Authors: Taghli-Lamallem O; Akasaka T; Hogg G; Nudel U; Yaffe D; Chamberlain JS; Ocorr K; Bodmer R
Abstract: A number of studies have been conducted recently on the model organism Drosophila to determine the function of genes involved in human disease, including those implicated in neurological disorders, cancer and metabolic and cardiovascular diseases. The simple structure and physiology of the Drosophila heart tube together with the available genetics provide a suitable in vivo assay system for studying cardiac gene functions. In our study, we focus on analysis of the role of dystrophin (Dys) in heart physiology. As in humans, the Drosophila dys gene encodes multiple isoforms, of which the large isoforms (DLPs) and a truncated form (Dp117) are expressed in the adult heart. Here, we show that the loss of dys function in the heart leads to an age-dependent disruption of the myofibrillar organization within the myocardium as well as to alterations in cardiac performance. dys RNAi-mediated knockdown in the mesoderm also shortens lifespan. Knockdown of all or deletion of the large isoforms increases the heart rate by shortening the diastolic intervals (relaxation phase) of the cardiac cycle. Morphologically, loss of the large DLPs isoforms causes a widening of the cardiac tube and a lower fractional shortening, a phenotype reminiscent of dilated cardiomyopathy. The dilated dys mutant phenotype was reversed by expressing a truncated mammalian form of dys (Dp116). Our results illustrate the utility of Drosophila as a model system to study dilated cardiomyopathy and other muscular-dystrophy-associated phenotypes.
Keywords: Age Factors; Animals; Cardiomyopathy, Dilated/genetics/*mortality/*physiopathology; Disease Models, Animal; Drosophila/embryology/genetics/*metabolism; Drosophila Proteins/analysis/genetics/metabolism; Dystrophin/*deficiency/genetics; Heart Defects, Congenital/mortality/pathology/physiopathology; Heart Rate; *Longevity/genetics; Muscular Dystrophy, Animal/congenital/pathology/physiopathology; Myocardial Contraction; Myocytes, Cardiac/pathology; Myofibrils/genetics/pathology; Phenotype; Protein Isoforms; Sequence Deletion|
Journal: Aging cell Volume: 7 Issue: 2 Pages: 237-49 Date: Jan. 29, 2008 PMID: 18221418 |
Taghli-Lamallem O, Akasaka T, Hogg G, Nudel U, Yaffe D, Chamberlain JS, Ocorr K, Bodmer R (2008) Dystrophin deficiency in Drosophila reduces lifespan and causes a dilated cardiomyopathy phenotype. Aging cell 7: 237-49.
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