Endogenous hydrogen peroxide regulates glutathione redox via nuclear factor erythroid 2-related factor 2 downstream of phosphatidylinositol 3-kinase during muscle differentiation

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

Research output: Contribution to journalArticle

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Abstract

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, H 2O2) 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.

Original languageEnglish
Pages (from-to)1529-1541
Number of pages13
JournalAmerican Journal of Pathology
Volume172
Issue number6
DOIs
Publication statusPublished - 2008 Jan 1

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Phosphatidylinositol 3-Kinase
Glutamate-Cysteine Ligase
Glutathione Reductase
Hydrogen Peroxide
Oxidation-Reduction
Glutathione
Muscles
Reactive Oxygen Species
Antioxidant Response Elements
Glutathione Disulfide
Muscle Development
Nuclear Proteins
RNA Interference
Catalase
Genes
Catalytic Domain
Up-Regulation
Gene Expression

All Science Journal Classification (ASJC) codes

  • Pathology and Forensic Medicine

Cite this

Ding, Yan ; Kyu, Jin Choi ; Jin, Hwan Kim ; Han, Xuezhe ; Piao, Yuji ; Jeong, Jin-Hyun ; Choe, Wonchae ; Kang, Insug ; Ha, Joohun ; Forman, Henry Jay ; Lee, Jinhwa ; Yoon, Kyung Sik ; Sung, Soo Kim. / Endogenous hydrogen peroxide regulates glutathione redox via nuclear factor erythroid 2-related factor 2 downstream of phosphatidylinositol 3-kinase during muscle differentiation. In: American Journal of Pathology. 2008 ; Vol. 172, No. 6. pp. 1529-1541.
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abstract = "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, H 2O2) 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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Endogenous hydrogen peroxide regulates glutathione redox via nuclear factor erythroid 2-related factor 2 downstream of phosphatidylinositol 3-kinase during muscle differentiation. / Ding, Yan; Kyu, Jin Choi; Jin, Hwan Kim; Han, Xuezhe; Piao, Yuji; Jeong, Jin-Hyun; Choe, Wonchae; Kang, Insug; Ha, Joohun; Forman, Henry Jay; Lee, Jinhwa; Yoon, Kyung Sik; Sung, Soo Kim.

In: American Journal of Pathology, Vol. 172, No. 6, 01.01.2008, p. 1529-1541.

Research output: Contribution to journalArticle

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AU - Ding, Yan

AU - Kyu, Jin Choi

AU - Jin, Hwan Kim

AU - Han, Xuezhe

AU - Piao, Yuji

AU - Jeong, Jin-Hyun

AU - Choe, Wonchae

AU - Kang, Insug

AU - Ha, Joohun

AU - Forman, Henry Jay

AU - Lee, Jinhwa

AU - Yoon, Kyung Sik

AU - Sung, Soo Kim

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N2 - 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, H 2O2) 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.

AB - 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, H 2O2) 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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