Abstract 14779: Lack of Adiponectin Receptor 1 Impairs Mitochondrial Function in the Heart
In Type 2 diabetic rodent models, myocardial mitochondrial dysfunction and downregulation of electron transport chain (ETC) proteins is associated with reduced expression of adiponectin receptors, the myocardial function of which is poorly understood. In skeletal muscle, lack of adiponectin receptor 1 impairs mitochondrial respiratory function by suppressing mitochondrial biogenic signaling via PGC-1alpha. Thus, we hypothesized that reduced myocardial expression of adiponectin receptors may contribute to the pathogenesis of mitochondrial dysfunction in diabetic hearts. To this end, 10 week-old mice lacking adiponectin receptor 1 (AdipoR1-KO) or 2 (AdipoR2-KO) were investigated. In AdipoR1-KO, mitochondrial respiratory capacity of skinned myocardial fibers (16.3±0.6 vs. 18.8±0.5 nmolO2/min/mg;p<0.05) and enzymatic activity of mitochondrial ETC complexes (complex I -29%; complex II -25%, complex IV -20%; all p<0.05) was reduced compared to wildtypes. This functional impairment was accompanied by a significant decrease in AMPK phosphorylation (-21%), SIRT 1 activity (-11%), PGC-1alpha protein expression (-20 %), and expression of ETC subunits on the mRNA (COX 5b -26%, COX II -57%, SDH1 -41%) and protein level (complex II -41%, complex IV -29%) in AdipoR1-KO. Electron microscopy analysis revealed an 11% decrease in myocardial mitochondrial volume density in AdipoR1-KO. In contrast, hearts of AdipoR2-KO showed no decrease in ETC complex activities, AMPK phosphorylation, SIRT1 activity, PGC-1alpha expression and ETC subunit expression. Thus, lack of adiponectin receptor 1 but not adiponectin receptor 2 impairs mitochondrial function in the heart, at least in part due to impaired AMPK/SIRT1/PGC-1alpha signaling. Adiponectin receptors regulate, at least in part, distinct signaling pathways in the heart.
- © 2012 by American Heart Association, Inc.