Journal
JOURNAL OF CELL BIOLOGY
Volume 181, Issue 5, Pages 761-775Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.200710049
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Funding
- NHLBI NIH HHS [R01 HL073017, P50 HL-O6H, R01 HL58081, R01 HL73017, R01 HL058081] Funding Source: Medline
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We explored the involvement of the muscle-specific intermediate. lament protein desmin in the model of tumor necrosis factor alpha (TNF-alpha) induced cardiomyopathy. We demonstrate that in mice overexpressing TNF-alpha in the heart (alpha-myosin heavy chain promoter-driven secretable TNF-alpha [MHCsTNF]), desmin is modified, loses its intercalated disk (ID) localization, and forms aggregates that colocalize with heat shock protein 25 and ubiquitin. Additionally, other ID proteins such as desmoplakin and beta-catenin show similar localization changes in a desmin-dependent fashion. To address underlying mechanisms, we examined whether desmin is a substrate for caspase-6 in vivo as well as the implications of desmin cleavage in MHCsTNF mice. We generated transgenic mice with cardiac-restricted expression of a desmin mutant (D263E) and proved that it is resistant to caspase cleavage in the MHCsTNF myocardium. The aggregates are diminished in these mice, and D263E desmin, desmoplakin, and beta-catenin largely retain their proper ID localization. Importantly, D263E desmin expression attenuated cardiomyocyte apoptosis, prevented left ventricular wall thinning, and improved the function of MHCsTNF hearts.
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