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Originally published online as doi:10.2353/ajpath.2008.070429 on May 5, 2008

Published online before print May 5, 2008
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(American Journal of Pathology. 2008;172:1529-1541.)
© 2008 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2008.070429

Endogenous Hydrogen Peroxide Regulates Glutathione Redox via Nuclear Factor Erythroid 2-Related Factor 2 Downstream of Phosphatidylinositol 3-Kinase during Muscle Differentiation

Yan Ding*, Kyu Jin Choi*, Jin Hwan Kim*, Xuezhe Han{dagger}, Yuji Piao*, Jin-Hyun Jeong{ddagger}, Wonchae Choe*, Insug Kang*, Joohun Ha*, Henry Jay Forman§, Jinhwa Lee, Kyung-Sik Yoon* and Sung Soo Kim*

From the Department of Biochemistry and Molecular Biology (BK21 Project),* Medical Research Center for Bioreaction to Reactive Oxygen Species and Biomedical Science Institute, School of Medicine, and the Department of Pharmaceutical Science,{ddagger} College of Pharmacy, Kyung Hee University, Seoul, Korea; the Department of Biomedical Laboratory Science, Dongseo University, Busan, Korea; the Department of Neurosurgery,{dagger} the First Hospital, Jilin University, Changchun, China; and the School of Natural Sciences,§ University of California at Merced, Atwater, California

We reported previously that endogenous reactive oxygen species (ROS) function as myogenic signaling molecules. It has also been determined that excess ROS induce electrophile-response element (EpRE)-driven gene expression via activation of nuclear factor erythroid 2-related factor 2 (Nrf2). Nonetheless, the relationship between the metabolism of ROS (eg, H2O2) through glutathione (GSH) up-regulation, GSH-dependent reduction of H2O2, and Nrf2-dependent gene regulation is not well established. Therefore, we attempted to determine whether H2O2 controls the intracellular GSH redox state via the Nrf2-glutamate-cysteine ligase (GCL)/glutathione reductase (GR)-GSH signaling pathway. In our experiments, enhanced H2O2 generation was accompanied by an increase in both total GSH levels and the GSH/GSSG ratio during muscle differentiation. Both GCL and GR transcriptional expression levels were markedly increased during muscle differentiation but reduced by catalase treatment. Nrf2 protein expression and nuclear translocation increased during myogenesis. The inhibition of GCL, GR, and Nrf2 both by inhibitors and by RNA interference blocked muscle differentiation. Phosphatidylinositol 3-kinase regulated the expression of the GCL C (a catalytic subunit) and GR genes via the induction of Nrf2 nuclear translocation and expression. In conclusion, endogenous H2O2 generated during muscle differentiation not only functions as a signaling molecule, but also regulates the GSH redox state via activation of the Nrf2-GCL/GR-GSH signaling pathway downstream of phosphatidylinositol 3-kinase.






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