Association of lithocholic acid with skeletal muscle hypertrophy through TGR5-IGF-1 and skeletal muscle mass in cultured mouse myotubes, chronic liver disease rats and humans

Yasuyuki Tamai; Akiko Eguchi; Ryuta Shigefuku; Hiroshi Kitamura; Mina Tempaku; Ryosuke Sugimoto; Yoshinao Kobayashi; Motoh Iwasa; Yoshiyuki Takei; Hayato Nakagawa

doi:10.7554/eLife.80638

Association of lithocholic acid with skeletal muscle hypertrophy through TGR5-IGF-1 and skeletal muscle mass in cultured mouse myotubes, chronic liver disease rats and humans

Elife. 2022 Oct 7:11:e80638. doi: 10.7554/eLife.80638.

Authors

Affiliations

¹ Department of Gastroenterology and Hepatology, Graduate school of medicine, Mie University, Tsu, Japan.
² Department of Veterinary Medicine, School of Veterinary Medicine, Rakuno Gakuen University, Ebetsu, Japan.
³ Center for Physical and mental health, Mie University Graduate School of Medicine, Tsu, Japan.

^# Contributed equally.

Abstract

Background: Hepatic sarcopenia is one of many complications associated with chronic liver disease (CLD) and has a high mortality rate; however, the liver-muscle axis is not fully understood. Therefore, few effective treatments exist for hepatic sarcopenia, the best of which being branched-chain amino acid (BCAA) supplementation to help increase muscle mass. Our aim was to investigate the molecular mechanism(s) of hepatic sarcopenia focused on bile acid (BA) composition.

Methods: The correlation between serum BA levels and psoas muscle mass index (PMI) was examined in 73 CLD patients. Gastrocnemius muscle phenotype and serum BA levels were assessed in CLD rats treated with BCAA. Mouse skeletal muscle cells (C2C12) were incubated with lithocholic acid (LCA), G-protein-coupled receptor 5 (TGR5) agonist or TGR5 antagonist to assess skeletal muscle hypertrophy.

Results: In human CLD, serum LCA levels were the sole factor positively correlated with PMI and were significantly decreased in both the low muscle mass group and the deceased group. Serum LCA levels were also shown to predict patient survival. Gastrocnemius muscle weight significantly increased in CLD rats treated with BCAA via suppression of protein degradation pathways, coupled with a significant increase in serum LCA levels. LCA treated C2C12 hypertrophy occurred in a concentration-dependent manner linked with TGR5-Akt pathways based upon inhibition results via a TGR5 antagonist.

Conclusions: Our results indicate LCA-mediated skeletal muscle hypertrophy via activation of TGR5-IGF1-Akt signaling pathways. In addition, serum LCA levels were associated with skeletal muscle mass in cirrhotic rats, as well as CLD patients, and predicted overall patient survival.

Funding: This research was supported by JSPS KAKENHI Grant Number 22K08011 and 21H02892, and AMED under Grant Number JP21fk0210090 and JP22fk0210115. Maintaining cirrhotic rats were partially supported by Otsuka Pharmaceutical Company.

Keywords: bile acids; cell biology; chronic liver diseases; human; lithocholic acid; liver-muscle axis; low muscle mass; medicine; rat; skeletal muscle.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amino Acids, Branched-Chain
Animals
Bile Acids and Salts
Humans
Hypertrophy
Insulin-Like Growth Factor I
Lithocholic Acid
Liver Cirrhosis / pathology
Liver Diseases* / pathology
Mice
Muscle Fibers, Skeletal / metabolism
Muscle, Skeletal / metabolism
Proto-Oncogene Proteins c-akt
Rats
Receptors, G-Protein-Coupled / metabolism
Sarcopenia* / pathology

Substances

Amino Acids, Branched-Chain
Bile Acids and Salts
Receptors, G-Protein-Coupled
Lithocholic Acid
Insulin-Like Growth Factor I
Proto-Oncogene Proteins c-akt

Grants and funding

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.