Stress-induced dilated cardiomyopathy in a knock-in mouse model mimicking human titin-based disease.
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.
Gramlich
Michael
M
Max-Delbrueck Center for Molecular Medicine, Robert-Roessle-Str. 10, 13125 Berlin, Germany.
Michely
Beate
B
Krohne
Christian
C
Heuser
Arnd
A
Erdmann
Bettina
B
Klaassen
Sabine
S
Hudson
Bryan
B
Magarin
Manuela
M
Kirchner
Florian
F
Todiras
Mihail
M
Granzier
Henk
H
Labeit
Siegfried
S
Thierfelder
Ludwig
L
Gerull
Brenda
B
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
D064211:Connectin; D009124:Muscle Proteins; D012333:RNA, Messenger; C577285:TTN protein, human; D011494:Protein Kinases