The effect of ex vivo human serum from liver disease patients on cellular protein synthesis and growth

Sophie L Allen, Alex P Seabright, Jonathan I Quinlan, Amritpal Dhaliwal, Felicity R Williams, Nicholas H F Fine, David J Hodson, Matthew J Armstrong, Ahmed M Elsharkaway, Carolyn A Greig, Yu-Chiang Lai, Janet M Lord, Gareth G Lavery, Leigh Breen

Research output: Contribution to journalArticlepeer-review

53 Downloads (Pure)

Abstract

Sarcopenia is a common complication affecting liver disease patients, yet the underlying mechanisms remain unclear. We aimed to elucidate the cellular mechanisms that drive sarcopenia progression using an in vitro model of liver disease. C2C12 myotubes were serum and amino acid starved for 1-h and subsequently conditioned with fasted ex vivo serum from four non-cirrhotic non-alcoholic fatty liver disease patients (NAFLD), four decompensated end-stage liver disease patients (ESLD) and four age-matched healthy controls (CON) for 4- or 24-h. After 4-h C2C12 myotubes were treated with an anabolic stimulus (5 mM leucine) for 30-min. Myotube diameter was reduced following treatment with serum from ESLD compared with CON (-45%) and NAFLD (-35%; p < 0.001 for both). A reduction in maximal mitochondrial respiration (24% and 29%, respectively), coupling efficiency (~12%) and mitophagy (~13%) was identified in myotubes conditioned with NAFLD and ESLD serum compared with CON ( p < 0.05 for both). Myostatin (43%, p = 0.04) and MuRF-1 (41%, p = 0.03) protein content was elevated in myotubes treated with ESLD serum compared with CON. Here we highlight a novel, experimental platform to further probe changes in circulating markers associated with liver disease that may drive sarcopenia and develop targeted therapeutic interventions.

Original languageEnglish
Article number1098
Number of pages19
JournalCells
Volume11
Issue number7
DOIs
Publication statusPublished - 24 Mar 2022

Bibliographical note

Funding Information:
Funding: This study was funded by the National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre (BRC-1215-20009). The views expressed are those of the authors and not necessarily of those of the NIHR, or the Department of Health and Social Care. D.J.H. was supported by MRC (MR/N00275X/1 and MR/S025618/1) Project and Diabetes UK (17/0005681) Project Grants. This project has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (Starting Grant 715884 to D.J.H.).

Publisher Copyright:
© 2022 by the authors. Licensee MDPI, Basel, Switzerland.

Keywords

  • End Stage Liver Disease
  • Humans
  • Muscle Fibers, Skeletal
  • Non-alcoholic Fatty Liver Disease/complications
  • Protein Biosynthesis
  • Sarcopenia/complications
  • Protein breakdown
  • Sarcopenia
  • Mitochondria
  • Chronic liver disease
  • Leucine

ASJC Scopus subject areas

  • General Medicine

Fingerprint

Dive into the research topics of 'The effect of ex vivo human serum from liver disease patients on cellular protein synthesis and growth'. Together they form a unique fingerprint.

Cite this