Clozapine activates AMP-activated protein kinase (AMPK) in C2C12 myotube cells and stimulates glucose uptake

Clozapine has previously been implicated in the dysregulation of energy balance and glucose metabolism in the central nervous system, but its effects in the periphery have yet to be thoroughly elucidated. The objective of this study was to characterize the effects of clozapine on AMP-activated prote...

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Bibliographic Details
Published in:	Life sciences (1973) Vol. 87; no. 1; pp. 42 - 48
Main Authors:	Kim, Ji Hae, Lee, Jung Ok, Lee, Soo Kyung, Jung, Jin Hee, You, Ga Young, Park, Sun Hwa, Park, Munho, Kim, Sang Dae, Kim, Hyeon Soo
Format:	Journal Article
Language:	English
Published:	Netherlands Elsevier Inc 03-07-2010
Subjects:	Acetyl-CoA Carboxylase - drug effects Acetyl-CoA Carboxylase - metabolism AMP-Activated Protein Kinases - drug effects AMP-Activated Protein Kinases - metabolism AMPK Animals Antipsychotic Agents - pharmacology Blotting, Western C2C12 myotubes Calcium Calcium - metabolism Calcium-Calmodulin-Dependent Protein Kinase Kinase - drug effects Calcium-Calmodulin-Dependent Protein Kinase Kinase - metabolism CaMKK Cell Line Clozapine Clozapine - pharmacology Glucose - metabolism Mice Muscle Fibers, Skeletal - cytology Muscle Fibers, Skeletal - drug effects Muscle Fibers, Skeletal - metabolism Phosphorylation - drug effects Scintillation Counting AMPK CaMKK Clozapine Calcium C2C12 myotubes
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Summary:	Clozapine has previously been implicated in the dysregulation of energy balance and glucose metabolism in the central nervous system, but its effects in the periphery have yet to be thoroughly elucidated. The objective of this study was to characterize the effects of clozapine on AMP-activated protein kinase (AMPK) activity in the skeletal muscles. Myotube C2C12 cells were incubated under control conditions, or with clozapine. Expression levels of phosphorylation status of AMPK and its direct downstream Acetyl-CoA carboxylase (ACC) were analyzed by Western blot. Intracellular calcium concentration was measured with calcium indicator dye, fluo-3 AM. 2-deoxyglucose uptake was assessed via the scintillation count. We reported that clozapine activated AMPK in mouse C2C12 myotubes and also stimulated glucose uptake. Clozapine also increased intracellular calcium concentrations of C2C12 cells, and pretreatment with either ethylenediaminetetraacetic acid (EDTA), an extracellular calcium chelator, or 1.8-naphthoylene benzimidazole-3-carboxylic acid (STO-609), a Ca 2+/calmodulin-dependent protein kinase kinase (CaMKK) inhibitor, blocked clozapine-induced AMPK activation. These results demonstrate that clozapine increases glucose uptake through CaMKK-AMPK pathway in myotube C2C12 cells.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0024-3205 1879-0631
DOI:	10.1016/j.lfs.2010.05.017