Stress-induced dilated cardiomyopathy in a knock-in mouse model mimicking human titin-based disease

Michael Gramlich, Beate Michely, Christian Krohne, Arnd Heuser, Bettina Erdmann, Sabine Klaassen, Bryan Hudson, Manuela Magarin, Florian Kirchner, Mihail Todiras, Hendrikus "Henk" Granzier, Siegfried Labeit, Ludwig Thierfelder, Brenda Gerull

Research output: Contribution to journalArticle

50 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)352-358
Number of pages7
JournalJournal of Molecular and Cellular Cardiology
Volume47
Issue number3
DOIs
StatePublished - Sep 2009

Fingerprint

Connectin
Dilated Cardiomyopathy
Mutation
Alleles
Messenger RNA
Sarcomeres
Penetrance
Insertional Mutagenesis
Mechanics
Isoproterenol
Angiotensin II
Dilatation
Fibrosis
Up-Regulation
Embryonic Structures
Muscles
Genes
Proteins

Keywords

  • Cardiomyopathy
  • Development
  • Genetics
  • Heart failure
  • Mouse model
  • Pathogenesis
  • Sarcomere formation
  • Titin

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

Cite this

Stress-induced dilated cardiomyopathy in a knock-in mouse model mimicking human titin-based disease. / Gramlich, Michael; Michely, Beate; Krohne, Christian; Heuser, Arnd; Erdmann, Bettina; Klaassen, Sabine; Hudson, Bryan; Magarin, Manuela; Kirchner, Florian; Todiras, Mihail; Granzier, Hendrikus "Henk"; Labeit, Siegfried; Thierfelder, Ludwig; Gerull, Brenda.

In: Journal of Molecular and Cellular Cardiology, Vol. 47, No. 3, 09.2009, p. 352-358.

Research output: Contribution to journalArticle

Gramlich, M, Michely, B, Krohne, C, Heuser, A, Erdmann, B, Klaassen, S, Hudson, B, Magarin, M, Kirchner, F, Todiras, M, Granzier, HH, Labeit, S, Thierfelder, L & Gerull, B 2009, 'Stress-induced dilated cardiomyopathy in a knock-in mouse model mimicking human titin-based disease', Journal of Molecular and Cellular Cardiology, vol. 47, no. 3, pp. 352-358. https://doi.org/10.1016/j.yjmcc.2009.04.014
Gramlich, Michael ; Michely, Beate ; Krohne, Christian ; Heuser, Arnd ; Erdmann, Bettina ; Klaassen, Sabine ; Hudson, Bryan ; Magarin, Manuela ; Kirchner, Florian ; Todiras, Mihail ; Granzier, Hendrikus "Henk" ; Labeit, Siegfried ; Thierfelder, Ludwig ; Gerull, Brenda. / Stress-induced dilated cardiomyopathy in a knock-in mouse model mimicking human titin-based disease. In: Journal of Molecular and Cellular Cardiology. 2009 ; Vol. 47, No. 3. pp. 352-358.
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