Mammalian γ2 AMPK Regulates Intrinsic Heart Rate

Nat Commun. 2017 Nov 2;8(1):1258. doi: 10.1038/s41467-017-01342-5.

Abstract

AMPK is a conserved serine/threonine kinase whose activity maintains cellular energy homeostasis. Eukaryotic AMPK exists as αβγ complexes, whose regulatory γ subunit confers energy sensor function by binding adenine nucleotides. Humans bearing activating mutations in the γ2 subunit exhibit a phenotype including unexplained slowing of heart rate (bradycardia). Here, we show that γ2 AMPK activation downregulates fundamental sinoatrial cell pacemaker mechanisms to lower heart rate, including sarcolemmal hyperpolarization-activated current (I f) and ryanodine receptor-derived diastolic local subsarcolemmal Ca2+ release. In contrast, loss of γ2 AMPK induces a reciprocal phenotype of increased heart rate, and prevents the adaptive intrinsic bradycardia of endurance training. Our results reveal that in mammals, for which heart rate is a key determinant of cardiac energy demand, AMPK functions in an organ-specific manner to maintain cardiac energy homeostasis and determines cardiac physiological adaptation to exercise by modulating intrinsic sinoatrial cell behavior.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / genetics*
  • Adult
  • Animals
  • Bradycardia / genetics*
  • Bradycardia / metabolism
  • Calcium / metabolism*
  • Electrocardiography, Ambulatory
  • Exercise
  • Heart / diagnostic imaging
  • Heart Rate / genetics*
  • Humans
  • Magnetic Resonance Imaging, Cine
  • Magnetic Resonance Spectroscopy
  • Mice
  • Microscopy, Electron, Transmission
  • Mutation
  • Myocardium / metabolism
  • Myocardium / pathology
  • Myocardium / ultrastructure
  • Physical Conditioning, Animal
  • Physical Endurance
  • Ryanodine Receptor Calcium Release Channel / metabolism
  • Sarcolemma / metabolism*
  • Sinoatrial Node / metabolism*
  • Sinoatrial Node / pathology

Substances

  • Ryanodine Receptor Calcium Release Channel
  • PRKAG2 protein, human
  • AMP-Activated Protein Kinases
  • Calcium