Atrial t-tubules adopt a distinct developmental state as Ca2+ handling matures postnatally

Abstract

Transverse (t)-tubules ensure a uniform rise in cellular Ca²⁺ facilitating cardiac contraction. They play a key role in the large mammalian atria (including human) and their loss in heart failure is associated with impaired Ca²⁺ release. While t-tubule restoration is therefore an ideal therapeutic target, atrial t-tubule development is not well understood. Here we sought to determine how atrial t-tubules develop and the impact on Ca²⁺ handling. Atrial postnatal development was examined in sheep from newborn through to adulthood. T-tubule development was assessed using confocal microscopy and serial block face Scanning Electron Microscopy. Voltage clamp coupled with Ca²⁺ epifluorescence was used to assess concomitant functional changes to Ca²⁺ handling. Atrial t-tubule density increased until 3 months of age when the t-tubule network was disordered. As development continued t-tubules became more ordered but surprisingly the distance of the cell interior to t-tubule membrane increased due to a lack of additional t-tubules coupled with increased cell width. As t-tubules developed, L-type Ca²⁺ current density (I_Ca-L) and sarcoplasmic reticulum (SR) Ca²⁺ content decreased. Although these changes would be expected to decrease Ca²⁺ transient amplitude, Ca²⁺ buffering was simultaneously reduced which our data suggests maintains Ca²⁺ transient amplitude during neonatal development. By understanding how the Ca²⁺ transient is preserved despite drastic changes in t-tubule density and structure during development, this study may provide insights into adaptive mechanisms in Ca²⁺ cycling that mitigate the impact of reduced t-tubule density.

Keywords: Atria; Calcium buffering; Neonatal development; T-tubule.