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

Abstract

SCOPE:

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.

METHOD AND RESULTS:

Fischer 344 rats are fed a choline-deficient l-amino acid-defined (CDAA) diet for 12 weeks and treated with oral losartan (30 mg kg-1 day-1 ) and/or BCAAs (Aminoleban EN, 2500 mg 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.

CONCLUSION:

These results indicate that this regimen could serve as a novel treatment for patients with sarcopenia and liver cirrhosis.

• Authors: Soichi Takeda, Kosuke Kaji, Norihisa Nishimura, Masahide Enomoto, Yuki Fujimoto, Koji Murata, Hiroaki Takaya, Hideto Kawaratani, Kei Moriya, Tadashi Namisaki, Takemi Akahane, Hitoshi Yoshiji
• Journal: Molecular nutrition & food research (Mol Nutr Food Res) Vol. 65 Issue 24 Pg. e2100526 (12 2021) ISSN: 1613-4133 [Electronic] Germany
• PMID: 34687151 (Publication Type: Journal Article)
• Copyright: © 2021 Wiley-VCH GmbH.

Chemical References

• Amino Acids, Branched-Chain
• Angiotensin Receptor Antagonists

Topics

• Amino Acids, Branched-Chain (metabolism)
• Angiotensin Receptor Antagonists (metabolism, pharmacology)
• Animals
• Humans
• Liver Cirrhosis (drug therapy, pathology)
• Muscle, Skeletal (metabolism)
• Muscular Atrophy (drug therapy, etiology, prevention & control)
• Rats
• Rats, Inbred F344