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

Elife. 2019 Mar 21;8:e41814. doi: 10.7554/eLife.41814.

Abstract

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 adult-specific 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 trans-sarcolemmal calcium fluxes, and AF, establishing a mechanism underlying the genetic basis for a Ca2+-dependent pathway for AF risk.

Keywords: SR calcium ATPase; Tbx5; atrial fibrillation; calcium handling; human biology; medicine; molecular biophysics; mouse; sodium-calcium exchanger; structural biology; triggered activity.

Publication types

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

MeSH terms

  • Animals
  • Atrial Fibrillation / physiopathology*
  • Calcium / metabolism*
  • Cations, Divalent / metabolism
  • Cells, Cultured
  • Disease Models, Animal
  • Mice
  • Mutant Proteins / metabolism*
  • Myocytes, Cardiac / pathology
  • Myocytes, Cardiac / physiology
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases / metabolism*
  • T-Box Domain Proteins / deficiency
  • T-Box Domain Proteins / metabolism*

Substances

  • Cations, Divalent
  • Mutant Proteins
  • T-Box Domain Proteins
  • T-box transcription factor 5
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases
  • Atp2a2 protein, mouse
  • Calcium