Restoring Atrial T-Tubules Augments Systolic Ca Upon Recovery From Heart Failure.

Background: Transverse (t)-tubules drive the rapid and synchronous Ca ²⁺ rise in cardiac myocytes. The virtual complete atrial t-tubule loss in heart failure (HF) decreases Ca ²⁺ release. It is unknown if or how atrial t-tubules can be restored and how this affects systolic Ca ²⁺ .
Methods: HF was induced in sheep by rapid ventricular pacing and recovered following termination of rapid pacing. Serial block-face scanning electron microscopy and confocal imaging were used to study t-tubule ultrastructure. Function was assessed using patch clamp, Ca ²⁺ , and confocal imaging. Candidate proteins involved in atrial t-tubule recovery were identified by western blot and expressed in rat neonatal ventricular myocytes to determine if they altered t-tubule structure.
Results: Atrial t-tubules were lost in HF but reappeared following recovery from HF. Recovered t-tubules were disordered, adopting distinct morphologies with increased t-tubule length and branching. T-tubule disorder was associated with mitochondrial disorder. Recovered t-tubules were functional, triggering Ca ²⁺ release in the cell interior. Systolic Ca ²⁺ , I _Ca-L , sarcoplasmic reticulum Ca ²⁺ content, and sarcoendoplasmic reticulum Ca ²⁺ ATPase function were restored following recovery from HF. Confocal microscopy showed fragmentation of ryanodine receptor staining and movement away from the z-line in HF, which was reversed following recovery from HF. Acute detubulation, to remove recovered t-tubules, confirmed their key role in restoration of the systolic Ca ²⁺ transient, the rate of Ca ²⁺ removal, and the peak L-type Ca ²⁺ current. The abundance of telethonin and myotubularin decreased during HF and increased during recovery. Transfection with these proteins altered the density and structure of tubules in neonatal myocytes. Myotubularin had a greater effect, increasing tubule length and branching, replicating that seen in the recovery atria.
Conclusions: We show that recovery from HF restores atrial t-tubules, and this promotes recovery of I _Ca-L , sarcoplasmic reticulum Ca ²⁺ content, and systolic Ca ²⁺ . We demonstrate an important role for myotubularin in t-tubule restoration. Our findings reveal a new and viable therapeutic strategy.
Competing Interests: None.