Hepatic steatosis contributes to the development of muscle atrophy via inter-organ cross-talk. Liver study

Individuals with hepatic steatosis are often characterized by several metabolic abnormalities including insulin resistance and muscle atrophy. Previously, we found that hepatic steatosis results in an altered hepatokine secretion profile, thereby inducing skeletal muscle insulin resistance via inter-organ cross-talk. In this study, we aimed to investigate whether the altered secretion profile in the state of hepatic steatosis also induces skeletal muscle atrophy via putative effects on muscle protein turnover. To investigate this, eight-week-old male C57BL/6J mice were placed on a chow (4.5% fat) or a high-fat diet (HFD; 45% fat) for 12 weeks to induce hepatic steatosis, after which the livers were excised and cut into ~200 µm slices. Slices were cultured to collect secretion products (conditioned medium; CM). Differentiated L6-GLUT4myc myotubes were incubated with chow and HFD CM to measure glucose uptake and differentiated C2C12 myotubes were incubated with chow and HFD CM to measure protein synthesis and breakdown, and gene expression via RNA sequencing. It was found that 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 there was no difference in protein synthesis. Transcriptome profiling of C2C12 cells indicated that 46 genes were upregulated and 151 genes were downregulated by HFD CM compared with chow CM. Pathway analysis showed that pathways related to anatomical structure and function were enriched. The results of this study support the hypothesis that secretion products from the liver contribute to the development of muscle atrophy in individuals with hepatic steatosis.