Stimulation of glucose uptake in muscle cells by prolonged treatment with scriptide, a histone deacetylase inhibitor.
Glucose incorporation is regulated mainly by GLUT4 in skeletal muscles. Here we report that treatment of L6 myotubes with scriptide, a hydroxamic acid-based histone deacetylase (HDAC) inhibitor, stimulated 2-deoxyglucose uptake. The effect appeared only after 24 hr, resulting in 2.4-fold glucose uptake at treatment day 6. Scriptide acted synergistically with insulin, indicating it stimulated a distinct pathway from the insulin signaling pathway. It was not observed in undifferentiated myoblasts or 3T3-L1 adipocytes, suggesting a muscle-specific effect of scriptide. A five-carbon chain and hydroxamic acid, essential for histone deacetylase inhibition, were indispensable for this effect, and trichostatin A stimulated glucose uptake as well. Scriptide increased the cellular content of GLUT4, and induced GLUT4 translocation, but GLUT4 mRNA level did not change, indicating scriptide functions posttranslationally. Our results indicated a novel function for HDAC inhibitors of increasing GLUT4 content and its translocation in muscle cells, resulting in stimulation of glucose uptake.
Takigawa-Imamura
Hisako
H
Medicinal Research Laboratories, Taisho Pharmaceutical Co., Ltd., Saitama, Japan.
Sekine
Takumi
T
Murata
Mitsuo
M
Takayama
Kiyoshi
K
Nakazawa
Kiyoshi
K
Nakagawa
Junichi
J
D041721:3T3-L1 Cells; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D003847:Deoxyglucose / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D051275:Glucose Transporter Type 4; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids / Q000494:pharmacology*; D051379:Mice; D015394:Molecular Structure; D009004:Monosaccharide Transport Proteins / Q000378:metabolism; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000378:metabolism; D009124:Muscle Proteins; D009132:Muscles / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D043803:Phenalenes / Q000494:pharmacology*; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D013329:Structure-Activity Relationship; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects
D051275:Glucose Transporter Type 4; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; D043803:Phenalenes; D018160:Receptors, Cytoplasmic and Nuclear; C495693:Slc2a4 protein, mouse; C495694:Slc2a4 protein, rat; D014157:Transcription Factors; C485580:scriptide; D003847:Deoxyglucose; D005947:Glucose