Dataset Information

Nrf2 bindng in C2C12 myotubes

ABSTRACT: Nrf2 (NF-E2-related-factor-2) contributes to the maintenance of glucose homeostasis in vivo. Nrf2 suppresses blood glucose levels by protecting pancreatic β-cells from oxidative stress and improving peripheral tissue glucose utilization. To elucidate the molecular mechanisms by which Nrf2 contributes to the maintenance of glucose homeostasis, we generated skeletal muscle (SkM)-specific Keap1-knockout (Keap1MuKO) mice that express abundant Nrf2 in SkM and then examined Nrf2-target gene expression in this tissue. In Keap1MuKO mice, blood glucose levels were significantly downregulated, and the levels of glycogen branching enzyme (Gbe1) mRNA, along with those of glycogen branching enzyme (GBE) protein, were significantly upregulated in mouse SkM. Consistent with this result, chemical Nrf2-inducers promoted Gbe1 mRNA expression in both mouse SkM and C2C12 myotubes. Chromatin-immunoprecipitation analysis demonstrated that Nrf2 binds the Gbe1 upstream promoter regions. In Keap1MuKO mice, muscle glycogen content was strongly reduced, and forced GBE expression in C2C12 myotubes promoted glucose uptake. Therefore, our results demonstrate that Nrf2-induction in SkM increases GBE expression and reduces muscle glycogen content, resulting in improved glucose tolerance.

ORGANISM(S): Mus musculus

PROVIDER: GSE78780 | GEO | 2016/04/06

SECONDARY ACCESSION(S): PRJNA313517

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:Aim. Hyperthyroidism reduces the oxidative capacity of skeletal muscle (SKM) and promotes development of a glycolytic phenotype by altering the expression of metabolic proteins. Our previous results showed that smoothelin-like protein 1 (SMTNL1), a transcriptional coregulator, promotes insulin sensitivity in SKM. Our aim was to elucidate the role of SMTNL1 in SKM under physiological and pathological 3,3′,5-Triiodo-L-thyronine (T3) concentrations. Methods. Human hyper- and euthyroid SKM biopsies were used for microarray analysis and phospho-kinase arrays. Physiological and hyperthyroid concentrations of T3 were applied on differentiated C2C12 cells upon SMTNL1 overexpression to assess the activity and expression level of the element of insulin signaling. Real-time metabolic measurements of oxygen consumption rate and extracellular acidification rate were measured. Results. Expression of genes related to energy production, nucleic acid- and lipid metabolism were changed significantly in hyperthyroid samples. SMTNL1 expression decreased in the hyperthyroid samples and in T3 treated C2C12 cells. SMTNL1 regulated muscle cell differentiation and compensated for the glycolytic shift in SKM triggered by pathological T3 exposure. Moreover, it selectively regulated TR expression at the transcriptional level. T3 excess triggered the development of insulin resistance while overexpression of SMTNL1 induced insulin sensitivity through the inhibition of JNK activity and hampered the non-genomic effects of T3 by decreasing the activity of ERK1/2 through PKC. SMTNL1 overexpression induced GLUT4 expression in hyperthyroid model to restore the normal responsiveness of glucose transport to insulin. SMTNL1 regulated glucose phosphorylation and balances glycolysis and glycogen synthesis via the downregulation of hexokinase II. T3 overload strongly increased the rate of lactate production, while SMTNL1 overexpression antagonizes the T3 effects. Conclusion. These lines of evidence suggest that SMTNL1 potentially prevents hyperthyroidism-induced changes in SKM and it holds great promise as a novel therapeutic target. Smoothelin-like Protein 1 in Hyperthyroidism

Dataset Information

Nrf2 bindng in C2C12 myotubes

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets