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

BACKGROUND

Transverse (t)-tubules drive the rapid and synchronous Ca rise in cardiac myocytes. The virtual complete atrial t-tubule loss in heart failure (HF) decreases Ca release. It is unknown if or how atrial t-tubules can be restored and how this affects systolic Ca.

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, 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 release in the cell interior. Systolic Ca, , sarcoplasmic reticulum Ca content, and sarcoendoplasmic reticulum Ca 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 transient, the rate of Ca removal, and the peak L-type Ca 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 , sarcoplasmic reticulum Ca content, and systolic Ca. We demonstrate an important role for myotubularin in t-tubule restoration. Our findings reveal a new and viable therapeutic strategy.