The regulatory protein and gene expression profile of skeletal muscle in chronic liver disease patients

Background and aims: The molecular pathways which may underpin sarcopenia in Chronic Liver Disease (CLD) are largely unclear. The aim of this study was to characterize the intracellular signaling pathways that may underscore sarcopenia in CLD patients of different etiologies and disease stages.

Method: Muscle biopsy and blood samples were obtained from 9 non-cirrhotic non-alcoholic fatty liver disease patients (NAFLD; aged 61.1 ±9.0), 12 decompensated alcoholic related end-stage liver disease patients (ESLD;55.7±5.7) and 12 healthy, age-matched healthy controls (CON;55.7±8.7). The protein content of skeletal muscle anabolic, catabolic and mitochondrial signaling intermediates was determined via western blot. The muscle transcriptome was analyzed using RNA-sequencing.

Results: Citrate synthase activity (∼43%) and the protein content of OXPHOS complex I was significantly lower (∼26%) in ESLD vs. CON (p <0.01 for both), whereas OXPHOS complex IV was significantly lower in ESLD vs. CON (71%; p<0.01) and NAFLD (61%; p=0.04). Total mTOR protein was significantly lower in NAFLD (62%, p=0.01) and ESLD (52%, p=0.03) vs. CON. Myostatin protein content was significantly greater in NAFLD vs. CON (77%; p<0.01) and ESLD (70%; p<0.01). Gene pathway analysis revealed a significant enrichment in pathways related to oxidative stress in ESLD vs. CON. A significant enrichment in genes related to senescence was evident in NAFLD vs. CON.

Conclusion: Collectively these findings highlight some similar but largely distinct signaling pathways that may underscore sarcopenia in CLD patients across different etiologies and disease stages.