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.

Gastric emptying (GE) can be either delayed or accelerated in diabetes mellitus (DM). However, most research has focused on delayed GE mediated by a chronic hyperglycemic condition in DM. As such, the function of GE in the early stages of DM is not well understood. Interstitial cells of Cajal (ICC) are pacemaker cells in the gastrointestinal tract. In the present study, we investigated changes in GE and ICC networks in the early stages of DM using a streptozotocin-induced type 1 diabetic mouse model. The changes in GE were measured by the 13C-octanoic acid breath test. ICC networks were immunohistochemically detected by an antibody for c-Kit, a specific marker for ICC. Our results showed that GE in type 1 DM was significantly accelerated in the early stages of DM (2–4 weeks after onset). In addition, acute normalization of blood glucose levels by a single administration of insulin did not recover normal GE. ICC networks of the gastric antrum were significantly increased in DM and were not affected by the acute normalization of blood glucose. In conclusion, our results suggest that GE is accelerated in the early stages of DM, and it is associated with increased ICC networks. This mechanism may help to clarify a link between the onset of DM and GE disorders.

<b><i>Introduction:</i></b> The serotonin 3A receptor (5-HT_3AR) is involved in vomiting and gastrointestinal motility. However, it is not well understood the expression pattern of 5-HT_3AR in the gut immunohistochemically and how much contribution of 5-HT_3AR to upper or lower intestinal motility. <b><i>Objectives:</i></b> We investigated the contribution of 5-HT_3AR to gastrointestinal motor function by using 5-HT_3AR KO mice and sought to identify 5-HT_3AR-expressing cells via immunohistochemical staining using 5-HT_3AR-GFP reporter mice. <b><i>Methods:</i></b> The expression of 5-HT_3AR was measured in each section of the gut through real-time PCR. The motor function of the stomach and colon was assessed via the ¹³C-octanoic acid breath test and colonic bead expulsion test, respectively, using 5-HT_3AR KO mice. 5-HT_3AR-expressing cells in the muscle layer of the gut were identified by immunohistochemical staining using 5-HT_3AR-GFP reporter mice. <b><i>Results:</i></b> 5-HT_3AR was expressed throughout the digestive tract, and 5-HT_3AR expression in the stomach and lower digestive tract was higher than that in the other sections. Motor function in the stomach and colon was lower in 5-HT_3AR KO mice than in WT mice. As a result of immunohistochemical staining using GFP reporter mice, cholinergic neurons and PDGFRα⁺ cells were shown to express 5-HT_3AR. In contrast, 5-HT_3AR indicated by GFP fluorescence was rarely detected in ICC and smooth muscle cells. <b><i>Conclusions:</i></b> These results show that 5-HT_3AR is highly expressed in the stomach and large intestine and that the activation of 5-HT_3AR accelerates gastric emptying and large intestine transit. Additionally, 5-HT_3AR is highly expressed in cholinergic neurons and some interstitial cells, such as PDGFRα⁺ cells.

No abstract