Submitted on July 25, 2007
Accepted on March 26, 2008
Metabolic Actions of Metformin in the Heart Can Occur by AMPK-independent Mechanisms
Ramesh Saeedi1, Hannah L Parsons2, Richard B Wambolt3, Kim Paulson1, Vijay Sharma1, Jason R. B. Dyck4, Roger W Brownsey5, and Michael F. Allard6*
1 Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada
2 Pathology, UBC, Vancouver, Canada
3 Pathology & Laboratory Medicine, UBC / St Paul's Hospital, Vancouver, Canada
4 Pediatrics, University of Alberta, Edmonton, Canada
5 Biochemistry and Molecular Biology, University of British Columbia, Vancouver, Canada
6 McDonald Research Laboratories/iCAPTURE Centre, University of British Columbia, Vancouver,, Canada
* To whom correspondence should be addressed. E-mail: mallard{at}mrl.ubc.ca.
The metabolic actions of the anti-diabetic agent, metformin, reportedly occur via activation of AMP-activated protein kinase (AMPK) in the heart and other tissues, in the presence or absence of changes in cellular energy status. In this study, we tested the hypothesis that metformin activates AMPK and alters metabolism in heart muscle without alterations in energy status. Fatty acid oxidation and glucose utilization (glycolysis and glucose uptake) were measured in isolated working hearts from halothane -anesthetized male Sprague-Dawley rats and in cultured heart-derived H9c2 cells in the absence or in the presence of metformin (2mM). Fatty acid oxidation and glucose utilization were significantly altered by metformin in hearts and H9c2 cells. AMPK activity was not measurably altered by metformin in either model system and no impairment of energetic state was observed in the intact hearts. Further, inhibition of AMPK by Compound C, a well recognized pharmacological inhibitor of AMPK, or overexpression of a dominant negative form of AMPK failed to prevent the metabolic actions of metformin in H9c2 cells. Exposure of H9c2 cells to inhibitors of p38 mitogen activated protein kinase (p38 MAPK) or protein kinase C (PKC), partially or completely abrogated metformin-induced alterations in metabolism in these cells, respectively. Thus, the metabolic actions of metformin in heart muscle can occur independent of changes in AMPK activity and may be mediated by p38 MAPK- and PKC-dependent mechanisms.
