Electrical defects of the transverse-axial tubular system in cardiac diseases

Electrical excitability is an essential feature of cardiomyocytes and the homogenous propagation of the action potential is guaranteed by a complex network of membrane invaginations called the transverse-axial tubular system (TATS). TATS structural remodelling is a hallmark of cardiac diseases and we demonstrated that this can be accompanied by electrical defects at single T-tubular level. Using a random-access multi-photon (RAMP) microscope, we found that pathological T-tubules can fail to conduct action potentials, which delays local Ca²⁺ release. Although the underlying causes for T-tubular electrical failure are still unknown, our findings suggest that they are likely to be related to local ultrastructural alterations. Here, we first review the experimental approach that allowed us to observe and dissect the consequences of TATS electrical dysfunction and then propose two different strategies to unveil the reasons for T-tubular electrical failures. The first strategy consists in a correlative approach, in which the failing T-tubule identified with the RAMP microscope is then imaged with electron microscopy. The second approach exploits the diffusion of molecules within TATS to gain insights into the local TATS structure, even without a thorough reconstruction of the tubular network. Although challenging, the local electrical failure occurring at single T-tubules is a fundamental question that needs to be addressed and could provide novel insights in cardiac pathophysiology.