The γ2 subunit of AMP-activated protein kinase regulates mammalian heart rate. Mus musculus

AMP-activated protein 1 kinase (AMPK), a phylogenetically conserved serine/threonine kinase regarded as a key cellular energy sensor, exists in eukaryotes as a heterotrimer comprising a catalytic α and regulatory β and γ subunits. In humans, activating mutations in the gene encoding the γ2 subunit of AMPK (PRKAG2) display a cardiac phenotype of left ventricular hypertrophy (LVH), conduction system disease, ventricular pre-excitation and increased cardiomyocyte glycogen accumulation. While existing transgenic models have elucidated the pathogenesis of several aspects of the disease5-7, the slow heart rate (sinus bradycardia) – a prominent feature of the disease – remains poorly understood. Here, using gene-targeting to generate mice which recapitulate this bradycardia, we demonstrate that γ2 AMPK activation perturbs fundamental mechanisms that determine sinoatrial pacemaker cell function. Reduction in the sarcolemmal hyperpolarization activated (“funny”) current (If) and damping of ryanodine receptor-derived diastolic local subsarcolemmal Ca2+ releases (LCRs)12,13 contribute to reduced sinoatrial cell spontaneous activity and, ultimately, to a lower heart rate. Pharmacological activation of AMPK reversibly reduces the beating rate of murine pluripotent stem cell-derived induced sinoatrial bodies. In contrast, using a mouse knock-out of γ2 AMPK, which exhibits an increased heart rate, we demonstrate a role for γ2 AMPK in physiological heart rate regulation, including an indispensable role in the bradycardic adaptation to endurance exercise. Through regulating the cardiac pacemaker and thereby heart rate, γ2 AMPK by virtue of its energy-sensing role, is a key physiological determinant of overall cardiac energy homeostasis. Overall design: Four mouse SAN tissues were pooled from R299Q γ2 and WT littermate controls and processed together for the extraction of one sample of total RNA for a total of 4 homozygote R299Q γ2, 4 heterozygote R299Q γ2 and 3 WT samples.