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

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 <i>Tbx5</i>-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 <i>Tbx5</i>-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.