Post‐Myocardial Infarction T‐tubules Form Enlarged Branched Structures With Dysregulation of Junctophilin‐2 and Bridging Integrator 1 (BIN‐1)

Abstract

Background Heart failure is a common secondary complication following a myocardial infarction ( MI ), characterized by impaired cardiac contraction and t‐tubule (t‐t) loss. However, post‐ MI nano‐scale morphological changes to the remaining t‐ts are poorly understood. Method and Results We utilized a porcine model of MI , using a nonlethal microembolization method to generate controlled microinfarcts. Using serial block face scanning electron microscopy, we report that post‐ MI , after mild left‐ventricular dysfunction has developed, t‐ts are not only lost in the peri‐infarct region, but also the remnant t‐ts form enlarged, highly branched disordered structures, containing a dense intricate inner membrane. Biochemical and proteomics analyses showed that the calcium release channel, ryanodine receptor 2 (RyR2), abundance is unchanged, but junctophilin‐2 ( JP 2), important for maintaining t‐t trajectory, is depressed (−0.5×) in keeping with the t‐ts being disorganized. However, immunolabeling shows that populations of RyR2 and JP 2 remain associated with the remodeled t‐ts. The bridging integrator 1 protein ( BIN ‐1), a regulator of tubulogensis, is upregulated (+5.4×), consistent with an overdeveloped internal membrane system, a feature not present in control t‐ts. Importantly, we have determined that t‐ts, in the remote region, are narrowed and also contain dense membrane folds ( BIN ‐1 is up‐regulated +3.4×), whereas the t‐ts have a radial organization comparable to control JP 2 is upregulated +1.7×. Conclusions This study reveals previously unidentified remodeling of the t‐t nano‐architecture in the post‐ MI heart that extends to the remote region. Our findings highlight that targeting JP 2 may be beneficial for preserving the orientation of the t‐ts, attenuating the development of hypocontractility post‐ MI .