Striatin knock out induces a gain of function of I and impaired Ca handling in mESC-derived cardiomyocytes.

Aim: Striatin (Strn) is a scaffold protein expressed in cardiomyocytes (CMs) and alteration of its expression are described in various cardiac diseases. However, the alteration underlying its pathogenicity have been poorly investigated.

Methods: We studied the role(s) of cardiac Strn gene (STRN) by comparing the functional properties of CMs, generated from Strn-KO and isogenic WT mouse embryonic stem cell lines.

Results: The spontaneous beating rate of Strn-KO CMs was faster than WT cells, and this correlated with a larger fast I conductance and no changes in I. Paced (2-8 Hz) Strn-KO CMs showed prolonged action potential (AP) duration in comparison with WT CMs and this was not associated with changes in I and I. Motion video tracking analysis highlighted an altered contraction in Strn-KO CMs; this was associated with a global increase in intracellular Ca, caused by an enhanced late Na current density (I) and a reduced Na/Ca exchanger (NCX) activity and expression. Immunofluorescence analysis confirmed the higher Na channel expression and a more dynamic microtubule network in Strn-KO CMs than in WT. Indeed, incubation of Strn-KO CMs with the microtubule stabilizer taxol, induced a rescue (downregulation) of I conductance toward WT levels.

Conclusion: Loss of STRN alters CMs electrical and contractile profiles and affects cell functionality by a disarrangement of Strn-related multi-protein complexes. This leads to impaired microtubules dynamics and Na channels trafficking to the plasma membrane, causing a global Na and Ca enhancement.