(Circulation. 2001;103:2402.)
© 2001 American Heart Association, Inc.
Basic Science Reports |
Mouse Model of Desmin-Related Cardiomyopathy
From the Divisions of Molecular Cardiovascular Biology (X.W., H.O., J.G., J.R.) and Pediatric Cardiology (S.W., T.K.), Children’s Hospital Research Foundation, Cincinnati, Ohio; Departments of Medicine (G.W.D.) and Molecular and Cellular Physiology (M.N., J.N.L.), University of Cincinnati Medical Center, Cincinnati, Ohio; and South Dakota Health Research Foundation–Cardiovascular Research Institute (A.M.G.), Sioux Falls, South Dakota.
Correspondence to Jeffrey Robbins, Division of Molecular Cardiovascular Biology, Children’s Hospital Research Foundation, 3333 Burnet Ave, Cincinnati, OH 45229. E-mail robbj0{at}chmcc.org
Background—The consequence of upregulation of desmin in the heart is unknown. Mutations in desmin have been linked to desmin-related myopathy (DRM), which is characterized by abnormal intrasarcoplasmic accumulation of desmin, but direct causative evidence that a desmin mutation leads to aberrant intrasarcoplasmic desmin accumulation, aggregation, and cardiomyopathy is lacking.
Methods and Results—Multiple transgenic mouse lines that expressed either murine wild-type desmin or a 7–amino acid deletion (R173 through E179) desmin (D7-des) mutation linked to DRM were made. The distribution of desmin protein was unchanged, and no overt phenotype was detected in the wild-type desmin transgenic mice. In contrast, the D7-des mouse heart showed aberrant intrasarcoplasmic and electron-dense granular filamentous aggregates that were desmin-positive and characteristic of human DRM. The desmin filament network was significantly disrupted, and myofibril alignment was visibly compromised. Although systolic function at the whole-organ level was substantially conserved in the young adult animals, the ability of the heart to respond to ß-agonist stimulation, as measured in the intact animal, was significantly blunted.
Conclusions—Upregulation of desmin protein at moderate levels is not detrimental. However, the D7-des mutation is dominant negative, and expression of the mutant protein leads to the appearance of aggregates that are characteristic of and diagnostic for human desmin-related cardiomyopathy.
Key Words: heart diseases • cardiomyopathy • molecular biology • physiology • pathology
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