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Microcystin‐LR (MC‐LR) is a widely produced monocyclic heptapeptides in eutrophication waterbodies. MC‐LR can induce various toxic effects in different cells. Our previous studies have found that MC‐LR exposure can disrupt insulin signaling pathway in human liver cells (HL 7702). Skeletal muscle is one of the major organs for glucose disposal and responsive to insulin. However, the effects of MC‐LR on insulin signaling pathway in muscle cells have not been fully explored. By using C2C12 mice muscle cells, this study aims to investigate the toxic effects of MC‐LR in muscle cells with a focus on its effects on insulin signaling pathways. It was found that MC‐LR entered into cells and inhibited protein phosphatase 2A (PP2A) significantly. Furthermore, MC‐LR increased phosphorylation of Ser302, Ser307, Ser612 of insulin receptor substrate 1, AKT‐Ser473, GSK3α‐Ser21, and S6K1‐Thr389 by inhibiting the activity of PP2A. The results in this study demonstrate that exposure of MCLR can disrupt the insulin pathway in muscle cells. [ABSTRACT FROM AUTHOR]

Microcystin-LR (MC-LR) is a cyanobacteria-derived heptapeptide that has been commonly characterized as a hepatotoxin. Although the liver is a primary organ in glucose homeostasis, the effect of MC-LR on glucose metabolism remains unclear. In this study, the human liver cell line HL7702 and ICR mice were exposed to various concentrations of MC-LR for 24 h, and the proteins involved in insulin signaling were investigated. The results showed that MC-LR treatment induced the hyperphosphorylation of insulin receptor substrate 1 (IRS1) at several serine sites, S307, S323, S636/639, and S1101 in HL7702 cells, and S302, S318, S632/635, and S1097 in mice livers. In addition, the activation of S6K1 was demonstrated to play an important role in MC-LR-induced IRS1 hyperphosphorylation at several serine sites. Decreased levels of total IRS1 were observed in the mice livers, but there was no significant change in HL7702 cells. MC-LR also induced glycogen synthase (GS) hyperphosphorylation at S641 (inactivating GS) both in vitro and in vivo, even glycogen synthase kinase 3, a well-known GS kinase, was inactivated after MC-LR treatment. Moreover, MC-LR could block insulin-induced GS activation. In addition, glucose transport in liver cells was not impacted by MC-LR either with or without insulin stimulation. Our study implies that MC-LR can interfere with the actions of IRS1 and GS in insulin signaling and may have a toxic effect on glucose metabolism in the liver. [ABSTRACT FROM AUTHOR]