Dysfunction of dysferlin-deficient hearts.
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.
Wenzel
Katrin
K
Department of Cardiology, Franz Volhard Clinic, Helios Clinic and Campus Virchow Clinic, Charité, Berlin, Germany.
Geier
Christian
C
Qadri
Fatimunnisa
F
Hubner
Norbert
N
Schulz
Herbert
H
Erdmann
Bettina
B
Gross
Volkmar
V
Bauer
David
D
Dechend
Ralf
R
Dietz
Rainer
R
Osterziel
Karl Josef
KJ
Spuler
Simone
S
Ozcelik
Cemil
C
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