title: Dysfunction of dysferlin-deficient hearts.
abstract: Mutations in the gene encoding dysferlin cause limb-girdle muscular dystrophy 2B (LGMD2B), a disorder that is believed to spare the heart. We observed dilated cardiomyopathy in two out of seven LGMD2B patients and cardiac abnormalities in three others. Cardiac biopsies showed that dysferlin was completely absent from the sarcolemma and appeared to be trapped within the cardiomyocytes. SJL/J mice (33-week-old) had diminished end-systolic pressure and reduced dP/dt; however, the hearts were histologically normal. Gene expression profiles of cardiac tissue were obtained and later confirmed by quantitative RT-PCR. Dysferlin-deficient and control mice had different gene expression patterns in terms of cardiomyocyte Z-disc and signal transduction proteins. CapZ, LIM-domain-binding protein 3 (LDB3, MLP), cypher (ZASP), desmin, and the cardiac ankyrin-repeated protein (CARP) were differentially expressed, compared to controls. Mechanical stress induced by the nonselective beta-adrenergic agonist isoproterenol (5 mg/kg body weight) given daily for 10 days resulted in reduced fractional shortening and increased cardiac fibrosis in SJL/J mice as compared to controls. Isoproterenol also caused metalloproteinase-2 upregulation in SJL/J mice. In A/J mice, the effect of isoproterenol injection was even more dramatic and lead to premature death as well as marked sarcolemmal injury as demonstrated by Evans blue dye penetration. Our data suggest that disturbances in dysferlin as well as Z-line proteins and transcription factors particularly under mechanical stress cause cardiomyopathy.
authors.affiliation: Department of Cardiology, Franz Volhard Clinic, Helios Clinic and Campus Virchow Clinic, Charité, Berlin, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Wenzel
authors.forename: Christian
authors.initials: C
authors.lastname: Geier
authors.forename: Fatimunnisa
authors.initials: F
authors.lastname: Qadri
authors.forename: Norbert
authors.initials: N
authors.lastname: Hubner
authors.forename: Herbert
authors.initials: H
authors.lastname: Schulz
authors.forename: Bettina
authors.initials: B
authors.lastname: Erdmann
authors.forename: Volkmar
authors.initials: V
authors.lastname: Gross
authors.forename: David
authors.initials: D
authors.lastname: Bauer
authors.forename: Ralf
authors.initials: R
authors.lastname: Dechend
authors.forename: Rainer
authors.initials: R
authors.lastname: Dietz
authors.forename: Karl Josef
authors.initials: KJ
authors.lastname: Osterziel
authors.forename: Simone
authors.initials: S
authors.lastname: Spuler
authors.forename: Cemil
authors.initials: C
authors.lastname: Ozcelik
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D015153:Blotting, Western; D000073939:Dysferlin; D004452:Echocardiography; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006321:Heart / Q000503:physiopathology*; D006334:Heart Function Tests; D006801:Humans; D007545:Isoproterenol; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency*; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009124:Muscle Proteins / Q000172:deficiency*; D049288:Muscular Dystrophies, Limb-Girdle / Q000235:genetics / Q000503:physiopathology; D009154:Mutation / Q000235:genetics; D009206:Myocardium / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure