increased eukaryotic initiation factor (eIF)-4E binding protein-1 (4E-BP1) phosphorylation, eIF4E·eIF4G binding, 4E-BP1·raptor binding, and eIF3·raptor binding without a change in the mTOR·raptor complex in muscle. LPS decreased muscle protein synthesis in WT mice, a change associated with decreased 4E-BP1 phosphorylation as well as decreased formation of eIF4E·eIF4G, 4E-BP1·raptor, and eIF3·raptor complexes. In BCATm knockout mice given LPS, muscle protein synthesis only decreased to values found in vehicle-treated WT control mice, and this ameliorated LPS effect was associated with a coordinate increase in 4E-BP1·raptor, eIF3·raptor, and 4E-BP1 phosphorylation. Additionally, the LPS-induced increase in muscle cytokines was blunted in BCATm knockout mice, compared with WT animals. In a separate study, 7-day survival and muscle mass were increased in BCATm knockout vs. WT mice after polymicrobial peritonitis. These data suggest that elevating blood BCAA is sufficient to ameliorate the catabolic effect of LPS on skeletal muscle protein synthesis via alterations in protein-protein interactions within mTOR complex-1, and this may provide a survival advantage in response to bacterial infection.branched-chain amino acids; raptor; mTOR; skeletal muscle; eIF3 GRAM-NEGATIVE BACTERIAL infection, when sustained, leads to muscle atrophy, which is due, in part, to coordinated decreases in both myofibrillar and sacroplasmic protein synthesis (35,53). However, live bacteria are not essential for the development of this catabolic condition as endotoxin (e.g., LPS) decreases skeletal muscle protein synthesis in a time-and dose-dependent manner (30,33). Both sepsis and LPS impair muscle protein synthesis by decreasing translational efficiency, in general, and peptide-chain initiation, in particular, as opposed to reducing the number of ribosomes (30,43,55). Central to the sepsis-and LPS-induced decrease in translation initiation in muscle is the inhibition of the serine (Ser)/threonine (Thr) kinase mammalian target of rapamycin (mTOR), the activity of which is typically characterized by the reduced phosphorylation of two downstream substrates, eukaryotic initiation facto...

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“…(FOXO)1 and -3a (11,12,21,22,52) regulate muscle-wastingrelated genes in sepsis and other catabolic conditions.…”

mentioning

confidence: 99%

Sepsis and glucocorticoids upregulate p300 and downregulate HDAC6 expression and activity in skeletal muscle

Alamdari

Smith

Aversa

et al. 2010

American Journal of Physiology-Regulatory, Integrative and Comp

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Alamdari N, Smith IJ, Aversa Z, Hasselgren PO. Sepsis and glucocorticoids upregulate p300 and downregulate HDAC6 expression and activity in skeletal muscle. Am J Physiol Regul Integr Comp Physiol 299: R509 -R520, 2010. First published June 10, 2010 doi:10.1152/ajpregu.00858.2009.-Muscle wasting during sepsis is in part regulated by glucocorticoids. In recent studies, treatment of cultured muscle cells in vitro with dexamethasone upregulated expression and activity of p300, a histone acetyl transferase (HAT), and reduced expression and activity of the histone deacetylases-3 (HDAC3) and -6, changes that favor hyperacetylation. Here, we tested the hypothesis that sepsis and glucocorticoids regulate p300 and HDAC3 and -6 in skeletal muscle in vivo. Because sepsis-induced metabolic changes are particularly pronounced in white, fast-twitch skeletal muscle, most experiments were performed in extensor digitorum longus muscles. Sepsis in rats upregulated p300 mRNA and protein levels, stimulated HAT activity, and reduced HDAC6 expression and HDAC activity. The sepsis-induced changes in p300 and HDAC expression were prevented by the glucocorticoid receptor antagonist RU38486. Treatment of rats with dexamethasone increased expression of p300 and HAT activity, reduced expression of HDAC3 and -6, and inhibited HDAC activity. Finally, treatment with the HDAC inhibitor trichostatin A resulted in increased muscle proteolysis and expression of the ubiquitin ligase atrogin-1. Taken together, our results suggest for the first time that sepsis-induced muscle wasting may be regulated by glucocorticoid-dependent hyperacetylation caused by increased p300 and reduced HDAC expression and activity. The recent development of pharmacological HDAC activators may provide a novel avenue to prevent and treat muscle wasting in sepsis and other catabolic conditions. acetylation; muscle wasting MUSCLE WASTING DURING SEPSIS is, at least in part, regulated by glucocorticoids (15, 50) and is mainly caused by increased degradation of myofibrillar proteins, although inhibited protein synthesis may contribute as well (16,25). Gene transcription is altered in atrophying muscle, and in recent studies in experimental animals, a common set of genes, so called atrogenes, was upregulated in different catabolic conditions (27). Among the atrogenes, the genes for the ubiquitin ligases muscle atrophy F-box, also known as atrogin-1 (MAFbx/atrogin-1) and muscle ring finger 1 (MuRF1) are particularly important (3,14). Because changes in gene transcription play an important role in loss of muscle mass it is likely that transcription factors are involved in muscle wasting. Indeed, recent reports from our and other laboratories suggest that the transcription factors NF-B (4, 44, 59), CCAAT/enhancer-binding protein (C/ EBP)␤ and -␦ (43, 62), AP-1 (41, 44), and forkhead box (FOXO)1 and -3a (11, 12, 21, 22, 52) regulate muscle-wastingrelated genes in sepsis and other catabolic conditions.In addition to transcription factors, gene activation is also regulated by other f...

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Sepsis increases the expression and activity of the transcription factor Forkhead Box O 1 (FOXO1) in skeletal muscle by a glucocorticoid-dependent mechanism

Cited by 73 publications

References 57 publications

Cerium oxide nanoparticle treatment ameliorates peritonitis-induced diaphragm dysfunction

Cerium oxide nanoparticle treatment ameliorates peritonitis-induced diaphragm dysfunction

BCATm deficiency ameliorates endotoxin-induced decrease in muscle protein synthesis and improves survival in septic mice

Sepsis and glucocorticoids upregulate p300 and downregulate HDAC6 expression and activity in skeletal muscle

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