Journal
FREE RADICAL RESEARCH
Volume 52, Issue 2, Pages 288-303Publisher
TAYLOR & FRANCIS LTD
DOI: 10.1080/10715762.2018.1431626
Keywords
C2C12; cystathionine-gamma-lyase (CSE); glucose homeostasis; GLUT4; glutathione; hydrogen sulfide (H2S); Slc7a11/xCT
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Funding
- National Institutes of Health/National Center for Complementary and Integrative Health [RO1 AT007442]
- Malcolm W. Feist Cardiovascular Research Fellowship and Endowed Chair in Diabetes, Center for Cardiovascular Diseases and Sciences (CCDS) from LSUHSC, Shreveport
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Diabetic patients have lower blood concentrations of hydrogen sulfide (H2S), L-cysteine (LC), and glutathione (GSH). Using C2C12 mouse myotubes as a model, this study investigates the hypothesis that the beneficial effects of LC supplementation are mediated by upregulation of the H2S status under diabetic conditions. Results show that exogenous administration of sodium hydrosulfide (NaHS, 10 or 20 mu M; 6hours), a H2S donor, significantly (p<.05) upregulates the gene expression of cystathionine-gamma-lyase (CSE), LC transporter (Slc7a11/xCT), and the genes involved in GSH biosynthesis. Additionally, it reduces homocysteine (HCys), reactive oxygen species (ROS) production, and enhances cellular LC, H2S, and glucose uptake and utilisation in myoblasts. The use of CSE siRNA to induce deficient endogenous H2S production causes an increase in H2O2, ROS, HCys levels, and downregulation of GSH biosynthesis pathway enzymes. In additional, CSE knockdown downregulates glucose transporter type 4 (GLUT4) and gene expression of its key transcription factors, and reduces glucose uptake in C2C12 myotubes. CSE knockdown cells showed specific increases in the protein S-glutathionylation of LC transporter and GLUT4 along with increased total protein S-glutathionylation. Taken together, evidence from this study provides molecular insights into the importance of the CSE/H2S system in maintaining the cellular glutathione and glucose homeostasis in C2C12 myotubes.
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