Atrial AMP-activated protein kinase is critical for prevention of dysregulation of electrical excitability and atrial fibrillation

• Published in: JCI insight Vol. 7; no. 8
• Main Authors: Su, Kevin N, Ma, Yina, Cacheux, Marine, Ilkan, Zeki, Raad, Nour, Muller, Grace K, Wu, Xiaohong, Guerrera, Nicole, Thorn, Stephanie L, Sinusas, Albert J, Foretz, Marc, Viollet, Benoit, Akar, Joseph G, Akar, Fadi G, Young, Lawrence H
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 22.04.2022; American Society for Clinical investigation
• Subjects: AMP-Activated Protein Kinases - metabolism; Animals; Atrial Fibrillation - metabolism; Atrial Remodeling; Biochemistry; Biochemistry, Molecular Biology; Cardiology; Cardiology and cardiovascular system; Connexins - genetics; Connexins - metabolism; Human health and pathology; Ion Channels - genetics; Ion Channels - metabolism; Life Sciences; Mice; Molecular biology; Myocytes, Cardiac - metabolism; Transcription Factors - genetics; Transcription Factors - metabolism; Cardiology; Protein kinases; Arrhythmias
• ISSN: 2379-3708; 2379-3708
• DOI: 10.1172/jci.insight.141213

Metabolic stress is an important cause of pathological atrial remodeling and atrial fibrillation. AMPK is a ubiquitous master metabolic regulator, yet its biological function in the atria is poorly understood in both health and disease. We investigated the impact of atrium-selective cardiac AMPK deletion on electrophysiological and structural remodeling in mice. Loss of atrial AMPK expression caused atrial changes in electrophysiological properties and atrial ectopic activity prior to the onset of spontaneous atrial fibrillation. Concomitant transcriptional downregulation of connexins and atrial ion channel subunits manifested with delayed left atrial activation and repolarization. The early molecular and electrophysiological abnormalities preceded left atrial structural remodeling and interstitial fibrosis. AMPK inactivation induced downregulation of transcription factors (Mef2c and Pitx2c) linked to connexin and ion channel transcriptional reprogramming. Thus, AMPK plays an essential homeostatic role in atria, protecting against adverse remodeling potentially by regulating key transcription factors that control the expression of atrial ion channels and gap junction proteins.