Abstracts Division 1
23. Hepatic steatosis contributes to the development of muscle atrophy via inter-organ crosstalk
Kenneth Pasmans1, Michiel E. Adriaens2, Peter Olinga3, Ramon Langen4, Sander S. Rensen5, Frank G. Schaap5,6, Steven W.M. Olde Damink5,6, Florian Caiment7, Luc J.C. van Loon1, Ellen E. Blaak1, Ruth C.R. Meex1
1Department of Human Biology, School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht, the Netherlands;
2Maastricht Centre for Systems Biology, Maastricht University, Maastricht, the Netherlands;
3Department of Pharmaceutical Technology and Biopharmacy, Groningen Research Institute of Pharmacy, University of Groningen, Groningen, the Netherlands;
4Department of Respiratory Medicine, School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht, the Netherlands.
5Department of Surgery, School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht, the Netherlands;
6Department of General, Visceral and Transplantation Surgery, RWTH University Hospital Aachen, Aachen, Germany;
7Department of Toxicogenomics, School of Oncology and Developmental Biology (GROW), Maastricht University, Maastricht, the Netherlands.
Individuals with hepatic steatosis often display metabolic abnormalities including insulin resistance and muscle atrophy. Previously, we found that hepatic steatosis changes the hepatokine secretion profile, thereby inducing muscle insulin resistance. In this study, we investigated whether the altered secretion profile in the state of hepatic steatosis induces alterations in muscle protein turnover associated with muscle atrophy.
Eight-week-old male C57BL/6J mice were fed a chow (4.5% fat) or high-fat diet (HFD; 45% fat) for 12 weeks to induce hepatic steatosis, after which the livers were excised and cut into slices with a thickness of ±200 µm. Slices were cultured to collect secretion products (conditioned medium; CM). L6-GLUT4myc myotubes were incubated with chow or HFD CM to measure glucose uptake. C2C12 myotubes were incubated with chow or HFD CM to measure protein synthesis and breakdown, and gene expression via RNA sequencing. Furthermore, proteomics analysis was performed on CM.
HFD CM caused insulin resistance in L6-GLUT4myc myotubes compared with chow CM, as indicated by a blunted insulin-stimulated increase in glucose uptake. Furthermore, protein breakdown was increased in C2C12 cells incubated with HFD CM, while protein synthesis was unaffected. RNA profiling of C2C12 cells indicated that 197 genes were differentially expressed after incubation with HFD CM, compared with chow CM, and pathway analysis showed that pathways related to anatomical structure and function were enriched. Proteomics analysis of CM showed that 32 proteins were differentially expressed in HFD CM compared with chow CM. Pathway enrichment analysis indicated that these proteins had important functions related to insulin-like growth factor transport and uptake, and that they affect post-translational processes, including protein folding, protein secretion, and protein phosphorylation.
The results of this study support our hypothesis that secretion products from the liver contribute to the development of muscle atrophy in individuals with hepatic steatosis.
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