Loss of muscle mass, or sarcopenia, is nearly universal in cirrhosis and adversely affects patient outcome. The underlying cross-talk between the liver and skeletal muscle mediating sarcopenia is not well understood. Hyperammonemia is a consistent abnormality in cirrhosis due to impaired hepatic detoxification to urea. We observed elevated levels of ammonia in both plasma samples and skeletal muscle biopsies from cirrhotic patients compared with healthy controls. Furthermore, skeletal muscle from cirrhotics had increased expression of myostatin, a known inhibitor of skeletal muscle accretion and growth. In vivo studies in mice showed that hyperammonemia reduced muscle mass and strength and increased myostatin expression in wild-type compared with postdevelopmental myostatin knockout mice. We postulated that hyperammonemia is an underlying link between hepatic dysfunction in cirrhosis and skeletal muscle loss. Therefore, murine C2C12 myotubes were treated with ammonium acetate resulting in intracellular concentrations similar to those in cirrhotic muscle. In this system, we demonstrate that hyperammonemia stimulated myostatin expression in a NF-κB-dependent manner. This finding was also observed in primary murine muscle cell cultures. Hyperammonemia triggered activation of IκB kinase, NF-κB nuclear translocation, binding of the NF-κB p65 subunit to specific sites within the myostatin promoter, and stimulation of myostatin gene transcription. Pharmacologic inhibition or gene silencing of NF-κB abolished myostatin up-regulation under conditions of hyperammonemia. Our work provides unique insights into hyperammonemia-induced myostatin expression and suggests a mechanism by which sarcopenia develops in cirrhotic patients.signaling | portosystemic shunting
SV, Dasarathy S. Hyperammonemia-mediated autophagy in skeletal muscle contributes to sarcopenia of cirrhosis. Am J Physiol Endocrinol Metab 303: E983-E993, 2012. First published August 14, 2012; doi:10.1152/ajpendo.00183.2012.-Hyperammonemia and sarcopenia (loss of skeletal muscle) are consistent abnormalities in cirrhosis and portosystemic shunting. We have shown that muscle ubiquitin-proteasome components are not increased with hyperammonemia despite sarcopenia. This suggests that an alternative mechanism of proteolysis contributes to sarcopenia in cirrhosis. We hypothesized that autophagy could be this alternative pathway since we observed increases in classic autophagy markers, increased LC3 lipidation, beclin-1 expression, and p62 degradation in immunoblots of skeletal muscle protein in cirrhotic patients. We observed similar changes in these autophagy markers in the portacaval anastamosis (PCA) rat model. To determine the mechanistic relationship between hyperammonemia and autophagy, we exposed murine C2C12 myotubes to ammonium acetate. Significant increases in LC3 lipidation, beclin-1 expression, and p62 degradation occurred by 1 h, whereas autophagy gene expression (LC3, Atg5, Atg7, beclin-1) increased at 24 h. C2C12 cells stably expressing GFP-LC3 or GFPmCherry-LC3 constructs showed increased formation of mature autophagosomes supported by electron microscopic studies. Hyperammonemia also increased autophagic flux in mice, as quantified by an in vivo autophagometer. Because hyperammonemia induces nitration of proteins in astrocytes, we quantified global muscle protein nitration in cirrhotic patients, in the PCA rat, and in C2C12 cells treated with ammonium acetate. Increased protein nitration was observed in all of these systems. Furthermore, colocalization of nitrated proteins with GFP-LC3-positive puncta in hyperammonemic C2C12 cells suggested that autophagy is involved in degradation of nitrated proteins. These observations show that increased skeletal muscle autophagy in cirrhosis is mediated by hyperammonemia and may contribute to sarcopenia of cirrhosis.
Background and Aim Pre-transplant sarcopenia (reduced skeletal muscle mass) predicts poor outcome in cirrhosis. In contrast, whether muscle mass increases post orthotopic liver transplantation (OLT) is not known and was studied prospectively. Methods Consecutive patients who underwent a comprehensive nutritional evaluation in a liver transplant nutrition clinic were included. Core abdominal muscle area was measured on abdominal CT obtained pre- and post-OLT. Age and gender based controls were used to define sarcopenia. Measures of body composition pre-transplant were correlated with CT measurements. Predictors and clinical impact of post-OLT change in muscle area were examined. In 3 subjects post-OLT and 3 controls, expression of genes regulating skeletal muscle mass were quantified. Results During the study period, 53 patients (M:F 41:12; age 56.9±7.5 years) were followed up after OLT for 19.3±9 months. Five patients died and another 5 had acute graft rejection. Pre-OLT sarcopenia was present in 33 (66.2%). Pre-transplant clinical characteristics including Child’s score, MELD score and nutritional status or post transplantation immunosuppression regimen did not predict post transplant change in muscle mass. New onset post-OLT sarcopenia developed in 14 patients. Loss of muscle mass post-OLT increased risk of diabetes mellitus and a trend towards higher mortality. Skeletal muscle expression of myostatin was higher and that of ubiquitin proteasome proteolytic components lower post-OLT than in controls. Conclusions Post transplantation sarcopenia is common and could not be attributed to pre-transplant characteristics or the type or duration of post-OLT immunosuppression. Post-transplant sarcopenia contributes to adverse consequences and strategies targeting myostatin may be beneficial.
Psychiatric illness was common among individuals who sustained orthopaedic polytrauma, and patients with depression had more complications. This study highlights the need for greater attention to mental health disorders in this population.
Background Innate defense regulator peptide-1018 (IDR-1018) is a 12-amino acid, synthetic, immunomodulatory host defense peptide that can reduce soft tissue infections and is less likely to induce bacterial resistance than conventional antibiotics. However, IDRs have not been tested on orthopaedic infections and the immunomodulatory effects of IDR-1018 have only been characterized in response to lipopolysacharide, which is exclusively produced by Gram-negative bacteria. Questions/purposes We sought (1) to more fully characterize the immunomodulatory effects of IDR-1018, especially in response to Staphylococcus aureus; and (2) to determine whether IDR-1018 decreases S aureus infection of orthopaedic implants in mice and thereby protects the implants from failure to osseointegrate. Methods In vitro effects of IDR-1018 on S aureus were assessed by determining minimum inhibitory concentrations in bacterial broth without and with supplementation of physiologic ion levels. In vitro effects of IDR-1018 on macrophages were determined by measuring production of monocyte chemoattractant protein-1 (MCP-1) and proinflammatory cytokines by enzyme-linked immunosorbent assay. In vivo effects of IDR-1018 were determined in a murine model of S aureus implant infection by quantitating bacterial burden, macrophage recruitment, MCP-1, proinflammatory cytokines, and osseointegration in nine mice per group on Day 1 postimplantation and 20 mice per group on Day 15 postimplantation. Results IDR-1018 demonstrated antimicrobial activity by directly killing S aureus even in the presence of physiologic ion levels, increasing recruitment of macrophages to the site of infections by 40% (p = 0.036) and accelerating S aureus clearance in vivo (p = 0.008) with a 2.6-fold decrease in bacterial bioburden on Day 7 postimplantation.
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