PMID- 28473402 OWN - NLM STAT- MEDLINE DCOM- 20180306 LR - 20240221 IS - 2047-9980 (Electronic) IS - 2047-9980 (Linking) VI - 6 IP - 5 DP - 2017 May 4 TI - Post-Myocardial Infarction T-tubules Form Enlarged Branched Structures With Dysregulation of Junctophilin-2 and Bridging Integrator 1 (BIN-1). LID - 10.1161/JAHA.116.004834 [doi] LID - e004834 AB - 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 (JP2), important for maintaining t-t trajectory, is depressed (-0.5x) in keeping with the t-ts being disorganized. However, immunolabeling shows that populations of RyR2 and JP2 remain associated with the remodeled t-ts. The bridging integrator 1 protein (BIN-1), a regulator of tubulogensis, is upregulated (+5.4x), 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 +3.4x), whereas the t-ts have a radial organization comparable to control JP2 is upregulated +1.7x. 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 JP2 may be beneficial for preserving the orientation of the t-ts, attenuating the development of hypocontractility post-MI. CI - (c) 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley. FAU - Pinali, Christian AU - Pinali C AD - Division of Cardiovascular Sciences, Faculty of Biology, Medicine and Health, University of Manchester, United Kingdom. FAU - Malik, Nadim AU - Malik N AD - Division of Cardiovascular Sciences, Faculty of Biology, Medicine and Health, University of Manchester, United Kingdom. FAU - Davenport, J Bernard AU - Davenport JB AD - Division of Cardiovascular Sciences, Faculty of Biology, Medicine and Health, University of Manchester, United Kingdom. FAU - Allan, Laurence J AU - Allan LJ AD - Division of Cardiovascular Sciences, Faculty of Biology, Medicine and Health, University of Manchester, United Kingdom. FAU - Murfitt, Lucy AU - Murfitt L AD - Division of Cardiovascular Sciences, Faculty of Biology, Medicine and Health, University of Manchester, United Kingdom. FAU - Iqbal, Mohammad M AU - Iqbal MM AD - Division of Cardiovascular Sciences, Faculty of Biology, Medicine and Health, University of Manchester, United Kingdom. FAU - Boyett, Mark R AU - Boyett MR AD - Division of Cardiovascular Sciences, Faculty of Biology, Medicine and Health, University of Manchester, United Kingdom. FAU - Wright, Elizabeth J AU - Wright EJ AD - Division of Cardiovascular Sciences, Faculty of Biology, Medicine and Health, University of Manchester, United Kingdom. FAU - Walker, Rachel AU - Walker R AD - Division of Cardiovascular Sciences, Faculty of Biology, Medicine and Health, University of Manchester, United Kingdom. FAU - Zhang, Yu AU - Zhang Y AD - Division of Cardiovascular Sciences, Faculty of Biology, Medicine and Health, University of Manchester, United Kingdom. FAU - Dobryznski, Halina AU - Dobryznski H AD - Division of Cardiovascular Sciences, Faculty of Biology, Medicine and Health, University of Manchester, United Kingdom. FAU - Holt, Cathy M AU - Holt CM AD - Division of Cardiovascular Sciences, Faculty of Biology, Medicine and Health, University of Manchester, United Kingdom. FAU - Kitmitto, Ashraf AU - Kitmitto A AD - Division of Cardiovascular Sciences, Faculty of Biology, Medicine and Health, University of Manchester, United Kingdom ashraf.kitmitto@manchester.ac.uk. LA - eng GR - RG/11/2/28701/BHF_/British Heart Foundation/United Kingdom PT - Journal Article DEP - 20170504 PL - England TA - J Am Heart Assoc JT - Journal of the American Heart Association JID - 101580524 RN - 0 (Adaptor Proteins, Signal Transducing) RN - 0 (Membrane Proteins) RN - 0 (Ryanodine Receptor Calcium Release Channel) RN - 0 (junctophilin) SB - IM MH - Adaptor Proteins, Signal Transducing/*metabolism MH - Animals MH - Disease Models, Animal MH - Heart Failure/etiology/metabolism/pathology/physiopathology MH - Membrane Proteins/*metabolism MH - Myocardial Contraction MH - Myocardial Infarction/complications/*metabolism/pathology/physiopathology MH - Myocardium/*metabolism/ultrastructure MH - Ryanodine Receptor Calcium Release Channel/metabolism MH - Sarcolemma/*metabolism/ultrastructure MH - Sus scrofa MH - Ventricular Dysfunction, Left/etiology/metabolism/pathology/physiopathology MH - *Ventricular Function, Left MH - *Ventricular Remodeling PMC - PMC5524063 OTO - NOTNLM OT - 3D electron microscopy OT - Eps 15 homology domain protein OT - bridging integrator 1 protein OT - heart failure OT - junctophilin-2 OT - myocardial infarction OT - transverse-tubules EDAT- 2017/05/06 06:00 MHDA- 2018/03/07 06:00 PMCR- 2017/05/01 CRDT- 2017/05/06 06:00 PHST- 2017/05/06 06:00 [entrez] PHST- 2017/05/06 06:00 [pubmed] PHST- 2018/03/07 06:00 [medline] PHST- 2017/05/01 00:00 [pmc-release] AID - JAHA.116.004834 [pii] AID - JAH32072 [pii] AID - 10.1161/JAHA.116.004834 [doi] PST - epublish SO - J Am Heart Assoc. 2017 May 4;6(5):e004834. doi: 10.1161/JAHA.116.004834.