Nonmuscle α-Actinin-4 Couples Sarcomere Function to Cardiac Remodeling

作者：James B. Hayes, Dharmendra Choudhary, Dylan Ritter, Abigail C. Neininger, Alaina H. Willet, Leah Caplan, Yu Wang, Xiao Liu, Nilay Taneja, Zachary Sanchez, Kyra Smart, David Armstrong, Cynthia A. Reinhart‐King, Qi Liu, Matthew J. Tyska, Erdem D. Tabdanov, W. David Merryman, Quinn S. Wells, Ela W. Knapik, Dylan T. Burnette · 发表于：Circulation Research · 年份：2025 · DOI：10.1161/circresaha.125.326412 · 被引用次数：3 · 研究领域：Genetics and Physical Performance、Cardiomyopathy and Myosin Studies、Cardiovascular Effects of Exercise

BACKGROUND: Cardiac sarcomeres generate the fundamental forces of each heartbeat. Cardiac myocytes (CMs) express nonmuscle versions of muscle-specific sarcomere proteins, which have unknown relevance to sarcomere function or heart physiology. METHODS: Expression levels of nonmuscle cytoskeletal proteins versus muscle-specific counterparts in CMs were directly compared. Function and subcellular localization of the nonmuscle protein ACTN4 (alpha-actinin-4) in induced pluripotent stem cell–derived CMs were determined using small interfering RNA–mediated knockdown, overexpression, and pharmacological perturbation. Impacts of ACTN4 depletion or knockout on cardiac structure function were evaluated in zebrafish embryos. Left ventricular Actn4 expression was evaluated in a mouse model of chronic pressure overload. Human ACTN4 gene variants were tested for association with heart failure with preserved ejection fraction using the BioVU biobank. A meta-analysis was conducted on ventricular data sets of human cardiomyopathies. RESULTS: ACTN4 expression in human CMs met or exceeded some muscle-specific genes (eg, MYH6 ). Anti-ACTN4 antibodies colocalized with anti-ACTN2 (alpha-actinin-2) at the sarcomere Z-disc in human, mouse, and zebrafish ventricular tissue. Coimmunoprecipitation and structural modeling suggest a Z-disc ACTN4:ACTN2 complex. ACTN4 depletion from induced pluripotent stem cell–derived CMs resulted in increased sarcomere assembly, decreased sarcomere component turnover, e...