High fat diet induces change in mitochondria respiration, activation of K-ATP channel and action potential shortening in mice

Abstract

Obesity is associated with an increased risk of atrial fibrillation (AF). This epidemiologic observation may not be only due to shared co-morbidities but also from direct impacts of metabolic disorders on myocardium. To examine the impact of high fat diet (HFD) induced obesity on electrical properties in mice atria. Eight weeks old C57Bl/6 J mice were subjected to 4 months of HFD (60% fat) or normal diet (ND, 4% fat). Rapid burst atrial pacing were delivered using a trans-esophageal probe to induced AF in anesthetized animals. Action potential (AP) were recorded in left atrium using glass microelectrode technique. Potassium currents were recorded in isolated atrial myocytes using whole cell or perforated patch-clamp configurations. Mitochondrial respiration was studied in saponin-permeabilized atrial muscle fibers using a Clarke electrode. HFD mice showed higher atrial vulnerability to AF as indicated by longer AF episodes. APs were shorter in HFD versus ND mice (AP duration measured at 90% of repolarization: 49.3 ± 1.6 msec in HFD vs. 56.7 ± 2.3 msec in ND, P < 0.01). Glibenclamide, a KATP channel blocker, reversed AP shortening whereas cromakalim, a KATP channel activator, had no effect. Only in perforated patch-clamp configuration, without intracellular dialysis, KATP component of potassium current was enhanced in HFD mice (at +70 mV: 0.41 ± 0.12 pA/pF in HFD vs. 0.13 ± 0.08 pA/pF in ND, P < 0.05). There was no change in mitochondria respiration capacity between ND and HFD, however the ability of palmitoyl-CoA to support mitochondrial respiration was higher in HFD (25.99 ± 4.11% vs. 46.9 ± 3.96% in ND, P = 0.001). In addition, HADHA activity was enhanced in HFD mice. Obesity in mice is associated with atrial AP shortening which appears to result from increased activity of KATP-regulated currents and be associated with a metabolic shift. Shortening of AP duration could contribute to higher vulnerability to AF during obesity.