Biological Sciences Division
Published March 21, 2019 | Version v1
Journal article Open

A calcium transport mechanism for atrial fibrillation in Tbx5-mutant mice

Creators

  • 1. University of Chicago
  • 2. University of Wisconsin-Madison
  • 3. https://orcid.org/0000-0003-0552-9029

Description

Risk for Atrial Fibrillation (AF), the most common human arrhythmia, has a major genetic component. The T-box transcription factor TBX5 influences human AF risk, and adultspecific Tbx5-mutant mice demonstrate spontaneous AF. We report that TBX5 is critical for cellular Ca2+ homeostasis, providing a molecular mechanism underlying the genetic implication of TBX5 in AF. We show that cardiomyocyte action potential (AP) abnormalities in Tbx5-deficient atrial cardiomyocytes are caused by a decreased sarcoplasmic reticulum (SR) Ca2+ ATPase (SERCA2)- mediated SR calcium uptake which was balanced by enhanced trans-sarcolemmal calcium fluxes (calcium current and sodium/calcium exchanger), providing mechanisms for triggered activity. The AP defects, cardiomyocyte ectopy, and AF caused by TBX5 deficiency were rescued by phospholamban removal, which normalized SERCA function. These results directly link transcriptional control of SERCA2 activity, depressed SR Ca2+ sequestration, enhanced transsarcolemmal calcium fluxes, and AF, establishing a mechanism underlying the genetic basis for a Ca2+-dependent pathway for AF risk.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files.

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Additional details

Identifiers

DOI
10.7554/eLife.41814
Other
oai:uchicago.tind.io:9954

Funding

National Institutes of Health
HL126509
American Heart Association
Collaborative Sciences Award
National Institutes of Health
T32HL007381
National Institutes of Health
HL114010
National Institutes of Health
R33 HL123857
National Institutes of Health
T32GM007281

UChicago Information

Division(s)
Biological Sciences Division
Department(s)
Human Genetics, Neurological Surgery, Pathology, Pediatrics, Surgery