title: Stress-induced dilated cardiomyopathy in a knock-in mouse model mimicking human titin-based disease.
abstract: Mutations in a variety of myofibrillar genes cause dilated cardiomyopathy (DCM) in humans, usually with dominant inheritance and incomplete penetrance. Here, we sought to clarify the functional effects of the previously identified DCM-causing TTN 2-bp insertion mutation (c.43628insAT) and generated a titin knock-in mouse model mimicking the c.43628insAT allele. Mutant embryos homozygous for the Ttn knock-in mutation developed defects in sarcomere formation and consequently died before E9.5. Heterozygous mice were viable and demonstrated normal cardiac morphology, function and muscle mechanics. mRNA and protein expression studies on heterozygous hearts demonstrated elevated wild-type titin mRNA under resting conditions, suggesting that up-regulation of the wild-type titin allele compensates for the unstable mutated titin under these conditions. When chronically exposed to angiotensin II or isoproterenol, heterozygous mice developed marked left ventricular dilatation (p<0.05) with impaired fractional shortening (p<0.001) and diffuse myocardial fibrosis (11.95+/-2.8% vs. 3.7+/-1.1%). Thus, this model mimics typical features of human dilated cardiomyopathy and may further our understanding of how titin mutations perturb cardiac function and remodel the heart.
authors.affiliation: Max-Delbrueck Center for Molecular Medicine, Robert-Roessle-Str. 10, 13125 Berlin, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Gramlich
authors.forename: Beate
authors.initials: B
authors.lastname: Michely
authors.forename: Christian
authors.initials: C
authors.lastname: Krohne
authors.forename: Arnd
authors.initials: A
authors.lastname: Heuser
authors.forename: Bettina
authors.initials: B
authors.lastname: Erdmann
authors.forename: Sabine
authors.initials: S
authors.lastname: Klaassen
authors.forename: Bryan
authors.initials: B
authors.lastname: Hudson
authors.forename: Manuela
authors.initials: M
authors.lastname: Magarin
authors.forename: Florian
authors.initials: F
authors.lastname: Kirchner
authors.forename: Mihail
authors.initials: M
authors.lastname: Todiras
authors.forename: Henk
authors.initials: H
authors.lastname: Granzier
authors.forename: Siegfried
authors.initials: S
authors.lastname: Labeit
authors.forename: Ludwig
authors.initials: L
authors.lastname: Thierfelder
authors.forename: Brenda
authors.initials: B
authors.lastname: Gerull
mesh_terms: D000483:Alleles; D000818:Animals; D002311:Cardiomyopathy, Dilated / Q000235:genetics* / Q000473:pathology*; D064211:Connectin; D003433:Crosses, Genetic; D004252:DNA Mutational Analysis; D004195:Disease Models, Animal; D006333:Heart Failure; D006579:Heterozygote; D051379:Mice; D008957:Models, Genetic; D009124:Muscle Proteins / Q000235:genetics*; D009154:Mutation; D010641:Phenotype; D011494:Protein Kinases / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors
chemical_list: D064211:Connectin; D009124:Muscle Proteins; D012333:RNA, Messenger; C577285:TTN protein, human; D011494:Protein Kinases