Role of the PDK1-PKB-GSK3 pathway in regulating glycogen synthase and glucose uptake in the heart

摘要: In order to investigate the importance of PDK1-PKB-GSK3 signalling network in regulating glycogen synthase (GS) heart, we have employed tissue specific conditional knockout mice lacking PDK1 muscle (mPDK1-/-), as well knockin which protein kinase B (PKB) phosphorylation site on kinase-3alpha (GSK3alpha) (Ser21) and GSK3beta (Ser9) is changed Ala. We demonstrate that hearts from mPDK1-/- or double GSK3alpha/GSK3beta mice, insulin failed stimulate activity GS induce its dephosphorylation at residues are phosphorylated by GSK3. also establish both GSK3 isoforms participate regulation GS, with playing a more prominent role. This contrasts skeletal where major regulator insulin-induced activity. Despite inability synthesis these animals possessed normal levels cardiac glycogen, demonstrating total regulated independently insulin's ability heart mechanisms such allosteric activation glucose-6-phosphate and/or contraction, could operate maintain mice. cardiomyocytes derived hearts, although glucose transporter type 4 (GLUT4) increased 2-fold, uptake, providing genetic evidence plays crucial role enabling promote uptake muscle.