title: Myofibril degeneration caused by tropomodulin overexpression leads to dilated cardiomyopathy in juvenile mice.
abstract: Loss of myofibril organization is a common feature of chronic dilated and progressive cardiomyopathy. To study how the heart compensates for myofibril degeneration, transgenic mice were created that undergo progressive loss of myofibrils after birth. Myofibril degeneration was induced by overexpression of tropomodulin, a component of the thin filament complex which determines and maintains sarcomeric actin filament length. The tropomodulin cDNA was placed under control of the alpha-myosin heavy chain gene promoter to overexpress tropomodulin specifically in the myocardium. Offspring with the most severe phenotype showed cardiomyopathic changes between 2 and 4 wk after birth. Hearts from these mice present characteristics consistent with dilated cardiomyopathy and a failed hypertrophic response. Histological analysis showed widespread loss of myofibril organization. Confocal microscopy of isolated cardiomyocytes revealed intense tropomodulin immunoreactivity in transgenic mice together with abnormal coincidence of tropomodulin and alpha-actinin reactivity at Z discs. Contractile function was compromised severely as determined by echocardiographic analyses and isolated Langendorff heart preparations. This novel experimentally induced cardiomyopathy will be useful for understanding dilated cardiomyopathy and the effect of thin filament-based myofibril degeneration upon cardiac structure and function.
authors.affiliation: The Children's Hospital and Research Foundation, Cincinnati, Ohio 45229, USA. sussman@heart.chmcc.org
authors.forename: M A
authors.initials: MA
authors.lastname: Sussman
authors.forename: S
authors.initials: S
authors.lastname: Welch
authors.forename: N
authors.initials: N
authors.lastname: Cambon
authors.forename: R
authors.initials: R
authors.lastname: Klevitsky
authors.forename: T E
authors.initials: TE
authors.lastname: Hewett
authors.forename: R
authors.initials: R
authors.lastname: Price
authors.forename: S A
authors.initials: SA
authors.lastname: Witt
authors.forename: T R
authors.initials: TR
authors.lastname: Kimball
mesh_terms: D000818:Animals; D000963:Antimetabolites; D002311:Cardiomyopathy, Dilated / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D015870:Gene Expression; D006439:Hemodynamics / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D008840:Microfilament Proteins; D009200:Myocardial Contraction; D009210:Myofibrils / Q000378:metabolism / Q000473:pathology*; D011441:Propylthiouracil; D051348:Tropomodulin
chemical_list: D000963:Antimetabolites; D002352:Carrier Proteins; D008840:Microfilament Proteins; C495831:Tmod1 protein, mouse; D051348:Tropomodulin; D011441:Propylthiouracil