Role of transglutaminase 2 in acute colitis and skeletal muscle atrophy

Abstract

Transglutaminase 2 (TG2) is an enzyme that catalyzes post-translational modification including crosslinking, polyamination, and deamidation of proteins. TG2 is ubiquitously expressed and known to be involved in the pathogenesis of various diseases such as cataract, fibrosis, and cancer. In the first part of this study, since TG2 is required to trigger inflammation via the induction of TH17 cell differentiation in response to tissue damage, role of TG2 in inflammatory bowel disease, which is thought to be a TH17 cell-associated disease, was investigated using dextran sulfate sodium (DSS)-induced colitis. DSS-treated TG2-/- mice showed no significant differences in changes of body weight, colon length, morphology, immune cell infiltration, and in vivo intestinal permeability, but showed higher mortality compared with wild-type. These results indicate that TG2 is dispensable but required for the survival of mice in dextran sulfate sodium-induced colitis In the second part of this study, insulin/IGF1 signaling pathway impaired by steroid hormone was investigated using cellular and mouse models of dexamethasone-induced muscle atrophy. Dexamethasone-treated C2C12 myotubes showed decreased caveolin-1 protein and mRNA that lead to reduction in insulin receptor and IR substrate1 levels. These results indicate that caveolin-1 is a glucocorticoid target gene that links glucocorticoid signaling to the insulin signaling pathway. In the third part of this study, role of TG2 in skeletal muscle homeostasis was investigated to explain the impairment of exercise ability of TG2-/- mice. Gastrocnemius (GA) muscle from TG2-/- mice showed a significant reduction of muscle fiber size. Analyses of insulin/IGF signaling pathway in GA muscle revealed that protein level of PDK1 was decreased even though increased level of upstream PI3K. Using C2C12 myotubes, promoter analysis of PDK1 gene showed that treatment with inhibitor and siRNA of TG2 suppresses the reporter activity of c-Jun responsive element. Western blot and real-time RT-PCR analysis demonstrated that TG2 regulates the level of c-Jun protein, but not of mRNA through inhibition of proteasomal degradation of c-Jun. These results indicate that TG2 play a role in the maintenance of skeletal muscle homeostasis.