Angiotensin Receptor Blockers Potentiate the Protective Effect of Branched-Chain Amino Acids on Skeletal Muscle Atrophy in Cirrhotic Rats.

Abstract

This study investigated the combined effect of the angiotensin II (AT-II) receptor blocker losartan and branched-chain amino acids (BCAAs) on skeletal muscle atrophy in rats with cirrhosis and steatohepatitis. Fischer 344 rats are fed a choline-deficient l-amino acid-defined (CDAA) diet for 12 weeks and treated with oral losartan (30mg kg-1 day-1 ) and/or BCAAs (Aminoleban EN, 2500mg kg-1 day-1 ). Treatment with losartan and BCAAs attenuated hepatic inflammation and fibrosis and improved skeletal muscle atrophy and strength in CDAA-fed rats. Both agents reduced intramuscular myostatin and pro-inflammatory cytokine levels, resulting in inhibition of the ubiquitin-proteasome system (UPS) through interference with the SMAD and nuclear factor-kappa B pathways, respectively. Losartan also augmented the BCAA-mediated increase of skeletal muscle mass by promoting insulin growth factor-I production and mitochondrial biogenesis. Moreover, losartan decreased the intramuscular expression of transcription factor EB (TFEB), a transcriptional inducer of E3 ubiquitin ligase regulated by AT-II. In vitro assays illustrated that losartan promoted mitochondrial biogenesis and reduced TFEB expression in AT-II-stimulated rat myocytes, thereby potentiating the inhibitory effects of BCAAs on the UPS and caspase-3 cleavage. These results indicate that this regimen could serve as a novel treatment for patients with sarcopenia and liver cirrhosis.