title: Arginylation regulates myofibrils to maintain heart function and prevent dilated cardiomyopathy.
abstract: Protein arginylation mediated by arginyltransferase (ATE1) is essential for heart formation during embryogenesis, however its cell-autonomous role in cardiomyocytes and the differentiated heart muscle has never been investigated. To address this question, we generated cardiac muscle-specific Ate1 knockout mice, in which Ate1 deletion was driven by α-myosin heavy chain promoter (αMHC-Ate1 mouse). These mice were initially viable, but developed severe cardiac contractility defects, dilated cardiomyopathy, and thrombosis over time, resulting in high rates of lethality after 6months of age. These symptoms were accompanied by severe ultrastructural defects in cardiac myofibrils, seen in the newborns and far preceding the onset of cardiomyopathy, suggesting that these defects were primary and likely underlay the development of the future heart defects. Several major sarcomeric proteins were arginylated in vivo. Moreover, Ate1 deletion in the hearts resulted in a significant reduction of active and passive myofibril forces, suggesting that arginylation is critical for both myofibril structural integrity and contractility. Thus, arginylation is essential for maintaining the heart function by regulation of the major myofibril proteins and myofibril forces, and its absence in the heart muscle leads to progressive heart failure through cardiomyocyte-specific defects.
authors.affiliation: Department of Animal Biology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia 19104, USA.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kurosaka
authors.forename: N Adrian
authors.initials: NA
authors.lastname: Leu
authors.forename: Ivan
authors.initials: I
authors.lastname: Pavlov
authors.forename: Xuemei
authors.initials: X
authors.lastname: Han
authors.forename: Paula Aver Bretanha
authors.initials: PA
authors.lastname: Ribeiro
authors.forename: Tao
authors.initials: T
authors.lastname: Xu
authors.forename: Ralph
authors.initials: R
authors.lastname: Bunte
authors.forename: Sougata
authors.initials: S
authors.lastname: Saha
authors.forename: Junling
authors.initials: J
authors.lastname: Wang
authors.forename: Anabelle
authors.initials: A
authors.lastname: Cornachione
authors.forename: Wilfried
authors.initials: W
authors.lastname: Mai
authors.forename: John R
authors.initials: JR
authors.lastname: Yates
authors.forename: Dilson E
authors.initials: DE
authors.lastname: Rassier
authors.forename: Anna
authors.initials: A
authors.lastname: Kashina
mesh_terms: D019881:Aminoacyltransferases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002311:Cardiomyopathy, Dilated / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control; D005804:Genes, Lethal; D006321:Heart / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009200:Myocardial Contraction / Q000235:genetics; D009206:Myocardium / Q000378:metabolism / Q000648:ultrastructure; D009210:Myofibrils / Q000378:metabolism* / Q000502:physiology; D012518:Sarcomeres / Q000378:metabolism
chemical_list: D019881:Aminoacyltransferases; C019727:arginyltransferase