Lithium Chloride Regulates Connexin43 in Skeletal Myoblasts In Vitro: Possible Involvement in Wnt/β-Catenin Signaling

Abstract

Gap junction channels composed of connexin43 (Cx43) are essential for normal myogenic differentiation and skeletal muscle regeneration. Here, the aim was to study whether lithium chloride (LiCl) could regulate Cx43 expression and gap junction channel function by mimicking the Wnt/b-catenin pathway in primary myoblasts. Cx43 mRNA expression in myoblasts was up-regulated in response to 5 mM LiCl. The enhanced Cx43 protein expression resulting from treatment with 5 and 10 mM LiCl for 24 h increased gap-junctional coupling in myoblasts. However, no obvious changes were observed with 20 mM LiCl. Furthermore, chronic treatment with 10 mM LiCl decreased Cx43 protein expression compared with untreated cells. The authors showed that LiCl mimicked the active canonical Wnt/b-catenin signaling by glycogen synthase kinase-3b (GSK-3b) inactivation and accumulation of the effector protein b-catenin into the nucleus. These results suggest that LiCl regulates Cx43 expression in skeletal myoblasts in vitro partly by a Wnt/b-cateninÁdependent pathway.

Segregation of myoblast fusion and muscle-specific gene expression by distinct ligand-dependent inactivation of GSK-3β

“…Wnt-3a as well as LiCl-induced GSK-3 inactivation stabilized and increased cellular levels of β-catenin leading to β-catenin-dependent TCF/LEF transcriptional activity in differentiating myoblasts, which is in agreement with previous reports [11, 56, 57]. In addition, over-expression of WT-GSK-3β in myoblasts confirmed direct inhibition of β-catenin-induced TCF/LEF transcriptional activity by GSK-3β.…”

“…This notion is further supported by in vivo evidence revealing that markers of muscle differentiation and regeneration are inversely related to GSK-3β activity during skeletal muscle regrowth [10]. Of note is that pharmacological inhibition of GSK-3β activity by lithium (LiCl) has a more striking effect on myoblast fusion and myotube formation than IGF-I [8], which could be related to the ability of LiCl to mimic Wnt/β-catenin signaling [11, 12]. …”

S-Adenosylmethionine regulates connexins sub-types expressed by hepatocytes

“…Several studies have demonstrated that β-catenin interacts with Cx43 promoter regulating its mRNA expression (Xia et al, 2010; Du W et al, 2008; Zhai Y et al, 2002; Ai Z. et al, 2000; Van der Heyden et al, 1998). Analysis by western blot of nuclear protein extracts from hepatocytes supplemented with SAMe 1h after the second supplementation, showed decreased nuclear β-catenin levels (Figure 5A).…”

Connexin 43 hemichannel regulates H9c2 cell proliferation by modulating intracellular ATP and [Ca<sup>2</sup><sup>+</sup>]

“…Cx43 has been shown to be a downstream target of Wnt pathway and Wnt/b-catenin signaling pathway in many cell types, including ovarian endometrioid adenocarcinomas (OEAs) and osteoblasts [36][37][38]. In mammary epithelial cells, Wnt-3a has been shown to up-regulate the expression of Cx43 gene and phenotypically increased transepithelial resistance across the cell monolayer [39].…”