Sarcopenia associated with portosystemic shunting is reversed by follistatin

J Hepatol. 2011 May;54(5):915-21. doi: 10.1016/j.jhep.2010.08.032. Epub 2010 Oct 25.


Background & aims: The distinct role of portosystemic shunting (PSS) in the pathogenesis of sarcopenia (skeletal muscle loss) that occurs commonly in cirrhosis is unclear. We have previously shown increased expression of myostatin (inhibitor of skeletal muscle mass) in the portacaval anastamosis (PCA) rat model of sarcopenia of PSS. The present study was performed to examine the mechanisms of sarcopenia following PCA.

Methods: In PCA and sham operated pair fed control rats, the phenylalanine flooding dose method was used to quantify the fractional and absolute protein synthesis rates in the skeletal muscle over time and in response to follistatin, a myostatin antagonist. The expression of myostatin and markers of satellite cell (myocyte precursors) proliferation and differentiation were quantified by real-time PCR and Western blot analyses.

Results: The absolute synthesis rate (ASR) was lower at 2, 4, and 6 weeks (p<0.05) and the fractional synthesis rate (FSR) of skeletal muscle protein was significantly lower (p<0.05) at week 2 in the PCA rats compared to control rats. Expression of myostatin was elevated while markers of satellite cell proliferation and differentiation were lower at 4 and 6 weeks after PCA. Follistatin increased skeletal muscle mass, muscle FSR and ASR, decreased expression of myostatin protein, and increased expression of markers of satellite cell function.

Conclusions: Sarcopenia associated with PSS is caused by impaired protein synthesis and reduced satellite cell function due to increased myostatin expression. Confirming these alterations in human patients with cirrhosis will provide novel therapeutic targets for sarcopenia of liver disease.

MeSH terms

  • Adenylate Kinase / metabolism
  • Animals
  • Disease Models, Animal
  • Follistatin / metabolism
  • Follistatin / pharmacology*
  • Liver Diseases / complications*
  • Liver Diseases / surgery*
  • Male
  • Muscle, Skeletal / drug effects
  • Muscle, Skeletal / metabolism
  • Muscle, Skeletal / pathology
  • Myostatin / genetics
  • Myostatin / metabolism
  • Portasystemic Shunt, Surgical / adverse effects*
  • Postoperative Complications / drug therapy
  • Postoperative Complications / metabolism
  • Proteasome Endopeptidase Complex / drug effects
  • Proteasome Endopeptidase Complex / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Sarcopenia* / drug therapy
  • Sarcopenia* / etiology
  • Sarcopenia* / metabolism
  • Satellite Cells, Skeletal Muscle / drug effects
  • Satellite Cells, Skeletal Muscle / metabolism
  • Satellite Cells, Skeletal Muscle / pathology
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • TOR Serine-Threonine Kinases / metabolism


  • Follistatin
  • Mstn protein, rat
  • Myostatin
  • TOR Serine-Threonine Kinases
  • mTOR protein, rat
  • Adenylate Kinase
  • Proteasome Endopeptidase Complex