RRC ID 68987
Author Sakagami H, Makino Y, Mizumoto K, Isoe T, Takeda Y, Watanabe J, Fujita Y, Takiyama Y, Abiko A, Haneda M.
Title Loss of HIF-1α impairs GLUT4 translocation and glucose uptake by the skeletal muscle cells.
Journal Am J Physiol Endocrinol Metab
Abstract Defects in glucose uptake by the skeletal muscle cause diseases linked to metabolic disturbance such as type 2 diabetes. The molecular mechanism determining glucose disposal in the skeletal muscle in response to cellular stimuli including insulin, however, remains largely unknown. The hypoxia-inducible factor-1α (HIF-1α) is a transcription factor operating in the cellular adaptive response to hypoxic conditions. Recent studies have uncovered pleiotropic actions of HIF-1α in the homeostatic response to various cellular stimuli, including insulin under normoxic conditions. Thus we hypothesized HIF-1α is involved in the regulation of glucose metabolism stimulated by insulin in the skeletal muscle. To this end, we generated C2C12 myocytes in which HIF-1α is knocked down by short-hairpin RNA and examined the intracellular signaling cascade and glucose uptake subsequent to insulin stimulation. Knockdown of HIF-1α expression in the skeletal muscle cells resulted in abrogation of insulin-stimulated glucose uptake associated with impaired mobilization of glucose transporter 4 (GLUT4) to the plasma membrane. Such defect seemed to be caused by reduced phosphorylation of the protein kinase B substrate of 160 kDa (AS160). AS160 phosphorylation and GLUT4 translocation by AMP-activated protein kinase activation were abrogated as well. In addition, expression of the constitutively active mutant of HIF-1α (CA-HIF-1α) or upregulation of endogenous HIF-1α in C2C12 cells shows AS160 phosphorylation comparable to the insulin-stimulated level even in the absence of insulin. Accordingly GLUT4 translocation was increased in the cells expressing CA-HIF1α. Taken together, HIF-1α is a determinant for GLUT4-mediated glucose uptake in the skeletal muscle cells thus as a possible target to alleviate impaired glucose metabolism in, e.g., type 2 diabetes.
Volume 306(9)
Pages E1065-76
Published 2014-5-1
DOI 10.1152/ajpendo.00597.2012
PII ajpendo.00597.2012
PMID 24619881
MeSH Animals Cells, Cultured GTPase-Activating Proteins / metabolism Gene Knockdown Techniques Glucose / metabolism* Glucose Transporter Type 4 / metabolism* Hypoxia-Inducible Factor 1, alpha Subunit / genetics* Insulin / pharmacology Mice Mice, Transgenic Muscle Fibers, Skeletal / drug effects Muscle Fibers, Skeletal / metabolism Muscle, Skeletal / drug effects Muscle, Skeletal / metabolism* Protein Transport / drug effects Protein Transport / genetics
IF 3.469
Human and Animal Cells C2C12(RCB0987)