Skeletal muscle atrophy is exacerbated by steatotic and fibrotic liver-derived TNF-alpha in senescence-accelerated mice

Background and Aim: Although liver diseases, including non-alcoholic steatohepatitis, are associated with skeletal muscle atrophy, the mechanism behind their association has not been fully elucidated. In this study, the effects of aging and non-alcoholic steatohepatitis on the skeletal muscle, and the interaction between the liver and muscle were investigated using a diet-induced non-alcoholic steatohepatitis model in senescence-accelerated mice.Methods: A total of four groups of senescence-accelerated mice and the control mice were fed either a non-alcoholic steatohepatitis-inducing or control diet, and their livers and skeletal muscles were removed for examinations.Results: In the senescence-accelerated/non-alcoholic steatohepatitis group, serum level of alanine aminotransferase was markedly elevated and histopathology of non-alcoholic steatohepatitis was significant. Skeletal muscles were also markedly atrophied. The expression of the ubiquitin ligase Murf1 in the muscle was significantly increased with muscle atrophy, while that of Tnfa was not significantly different. In contrast, the hepatic Tnfa expression and serum TNF-alpha levels were significantly increased in the senescence-accelerated/non-alcoholic steatohepatitis group. These results suggest that liver-derived TNF-alpha might promote muscle atrophy associated with steatohepatitis and aging through Murf-1. The metabolomic analysis of skeletal muscle indicated higher spermidine and lower tryptophan levels in the steatohepatitis-diet group.Conclusions: The findings of this study revealed an aspect of liver-muscle interaction, which might be important in developing treatments for sarcopenia associated with liver diseases.