Dataset Information

Mammalian ?2 AMPK regulates intrinsic heart rate.

ABSTRACT: AMPK is a conserved serine/threonine kinase whose activity maintains cellular energy homeostasis. Eukaryotic AMPK exists as ??? complexes, whose regulatory ? subunit confers energy sensor function by binding adenine nucleotides. Humans bearing activating mutations in the ?2 subunit exhibit a phenotype including unexplained slowing of heart rate (bradycardia). Here, we show that ?2 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 ?2 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.

SUBMITTER: Yavari A

PROVIDER: S-EPMC5668267 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Mammalian γ2 AMPK regulates intrinsic heart rate.

Yavari Arash A Bellahcene Mohamed M Bucchi Annalisa A Sirenko Syevda S Pinter Katalin K Herring Neil N Jung Julia J JJ Tarasov Kirill V KV Sharpe Emily J EJ Wolfien Markus M Czibik Gabor G Steeples Violetta V Ghaffari Sahar S Nguyen Chinh C Stockenhuber Alexander A Clair Joshua R St JRS Rimmbach Christian C Okamoto Yosuke Y Yang Dongmei D Wang Mingyi M Ziman Bruce D BD Moen Jack M JM Riordon Daniel R DR Ramirez Christopher C Paina Manuel M Lee Joonho J Zhang Jing J Ahmet Ismayil I Matt Michael G MG Tarasova Yelena S YS Baban Dilair D Sahgal Natasha N Lockstone Helen H Puliyadi Rathi R de Bono Joseph J Siggs Owen M OM Gomes John J Muskett Hannah H Maguire Mahon L ML Beglov Youlia Y Kelly Matthew M Dos Santos Pedro P N PPN Bright Nicola J NJ Woods Angela A Gehmlich Katja K Isackson Henrik H Douglas Gillian G Ferguson David J P DJP Schneider Jürgen E JE Tinker Andrew A Wolkenhauer Olaf O Channon Keith M KM Cornall Richard J RJ Sternick Eduardo B EB Paterson David J DJ Redwood Charles S CS Carling David D Proenza Catherine C David Robert R Baruscotti Mirko M DiFrancesco Dario D Lakatta Edward G EG Watkins Hugh H Ashrafian Houman H

Nature communications 20171102 1

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 sarcol ...[more]

PMID: 29097735

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Project description:Background: The time variation between consecutive heartbeats is commonly referred to as heart rate variability (HRV). Loss of complexity in HRV has been documented in several cardiovascular diseases and has been associated with an increase in morbidity and mortality. However, the mechanisms that control HRV are not well understood. Animal experiments are the key to investigating this question. However, to date, there are no standard open source tools for HRV analysis of mammalian electrocardiogram (ECG) data and no centralized public databases for researchers to access. Methods: We created an open source software solution specifically designed for HRV analysis from ECG data of multiple mammals, including humans. We also created a set of public databases of mammalian ECG signals (dog, rabbit and mouse) with manually corrected R-peaks (>170,000 annotations) and signal quality annotations. The platform (software and databases) is called PhysioZoo. Results: PhysioZoo makes it possible to load ECG data and perform very accurate R-peak detection (F 1 > 98%). It also allows the user to manually correct the R-peak locations and annotate low signal quality of the underlying ECG. PhysioZoo implements state of the art HRV measures adapted for different mammals (dogs, rabbits, and mice) and allows easy export of all computed measures together with standard data representation figures. PhysioZoo provides databases and standard ranges for all HRV measures computed on healthy, conscious humans, dogs, rabbits, and mice at rest. Study of these measures across different mammals can provide new insights into the complexity of heart rate dynamics across species. Conclusion: PhysioZoo enables the standardization and reproducibility of HRV analysis in mammalian models through its open source code, freely available software, and open access databases. PhysioZoo will support and enable new investigations in mammalian HRV research. The source code and software are available on www.physiozoo.com.

Dataset Information

Mammalian ?2 AMPK regulates intrinsic heart rate.

Publications

Mammalian γ2 AMPK regulates intrinsic heart rate.

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