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Role of Elevated Fibrinogen in Burn-Induced Mitochondrial Dysfunction: Protective Effects of Glycyrrhizin.

ABSTRACT: Skeletal muscle wasting and weakness with mitochondrial dysfunction (MD) are major pathological problems in burn injury (BI) patients. Fibrinogen levels elevated in plasma is an accepted risk factor for poor prognosis in many human diseases, and is also designated one of damage-associated molecular pattern (DAMPs) proteins. The roles of upregulated fibrinogen on muscle changes of critical illness including BI are unknown. The hypothesis tested was that BI-upregulated fibrinogen plays a pivotal role in the inflammatory responses and MD in muscles, and that DAMPs inhibitor, glycyrrhizin mitigates the muscle changes.After third degree BI to mice, fibrinogen levels in the plasma and at skeletal muscles were compared between BI and sham-burn (SB) mice. Fibrinogen effects on inflammatory responses and mitochondrial membrane potential (MMP) loss were analyzed in C2C12 myotubes. In addition to survival, the anti-inflammatory and mitochondrial protective effects of glycyrrhizin were tested using in vivo microscopy of skeletal muscles of BI and SB mice.Fibrinogen in plasma and its extravasation to muscles significantly increased in BI versus SB mice. Fibrinogen applied to myotubes evoked inflammatory responses (increased MCP-1 and TNF-?; 32.6 and 3.9-fold, respectively) and reduced MMP; these changes were ameliorated by glycyrrhizin treatment. In vivo MMP loss and superoxide production in skeletal muscles of BI mice were significantly attenuated by glycyrrhizin treatment, together with improvement of BI survival rate.Inflammatory responses and MMP loss in myotubes induced by fibrinogen were reversed by glycyrrhizin. Anti-inflammatory and mitochondrial protective effect of glycyrrhizin in vivo leads to amelioration of muscle MD and improvement of BI survival rate.

SUBMITTER: Ueki R

PROVIDER: S-EPMC5026541 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Role of Elevated Fibrinogen in Burn-Induced Mitochondrial Dysfunction: Protective Effects of Glycyrrhizin.

Ueki Ryusuke R Liu Li L Kashiwagi Shizuka S Kaneki Masao M Khan Mohammed A S MA Hirose Munetaka M Tompkins Ronald G RG Martyn Jeevendra A J JA Yasuhara Shingo S

Shock (Augusta, Ga.) 20161001 4

<h4>Introduction</h4>Skeletal muscle wasting and weakness with mitochondrial dysfunction (MD) are major pathological problems in burn injury (BI) patients. Fibrinogen levels elevated in plasma is an accepted risk factor for poor prognosis in many human diseases, and is also designated one of damage-associated molecular pattern (DAMPs) proteins. The roles of upregulated fibrinogen on muscle changes of critical illness including BI are unknown. The hypothesis tested was that BI-upregulated fibrino ...[more]

PMID: 27172157

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Project description:BackgroundWe previously described increased levels of growth and differentiation factor 15 (GDF-15) in skeletal muscle and serum of patients with mitochondrial diseases. Here we evaluated GDF-15 as a biomarker for mitochondrial diseases affecting children and compared it to fibroblast-growth factor 21 (FGF-21). To investigate the mechanism of GDF-15 induction in these pathologies we measured its expression and secretion in response to mitochondrial dysfunction.MethodsWe analysed 59 serum samples from 48 children with mitochondrial disease, 19 samples from children with other neuromuscular diseases and 33 samples from aged-matched healthy children. GDF-15 and FGF-21 circulating levels were determined by ELISA.ResultsOur results showed that in children with mitochondrial diseases GDF-15 levels were on average increased by 11-fold (mean 4046pg/ml, 1492 SEM) relative to healthy (350, 21) and myopathic (350, 32) controls. The area under the curve for the receiver-operating-characteristic curve for GDF-15 was 0.82 indicating that it has a good discriminatory power. The overall sensitivity and specificity of GDF-15 for a cut-off value of 550pg/mL was 67.8% (54.4%-79.4%) and 92.3% (81.5%-97.9%), respectively. We found that elevated levels of GDF-15 and or FGF-21 correctly identified a larger proportion of patients than elevated levels of GDF-15 or FGF-21 alone. GDF-15, as well as FGF-21, mRNA expression and protein secretion, were significantly induced after treatment of myotubes with oligomycin and that levels of expression of both factors significantly correlated.ConclusionsOur data indicate that GDF-15 is a valuable serum quantitative biomarker for the diagnosis of mitochondrial diseases in children and that measurement of both GDF-15 and FGF-21 improves the disease detection ability of either factor separately. Finally, we demonstrate for the first time that GDF-15 is produced by skeletal muscle cells in response to mitochondrial dysfunction and that its levels correlate in vitro with FGF-21 levels.

Dataset Information

Role of Elevated Fibrinogen in Burn-Induced Mitochondrial Dysfunction: Protective Effects of Glycyrrhizin.

Publications

Role of Elevated Fibrinogen in Burn-Induced Mitochondrial Dysfunction: Protective Effects of Glycyrrhizin.

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