The gene expression profile of skeletal muscle in end-stage liver disease patients undergoing assessment for liver transplantation with muscle wasting

Background and aims: Sarcopenia, defined as a loss of muscle mass, strength and physical function is a common condition affecting endstage liver disease (ESLD) patients. However, the molecular pathways which may underpin the progression of sarcopenia in ESLD are largely unclear. Therefore, the aim of this study was to characterize intracellular signaling pathways that may contribute to sarcopenia progression in ESLD patients with differing levels of muscle mass and physical function.

Method: Fasted muscle and blood samples were obtained from 23 decompensated ESLD patients (aged 54.7±6.4 years, MELD 13.7± 4.6). Physical function and body composition assessments were also conducted. ESLD patients were divided into 3 clinically defined groups dependent on muscle mass and function; 1-adequate muscle mass and function (n=7), 2-adequate muscle mass, inadequate function (n=5) and 3-inadequate muscle mass and function (n=11). The skeletal muscle transcriptome was determined by RNA-sequencing using a QuantSeq 2′ kit (Lexogen, Austria) and sequenced on Illumina’s NextSeq500. Transcripts were mapped to the human genome(hg38)and were analyzed using Ingenuity Pathway Analysis (Qiagen, UK).

Results: BMI and weight was significantly lower in patients with inadequate muscle mass and function compared to patients with adequate muscle mass and function (p<0.05). Pathway analysis revealed a significant enrichment in canonical pathways related to mitochondrial dysfunction and oxidative phosphorylation in ESLD patients with inadequate muscle mass and function vs. patients with adequate muscle mass and function (Figure A), and patients with adequate muscle mass, with inadequate function (Figure B). A significant enrichment in canonical pathways related to oxidative stress and mTOR related signaling was also identified in patients with inadequate muscle mass and function compared to those with adequate muscle mass and inadequate function. Furthermore, RICTOR and LARP1 were identified as predictive, inhibited upstream regulators in ESLD patients with inadequate muscle mass and function vs. patients with adequate muscle mass and function, and adequate muscle mass and inadequate function.

Conclusion: Collectively, these findings highlight distinct signaling pathways which may underscore alterations in skeletal muscle mass and function in ESLD patients. These findings suggest a number of novel therapeutic targets for future interventions which aim to treat sarcopenia.