Rifaximin enhances the L‑carnitine‑mediated preventive effects on skeletal muscle atrophy in cirrhotic rats by modulating the gut‑liver‑muscle axis.

Abstract

The gut-liver-muscle axis is associated with the development of sarcopenia in liver cirrhosis. The present study aimed to illustrate the combined effects of rifaximin and L-carnitine on skeletal muscle atrophy in cirrhotic rats with steatohepatitis. For this purpose, a total of 344 Fischer rats were fed a choline-deficient L-amino acid-defined (CDAA) diet with the daily oral administration of rifaximin (100 mg/kg) and/or L-carnitine (200 mg/kg), and measurements of psoas muscle mass index and forelimb grip strength were performed. After feeding for 12 weeks, blood samples, and liver, ileum and gastrocnemius muscle tissues were harvested. The effects of L-carnitine on rat myocytes were assessed using in vitro assays. Treatment with rifaximin attenuated hyperammonemia and liver fibrosis in the CDAA-fed rats. Moreover, it improved intestinal permeability with the restoration of tight junction proteins and suppressed the lipopolysaccharide (LPS)-mediated hepatic macrophage activation and pro-inflammatory response. In addition, rifaximin prevented skeletal muscle mass atrophy and weakness by decreasing intramuscular myostatin and pro-inflammatory cytokine levels. Moreover, rifaximin synergistically enhanced the L-carnitine-mediated improvement of skeletal muscle wasting by promoting the production of insulin-like growth factor-1 and mitochondrial biogenesis, resulting in the inhibition of the ubiquitin-proteasome system (UPS). The in vitro assays revealed that L-carnitine directly attenuated the impairment of mitochondrial biogenesis, thereby inhibiting the UPS in rat myocytes that were stimulated with LPS or tumor necrosis factor-α. On the whole, the present study demonstrates that the combination of rifaximin with L-carnitine may provide a clinical benefit for liver cirrhosis-related sarcopenia.