Liver cirrhosis is a critical health problem associated with several complications, including skeletal muscle atrophy, which adversely affects the clinical outcome of patients independent of their liver functions. However, the precise mechanism underlying liver cirrhosis-induced muscle atrophy has not been elucidated. Here we show that serum factor induced by liver fibrosis leads to skeletal muscle atrophy. Using bile duct ligation (BDL) model of liver injury, we induced liver fibrosis in mice and observed subsequent muscle atrophy and weakness. We developed culture system of human primary myotubes that enables an evaluation of the effects of soluble factors on muscle atrophy and found that serum from BDL mice contains atrophy-inducing factors. This atrophy-inducing effect of BDL mouse serum was mitigated upon inhibition of TNFα signalling but not inhibition of myostatin/activin signalling. The BDL mice exhibited significantly up-regulated serum levels of TNFα when compared with the control mice. Furthermore, the mRNA expression levels of Tnf were markedly up-regulated in the fibrotic liver but not in the skeletal muscles of BDL mice. The gene expression analysis of isolated nuclei revealed that Tnf is exclusively expressed in the non-fibrogenic diploid cell population of the fibrotic liver. These findings reveal the mechanism through which circulating TNFα produced in the damaged liver mediates skeletal muscle atrophy. Additionally, this study demonstrated the importance of inter-organ communication that underlies the pathogenesis of liver cirrhosis.

肝硬化是一种严重的健康问题，与多种并发症相关，包括骨骼肌萎缩，这会对患者的临床结果产生不利影响，而与其肝功能无关。然而，肝硬化引起的肌肉萎缩的确切机制尚未阐明。在这里我们表明肝纤维化诱导的血清因子导致骨骼肌萎缩。使用肝损伤的胆管结扎 (BDL) 模型，我们在小鼠中诱导肝纤维化并观察到随后的肌肉萎缩和无力。我们开发了人类原代肌管培养系统，可以评估可溶性因子对肌肉萎缩的影响，并发现 BDL 小鼠的血清含有萎缩诱导因子。BDL 小鼠血清的这种萎缩诱导作用在抑制 TNFα 信号但不抑制肌生长抑制素/激活素信号后得到缓解。与对照小鼠相比，BDL 小鼠的血清 TNFα 水平显着上调。此外，mRNA 的表达水平Tnf在纤维化肝脏中显着上调，但在 BDL 小鼠的骨骼肌中没有。分离细胞核的基因表达分析表明，Tnf仅在纤维化肝的非纤维化二倍体细胞群中表达。这些发现揭示了受损肝脏中产生的循环 TNFα 介导骨骼肌萎缩的机制。此外，这项研究证明了作为肝硬化发病机制基础的器官间交流的重要性。