Deletion of intestinal SIRT1 exacerbated muscle wasting in cirrhotic mice by decreasing the intestinal concentration of short-chain fatty acids and inflammation

Chien Fu Hsu, Chia Chang Huang, Tze Tze Liu, Ueng Cheng Yang, Chih Wei Liu, Shiang Fen Huang, Ying Ying Yang*, Yi Hsiang Huang, Ming Chih Hou, Han Chieh Lin

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Systemic sirtuin 1 (SIRT1) activation alleviates muscle wasting and improves muscle function by downregulation of myotropic and proteolytic markers. In this study, we evaluated the effects of the intestinal Sirt1 deletion on the dysregulated gutmuscle axis in cirrhotic mice. Cirrhosis-related muscle wasting was induced by common bile duct ligated (BDL) in either wild-type (WT) or intestine-specific Sirt1-deleted (Sirt1IEC-KO) mice, including WT-BDL, WT-sham, Sirt1IEC-KO-BDL and Sirt1IEC-KO-sham mice. Compared with WT-BDL mice, Sirt1IEC-KO-BDL mice showed worsened low lean mass, exacerbated muscle wasting, increased expression of myotropic markers, increased muscular protein degradation, and decreased expression of myogenic markers through aggravation of intestinal inflammation (as evidenced by increased fecal calprotectin/lipocalin-2 levels, increased intestinal macrophage infiltration, and increased intestinal TNFα/IL-6 levels), decrease in abundance of short-chain fatty acid (SCFA)-producing bacteria, decrease in levels of intestinal SCFAs (with anti-inflammatory effects), and downregulation of SCFA receptor GPR43. In biliary cirrhotic mice, a decrease in the abundance of SCFA-producing bacteria and an increase in the levels of intestinal/muscular inflammatory markers are involved in the pathogenesis of dysregulated gut-muscle axis-related muscle wasting, and intestinal deletion of Sirt1 exacerbated these changes.

Original languageEnglish
Pages (from-to)376-385
Number of pages10
JournalJournal of Pharmacological Sciences
Volume147
Issue number4
DOIs
StatePublished - Dec 2021

Keywords

  • Anti-inflammatory
  • Bacteria
  • Intestinal deletion of SIRT1
  • Muscle wasting

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