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: Michael Gramlich, Beate Michely, Christian Krohne, Arnd Heuser, Bettina Erdmann, Sabine Klaassen, Bryan Hudson, Manuela Magarin, Florian Kirchner, Mihail Todiras, Henk Granzier, Siegfried Labeit, Ludwig Thierfelder, Brenda Gerull
• Journal: Journal of molecular and cellular cardiology (J Mol Cell Cardiol) Vol. 47 Issue 3 Pg. 352-8 (Sep 2009) ISSN: 1095-8584 [Electronic] England
• PMID: 19406126 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Connectin
• Muscle Proteins
• RNA, Messenger
• TTN protein, human
• Protein Kinases

Topics

• Alleles
• Animals
• Cardiomyopathy, Dilated (genetics, pathology)
• Connectin
• Crosses, Genetic
• DNA Mutational Analysis
• Disease Models, Animal
• Heart Failure
• Heterozygote
• Mice
• Models, Genetic
• Muscle Proteins (genetics)
• Mutation
• Phenotype
• Protein Kinases (genetics)
• RNA, Messenger (metabolism)
• Time Factors