title: Arrhythmia causes lipid accumulation and reduced glucose uptake.
abstract: Atrial fibrillation (AF) is characterized by irregular contractions of atrial cardiomyocytes and increased energy demand. The aim of this study was to characterize the influence of arrhythmia on glucose and fatty acid (FA) metabolism in cardiomyocytes, mice and human left atrial myocardium. Compared to regular pacing, irregular (pseudo-random variation at the same number of contractions/min) pacing of neonatal rat cardiomyocytes induced shorter action potential durations and effective refractory periods and increased diastolic [Ca(2+)]c. This was associated with the activation of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) and AMP-activated protein kinase (AMPK). Membrane expression of fatty acid translocase (FAT/CD36) and (14)C-palmitic acid uptake were augmented while membrane expression of glucose transporter subtype 4 (GLUT-4) as well as (3)H-glucose uptake were reduced. Inhibition of AMPK and CaMKII prevented these arrhythmia-induced metabolic changes. Similar alterations of FA metabolism were observed in a transgenic mouse model (RacET) for spontaneous AF. Consistent with these findings samples of left atrial myocardium of patients with AF compared to matched samples of patients with sinus rhythm showed up-regulation of CaMKII and AMPK and increased membrane expression of FAT/CD36, resulting in lipid accumulation. These changes of FA metabolism were accompanied by decreased membrane expression of GLUT-4, increased glycogen content and increased expression of the pro-apoptotic protein bax. Irregular pacing of cardiomyocytes increases diastolic [Ca(2+)]c and activation of CaMKII and AMPK resulting in lipid accumulation, reduced glucose uptake and increased glycogen synthesis. These metabolic changes are accompanied by an activation of pro-apoptotic signalling pathways.
authors.affiliation: Klinik für Innere Medizin III, Kardiologie, Angiologie und Internistische Intensivmedizin, Universitätsklinikum des Saarlandes, 66421, Homburg, Germany, matthias.lenski@uks.eu.
authors.forename: Matthias
authors.initials: M
authors.lastname: Lenski
authors.forename: Gregor
authors.initials: G
authors.lastname: Schleider
authors.forename: Michael
authors.initials: M
authors.lastname: Kohlhaas
authors.forename: Lucas
authors.initials: L
authors.lastname: Adrian
authors.forename: Oliver
authors.initials: O
authors.lastname: Adam
authors.forename: Qinghai
authors.initials: Q
authors.lastname: Tian
authors.forename: Lars
authors.initials: L
authors.lastname: Kaestner
authors.forename: Peter
authors.initials: P
authors.lastname: Lipp
authors.forename: Michael
authors.initials: M
authors.lastname: Lehrke
authors.forename: Christoph
authors.initials: C
authors.lastname: Maack
authors.forename: Michael
authors.initials: M
authors.lastname: Böhm
authors.forename: Ulrich
authors.initials: U
authors.lastname: Laufs
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000200:Action Potentials; D000368:Aged; D000818:Animals; D001281:Atrial Fibrillation / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D005260:Female; D005947:Glucose / Q000378:metabolism*; D051275:Glucose Transporter Type 4 / Q000502:physiology; D006801:Humans; D050356:Lipid Metabolism; D008297:Male; D008875:Middle Aged; D032383:Myocytes, Cardiac / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction
chemical_list: D051275:Glucose Transporter Type 4; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D055372:AMP-Activated Protein Kinases; D005947:Glucose; D002118:Calcium