Sarcopenia associated with portosystemic shunting is reversed by follistatin

Dasarathy, Srinivasan; McCullough, Arthur J.; Muc, Sean; Schneyer, Alan L.; Bennett, Carole; Dodig, Milan; Kalhan, Satish C.

doi:10.1016/j.jhep.2010.08.032

Cited by 100 publications

(135 citation statements)

References 22 publications

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“…A consistent biochemical abnormality in both of these systems is hyperammonemia, and studies using in vivo mice injected with both ammonium acetate and differentiated murine C 2 C 12 myotubes demonstrated that hyperammonemia induces skeletal muscle autophagy. Previously, we have reported that the ubiquitin-mediated proteolysis in the PCA rat was unaltered, and this was accompanied by impaired muscle protein synthesis (10). Consistently, in the present study, we show that in patients with cirrhosis expression of the ubiquitin-proteasome components was unaltered in the skeletal muscle.…”

Section: Discussionsupporting

confidence: 92%

“…Plasma concentrations of ammonia were significantly (P Ͻ 0.01) elevated in the PCA compared with the sham rats (239.4 Ϯ 63.1 mol/l in PCA and 79.4 Ϯ 36.2 mol/l in sham-operated controls). Previously, we have reported unaltered ubiquitinproteasome-mediated proteolysis in this model despite loss of muscle mass (10). Analysis of autophagy markers in the muscle of PCA and sham control rats showed significant increases in LC3-II lipidation and beclin-1 expression as well as p62 degradation (Fig.…”

Section: Resultsmentioning

confidence: 50%

“…The 20S proteasome activity assay in whole muscle homogenate quantified degradation via the ubiquitin proteasome pathway, as described previously. The Chemicon Proteasome 20S activity assay kit (Chemicon International, Temecula, CA) based on detection of the fluorophore 7-amino-4-methylcoumarin (AMC) after cleavage from the labeled substrate LLVY-AMC was used for these studies (10). Enzyme activity of the 20S proteasome was expressed as relative fluorescence units per microgram of protein.…”

Section: Methodsmentioning

confidence: 99%

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Hyperammonemia-mediated autophagy in skeletal muscle contributes to sarcopenia of cirrhosis

Qiu¹,

Tsien

Thapalaya³

et al. 2012

American Journal of Physiology-Endocrinology and Metabolism

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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.

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Section: Discussionsupporting

confidence: 92%

Section: Resultsmentioning

confidence: 50%

Section: Methodsmentioning

confidence: 99%

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Hyperammonemia-mediated autophagy in skeletal muscle contributes to sarcopenia of cirrhosis

Qiu¹,

Tsien

Thapalaya³

et al. 2012

American Journal of Physiology-Endocrinology and Metabolism

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“…2 C and D). These data, in conjunction with our previous studies in the hyperammonemic portacaval anastamosis (PCA) rat (19)(20)(21) and the human studies (above), show that hyperammonemia in vivo induces myostatin expression and reduces muscle mass.…”

Section: Hyperammonemia In Vivo Induces Myostatin and Reduces Skeletalsupporting

confidence: 80%

Hyperammonemia in cirrhosis induces transcriptional regulation of myostatin by an NF-κB–mediated mechanism

Qiu¹,

Thapaliya²,

Runkana

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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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

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“…26,27 Also, there is impairment of skeletal muscle protein synthesis in portosystemic shunting due to increased expression of myostatin, a member of the transforming growth factor b superfamily, 24,28 and autophagy in skeletal muscle mediated by hyperammonemia. 29 In 2002, the MELD score replaced the Child-Pugh score for the prioritization of potential liver transplant recipients in North America, mainly because the MELD score had a rigorous statistical development and includes only objective laboratory parameters.…”

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confidence: 99%

Severe muscle depletion predicts postoperative length of stay but is not associated with survival after liver transplantation

Montano‐Loza

Meza–Junco²,

Baracos³

et al. 2014

Liver Transpl

263

234

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Muscle depletion or sarcopenia is associated with increased mortality in patients with cirrhosis; how it affects mortality after liver transplantation requires further study. In this study, we aimed to establish whether sarcopenia predicts increased morbidity or mortality after liver transplantation. We analyzed 248 patients with cirrhosis who had a computed tomography (CT) scan including the third lumbar vertebra before liver transplantation. Data were recovered from medical charts, the skeletal muscle cross-sectional area was measured with CT, and sarcopenia was defined with previously published sex-and body mass index-specific cutoffs. One hundred sixty-nine patients (68%) were male, and the mean age at transplantation was 55 6 1 years. The etiologies of cirrhosis were hepatitis C virus (51%), alcohol (19%), autoimmune liver diseases (15%), hepatitis B virus (8%), and other etiologies (7%). Sarcopenia was present in 112 patients (45%), and it was more frequent in males (P 5 0.002), patients with ascites (P 5 0.02), and patients with higher bilirubin levels (P 5 0.05), creatinine levels (P 5 0.02), international normalized ratios (P 5 0.04), Child-Pugh scores (P 5 0.002), and Model for End-Stage Liver Disease scores (P 5 0.002). The median survival period after liver transplantation was 117 6 17 months for sarcopenic patients and 146 6 20 months for nonsarcopenic patients (P 5 0.4). Sarcopenic patients had longer hospital stays (40 6 4 versus 25 6 3 days; P 5 0.005) and a higher frequency of bacterial infections within the first 90 days after liver transplantation (26% versus 15%, P 5 0.04) in comparison with nonsarcopenic patients. In conclusion, sarcopenia is one of the most common complications in patients with cirrhosis and is predictive of longer hospital stays and a higher risk of perioperative bacterial infections after liver transplantation, but it is not associated with increased mortality. Liver Transpl 20:640-648, 2014. V C 2014 AASLD.

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Sarcopenia associated with portosystemic shunting is reversed by follistatin

Cited by 100 publications

References 22 publications

Hyperammonemia-mediated autophagy in skeletal muscle contributes to sarcopenia of cirrhosis

Hyperammonemia-mediated autophagy in skeletal muscle contributes to sarcopenia of cirrhosis

Hyperammonemia in cirrhosis induces transcriptional regulation of myostatin by an NF-κB–mediated mechanism

Severe muscle depletion predicts postoperative length of stay but is not associated with survival after liver transplantation

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