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.
Tracking metabolic changes in skeletal muscle and bone using animal models of diabetes mellitus (DM) provides important insights for the management of DM complications. In this study, we aimed to establish a method for monitoring changes in body composition characteristics, such as fat mass, skeletal muscle mass (lean mass), bone mineral density, and bone mineral content, during DM progression using a dual-energy X-ray absorptiometry (DXA) system in a mouse model of streptozotocin (STZ)-induced type 1 DM. In the DM model, STZ administration resulted in increased blood glucose levels, increased water and food intake, and decreased body weight. Serum insulin levels were significantly decreased on day 30 of STZ administration. The DXA analysis revealed significant and persistent decreases in fat mass, lower limb skeletal muscle mass, and bone mineral content in DM mice. We measured tibialis anterior (TA) muscle weight and performed a quantitative analysis of tibial microstructure by micro-computed tomography imaging in DM mice. The TA muscle weight of DM mice was significantly lower than that of control mice. In addition, the trabecular bone volume fraction, trabecular thickness, trabecular number, and cortical thickness were significantly decreased in DM mice. Pearson’s product-moment correlation coefficient analysis showed a high correlation between the DXA-measured and actual body composition. In conclusion, longitudinal measurement of body composition changes using a DXA system may be useful for monitoring abnormalities in muscle and bone metabolism in animal models of metabolic diseases such as DM mice.
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In patients with liver fibrosis, muscle mass and muscle strength tend to decline, which affects their prognosis. In 2016, the Sarcopenia Criteria for Liver Disease (First Edition) was established. However, it is unclear why hepatic fibrosis leads to muscle weakness. We induced hepatic fibrosis by performing bile duct ligation (BDL) in mice and investigated the pathogenesis of muscle atrophy caused by hepatic fibrosis. In BDL mice, the weight and crosssectional area of the tibialis anterior muscle decreased from the first week after surgery in the early stage of fibrosis. We performed forelimb grip tests to confirm a significant decrease in muscle strength. From these results, we considered that hepatic fibrosis-dependent muscle sarcopenia model had been established. Using this model, we investigated the cause of hepatic fibrosis-dependent muscle atrophy. We applied BDL mouse serum to cultured myotube cells in vitro, and myotube atrophy was induced. This suggested the possibility of multiorgan linkage in which atrophy-inducing factor was transmitted via blood as a mechanism of muscle atrophy dependent on liver fibrosis. Currently, in order to search for atrophy-inducing factors present in the blood, we are analyzing several cytokines that have been reported to be involved in muscle atrophy.
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