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.
Original language | English |
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Article number | 1258 |
Journal | Nature Communications |
Volume | 8 |
Issue number | 1 |
DOIs | |
Publication status | Published - 2 Nov 2017 |
Keywords
- AMP-Activated Protein Kinases/genetics
- Adult
- Animals
- Bradycardia/genetics
- 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
- Physical Conditioning, Animal
- Physical Endurance
- Ryanodine Receptor Calcium Release Channel/metabolism
- Sarcolemma/metabolism
- Sinoatrial Node/metabolism