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In this study, we sought to investigate the effects of an ACTN2 missense variant of unknown significance (p.A868T) on cardiac muscle structure and function. Left ventricular free wall samples were obtained at the time of cardiac transplantation from a heart failure patient with the ACTN2 A868T heterozygous variant. This variant is in the EF 3\u20134 domain known to interact with titin and \u03b1-actinin. At the ultrastructural level, ACTN2 A868T cardiac samples presented small structural changes in cardiomyocytes when compared to healthy donor samples. However, contractile mechanics of permeabilized ACTN2 A868T variant cardiac tissue displayed higher myofilament Ca2+ sensitivity of isometric force, reduced sinusoidal stiffness, and faster rates of tension redevelopment at all Ca2+ levels. Small-angle X-ray diffraction indicated increased separation between thick and thin filaments, possibly contributing to changes in muscle kinetics. Molecular dynamics simulations indicated that while the mutation does not significantly impact the structure of \u03b1-actinin on its own, it likely alters the conformation associated with titin binding. Our results can be explained by two Z-disc mediated communication pathways: one pathway that involves \u03b1-actinin\u2019s interaction with actin, affecting thin filament regulation, and the other pathway that involves \u03b1-actinin\u2019s interaction with titin, affecting thick filament activation. This work establishes the role of \u03b1-actinin 2 in modulating cross-bridge kinetics and force development in the human myocardium as well as how it can be involved in the development of cardiac disease.<\/jats:p>","DOI":"10.3390\/ijms241914572","type":"journal-article","created":{"date-parts":[[2023,9,26]],"date-time":"2023-09-26T08:55:01Z","timestamp":1695718501000},"page":"14572","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Disruption of Z-Disc Function Promotes Mechanical Dysfunction in Human Myocardium: Evidence for a Dual Myofilament Modulatory Role by Alpha-Actinin 2"],"prefix":"10.3390","volume":"24","author":[{"given":"Michelle","family":"Rodriguez Garcia","sequence":"first","affiliation":[{"name":"Biomedical Sciences, Florida State University, Tallahassee, FL 32306, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9437-5871","authenticated-orcid":false,"given":"Jeffrey","family":"Schmeckpeper","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6696-8888","authenticated-orcid":false,"given":"Maicon","family":"Landim-Vieira","sequence":"additional","affiliation":[{"name":"Biomedical Sciences, Florida State University, Tallahassee, FL 32306, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9706-9319","authenticated-orcid":false,"given":"Isabella Leite","family":"Coscarella","sequence":"additional","affiliation":[{"name":"Biomedical Sciences, Florida State University, Tallahassee, FL 32306, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6394-4015","authenticated-orcid":false,"given":"Xuan","family":"Fang","sequence":"additional","affiliation":[{"name":"Department of Cell & Molecular Physiology, Loyola University, Chicago, IL 60660, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9535-7114","authenticated-orcid":false,"given":"Weikang","family":"Ma","sequence":"additional","affiliation":[{"name":"BioCAT, Department of Biological Sciences, Illinois Institute of Technology, Chicago, IL 60616, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Payton A.","family":"Spran","sequence":"additional","affiliation":[{"name":"Department of Biological Science, Florida State University, Tallahassee, FL 32306, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shengyao","family":"Yuan","sequence":"additional","affiliation":[{"name":"BioCAT, Department of Biological Sciences, Illinois Institute of Technology, Chicago, IL 60616, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Qi","sequence":"additional","affiliation":[{"name":"BioCAT, Department of Biological Sciences, Illinois Institute of Technology, Chicago, IL 60616, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6319-9614","authenticated-orcid":false,"given":"Aida Rahimi","family":"Kahmini","sequence":"additional","affiliation":[{"name":"Department of Nutrition and Integrative Physiology, Florida State University, Tallahassee, FL 32306, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. Benjamin","family":"Shoemaker","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James B.","family":"Atkinson","sequence":"additional","affiliation":[{"name":"Department of Pathology, Vanderbilt University Medical Center, Nashville, TN 37232, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter M.","family":"Kekenes-Huskey","sequence":"additional","affiliation":[{"name":"Department of Cell & Molecular Physiology, Loyola University, Chicago, IL 60660, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4848-3323","authenticated-orcid":false,"given":"Thomas C.","family":"Irving","sequence":"additional","affiliation":[{"name":"BioCAT, Department of Biological Sciences, Illinois Institute of Technology, Chicago, IL 60616, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9701-561X","authenticated-orcid":false,"given":"Prescott Bryant","family":"Chase","sequence":"additional","affiliation":[{"name":"Department of Biological Science, Florida State University, Tallahassee, FL 32306, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bj\u00f6rn C.","family":"Knollmann","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9092-4976","authenticated-orcid":false,"given":"Jose Renato","family":"Pinto","sequence":"additional","affiliation":[{"name":"Biomedical Sciences, Florida State University, Tallahassee, FL 32306, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,9,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2688","DOI":"10.1007\/s00018-008-8080-8","article-title":"Alpha-actinin structure and regulation","volume":"65","author":"Sjoblom","year":"2008","journal-title":"Cell. 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