title: Smad5 regulates Akt2 expression and insulin-induced glucose uptake in L6 myotubes.
abstract: Insulin-induced glucose uptake by skeletal muscle results from Akt2 activation and is severely impaired during insulin resistance. Recently, we and others have demonstrated that BMP9 improves glucose homeostasis in diabetic and non-diabetic rodents. However, the mechanism by which BMP9 modulates insulin action remains unknown. Here we demonstrate that Smad5, a transcription factor activated by BMP9, and Akt2, are upregulated in differentiated L6 myotubes. Smad5, rather than Smad1/8, is downregulated "in vivo" and "in vitro" by dexamethasone. Smad5 knockdown decreased Akt2 expression and serine phosphorylation and insulin-induced glucose uptake, and increased the expression of the lipid phosphatase Ship2. Additionally, binding of Smad5 to Akt2 gene is decreased in dexamethasone-treated rats and increased in L6 myotubes compared to myoblasts. The present study indicates that Smad5 regulates glucose uptake in skeletal muscle by controlling Akt2 expression and phosphorylation. These finding reveals Smad5 as a potential target for the therapeutic of type 2 diabetes.
authors.affiliation: Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, SP, Brazil.
authors.forename: Fernando F
authors.initials: FF
authors.lastname: Anhê
authors.forename: Camilo
authors.initials: C
authors.lastname: Lellis-Santos
authors.forename: Adriana R
authors.initials: AR
authors.lastname: Leite
authors.forename: Sandro M
authors.initials: SM
authors.lastname: Hirabara
authors.forename: Antonio C
authors.initials: AC
authors.lastname: Boschero
authors.forename: Rui
authors.initials: R
authors.lastname: Curi
authors.forename: Gabriel F
authors.initials: GF
authors.lastname: Anhê
authors.forename: Silvana
authors.initials: S
authors.lastname: Bordin
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D003907:Dexamethasone / Q000494:pharmacology; D005938:Glucocorticoids / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism*; D047468:Immunoprecipitation; D000072181:Inositol Polyphosphate 5-Phosphatases; D007328:Insulin / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000378:metabolism*; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D010766:Phosphorylation / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D034622:RNA Interference / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D051902:Smad5 Protein / Q000235:genetics / Q000378:metabolism*; D051904:Smad8 Protein / Q000378:metabolism; D014162:Transfection
chemical_list: D005938:Glucocorticoids; D007328:Insulin; D051902:Smad5 Protein; D051904:Smad8 Protein; D003907:Dexamethasone; D051057:Proto-Oncogene Proteins c-akt; D010744:Phosphoric Monoester Hydrolases; D000072181:Inositol Polyphosphate 5-Phosphatases; C000606436:Inppl1 protein, rat; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D005947:Glucose