Myocardial mitochondrial dysfunction in mice lacking adiponectin receptor 1

Abstract

Hypoadiponectinemia is an independent predictor of cardiovascular disease, impairs mitochondrial function in skeletal muscle, and has been linked to the pathogenesis of Type 2 diabetes. In models of Type 2 diabetes, myocardial mitochondrial function is impaired, which is improved by increasing serum adiponectin levels. We aimed to define the roles of adiponectin receptor 1 (AdipoR1) and 2 (AdipoR2) in adiponectin-evoked regulation of mitochondrial function in the heart. In isolated working hearts in mice lacking AdipoR1, myocardial oxygen consumption was increased without a concomitant increase in cardiac work, resulting in reduced cardiac efficiency. Activities of mitochondrial oxidative phosphorylation (OXPHOS) complexes were reduced, accompanied by reduced OXPHOS protein levels, phosphorylation of AMP-activated protein kinase, sirtuin 1 activity, and peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) signaling. Decreased ATP/O ratios suggested myocardial mitochondrial uncoupling in AdipoR1-deficient mice, which was normalized by lowering increased mitochondrial 4-hydroxynonenal levels following treatment with the mitochondria-targeted antioxidant Mn (III) tetrakis (4-benzoic acid) porphyrin. Lack of AdipoR2 did not impair mitochondrial function and coupling in the heart. Thus, lack of AdipoR1 impairs myocardial mitochondrial function and coupling, suggesting that impaired AdipoR1 signaling may contribute to mitochondrial dysfunction and mitochondrial uncoupling in Type 2 diabetic hearts.

The Adiponectin Receptor Agonist AdipoRon Ameliorates Diabetic Nephropathy in a Model of Type 2 Diabetes

“…This is in accordance with previous studies that associate reduced expression of AdipoR1 in the heart muscle to intolerance of ischemic injury 35 and consequent pathologic processes 36 and that reduced activities of mitochondrial oxidative phosphorylation complexes; i.e., of AMPK, and PGC1 signaling contribute to diabetic cardiomyopathy. 37 Results of this study clearly demonstrated that AdipoRon improved high-glucose-induced oxidative stress and lipotoxicity by activating intrarenal AdipoR1/AdipoR2, which in turn activated the intracellular Ca ++ /AMPK/PPARa pathway without affecting serum adiponectin level. Human diabetic kidneys exhibit decreased AdipoR1/AdipoR2, CaMKKb, phosphorylated AMPK, phosphorylated LKB1, and nephrin expression even in the early stages of CKD and show negligible changes in relevant molecular expression with increasing stages of CKD.…”

Adiponectin has a pivotal role in the cardioprotective effect of CP‐3(iv), a selective CD36 azapeptide ligand, after transient coronary artery occlusion in mice

“…Adiponectin was shown to attenuate vascular and myocardial oxidative stress by inhibiting NADPH oxidase‐derived superoxide anion in mice subjected to 30 min of transient myocardial ischemia (30). Evidence of ROS‐induced decrease in mitochondrial coupling efficiency and the presence of dysfunctional oxidative phosphorylation complexes were shown in isolated hearts from AdipoR1 –/– mice (41). In light of those observations, we investigated the effect of CP‐3(iv) pretreatment in reducing NADPH‐stimulated ROS production in LV homogenates after 6 h of reperfusion (Fig.…”

Dysregulation of the Mitochondrial Proteome Occurs in Mice Lacking Adiponectin Receptor 1

“…Male mice with global deficiency of AdipoR1 (Adipor1 −/− ) and respective C57BL/6J wildtype (WT) littermate controls were investigated at 8 weeks of age, as described previously (6). Mice were housed in individually-ventilated cages with 12 h daylight/dark cycles at 22 • C and were fed a laboratory standard chow and had free access to water.…”

“…Its role in regulating glucose homeostasis therefore suggests that the observed decrease in serum levels of adiponectin in non-insulin dependent (type 2) diabetes mellitus (NIDDM) is involved in the pathogenesis of insulin resistance and ultimately NIDDM (2,3). Impaired adiponectin activity has also been implicated in the development of end-organ diabetic complications including diabetic cardiomyopathy, nephropathy and non-alcoholic steatohepatitis (4)(5)(6). Maintaining or restoring intact adiponectin signaling is therefore a promising therapeutic strategy to attenuate these diabetic complications (7).…”

“…A common physiological intersection among these cascades is the regulation of mitochondrial function either by directly regulating substrate oxidation through modulation of enzymatic activity, or by controlling the gene expression of mitochondrial proteins via recruitment of PPARγ coactivator-1α (PGC-1α) (9,11,12). Both in skeletal and cardiac muscles, deletion of AdipoR1 in mice impairs mitochondrial function, decreases gene expression of oxidative phosphorylation (OXPHOS) subunits, induces mitochondrial oxidative stress and decreases mitochondrial content, again mediated by disruptions in AMPK/SIRT1/PGC-1α signaling (6,9).…”