The Absence of Desmin Leads to Cardiomyocyte Hypertrophy and Cardiac Dilation with Compromised Systolic Function

Milner, Derek J.; Taffet, George E.; Wang, Xuejun; Pham, Thuy T.; Tamura, Tetsutaro; Hartley, Craig J.; Gerdes, Martin; Capetanaki, Yassemi

doi:10.1006/jmcc.1999.1037

Cited by 158 publications

(153 citation statements)

References 49 publications

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“…Furthermore, in animal models, null mutation of the desmin gene gives rise to ultrastructural defects in cardiac muscle [26], degeneration of cardiomyocytes, accumulation of macrophages, and fibrosis [27]. Mice lacking desmin develop cardiomyocyte hypertrophy and age-dependent loss of cardiac performance, with chamber dilatation and compromised systolic function resembling cardiomyopathy [28]. On the other hand, desmin rescue mice with cardiomyocyte-specific desmin expression display a wildtype cardiac phenotype [29].…”

Section: Discussionmentioning

confidence: 99%

“…The present study did not ascertain the function of desmin in DCM and heart failure. Whereas this protein plays an essential role for cardiac integrity [22,[26][27][28][29]32], the consequences of desmin upregulation in DCM are still unknown. However, the inverse correlation between the amount of myocardial desmin and the ejection fraction in DCM patients [23] may establish desmin as a valuable myocardial marker for cardiac dysfunction.…”

Section: Discussionmentioning

confidence: 99%

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Immunoadsorption and subsequent immunoglobulin substitution decreases myocardial gene expression of desmin in dilated cardiomyopathy

et al. 2007

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Cardiac autoantibodies play a pathogenic role in dilated cardiomyopathy (DCM). Removal of antibodies by immunoadsorption (IA) induces hemodynamic improvement in DCM patients. The present study investigated the effects of IA on myocardial gene expression of the intermediate cytoskeletal filament desmin, which is upregulated in heart failure. RNA was isolated from five explanted nonfailing hearts and five explanted failing hearts of DCM patients, and myocardial gene expression of desmin was estimated by real-time polymerase chain reaction (PCR). In a case-control study in six DCM patients (LVEF < 40%,

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Immunoadsorption and subsequent immunoglobulin substitution decreases myocardial gene expression of desmin in dilated cardiomyopathy

et al. 2007

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“…7853-1) analysis was performed by Clontech (Clontech, San Diego, CA), using pools of three hearts of 4-month-old desmin-null and wild-type animals. Northern blots were performed as previously described 2 The samples were analyzed by SDS-PAGE, transferred to polyvinylidene difluoride membranes, and probed for decorin and osteopontin using the antibodies LF-113 and LF-123, respectively, in a 1:1000 dilution. The antibodies were kindly provided by Dr. Larry Fisher.…”

Section: Isolation Of Rna Differential Display Pcr Cdna Arrays Andmentioning

confidence: 99%

“…[1][2][3] Similarly, missense mutations of desmin have been identified in humans suffering from idiopathic dilated cardiomyopathy 4 as well as other more generalized myopathies with both skeletal and cardiac dysfunction. [5][6][7][8]9 The cellular and tissue pathology associated with cardiac dysfunction in desmin-null mice has been adequately addressed.…”

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confidence: 99%

Extensive Induction of Important Mediators of Fibrosis and Dystrophic Calcification in Desmin-Deficient Cardiomyopathy

Mavroidis

Capetanaki

2002

The American Journal of Pathology

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Mice lacking the intermediate filament protein desmin demonstrate abnormal mitochondria behavior, disruption of muscle architecture, and myocardial degeneration with extensive calcium deposits and fibrosis. These abnormalities are associated with cardiomyocyte hypertrophy, cardiac chamber dilation and eventually with heart failure. In an effort to elucidate the molecular mechanisms leading to the observed pathogenesis, we have analyzed gene expression changes in cardiac tissue using differential display polymerase chain reaction and cDNA atlas array methods. The most substantial changes were found in genes coding the small extracellular matrix proteins osteopontin and decorin that are dramatically induced in the desmin-null myocardium. We further analyzed their expression pattern both at the RNA and protein levels and we compared their spatial expression with the onset of calcification. Extensive osteopontin localization is observed by immunohistochemistry in the desmin-null myocardium in areas with massive myocyte death, as well as in hypercellular regions with variable degrees of calcification and fibrosis. Osteopontin is consistently co-localized with calcified deposits, which progressively are transformed to psammoma bodies surrounded by decorin, especially in the right ventricle. These data together with the observed up-regulation of transforming growth factor-␤1 and angiotensin-converting enzyme, could explain the extensive fibrosis and dystrophic calcification observed in the heart of desminnull mice, potentially crucial events leading to heart failure. Ablation of desmin, the muscle-specific intermediate filament protein, by gene targeting in mice leads to transient cardiomyocyte hypertrophy and extensive cardiomyocyte death, followed by cardiac chamber dilation and heart failure.

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“…Therefore, they may link myofibrils to the sarcolemma, organelles and neighboring myocytes (Granger and Lazarides, 1979;Holtzer et al, 1985;Milner et al, 2000;O'Neill et al, 2002) (see Clark et al, 2002 for review). In particular, intermediate filaments are thought to be involved in maintaining muscle stability as desmin-null mice exhibit a reduction of myofibril alignment, significant muscle degeneration and necrosis, and impaired force transmission (Milner et al, 1996;Li et al, 1997;Milner et al, 1999;Balogh et al, 2002). Exactly how the intermediate filaments assemble during development is not understood, although some require a specific subpopulation of microtubules -detyrosinated microtubules (Glu-MTs) -for their localization and integrity in some cell types (Gurland and Gundersen, 1995;Kreitzer et al, 1999).…”

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confidence: 99%

Muscle-specific RING finger-2 (MURF-2) is important for microtubule, intermediate filament and sarcomeric M-line maintenance in striated muscle development

McElhinny

Perry

Witt

et al. 2004

Journal of Cell Science

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The efficient functioning of striated muscle is dependent upon the structure of several cytoskeletal networks including myofibrils, microtubules, and intermediate filaments. However, little is known about how these networks function together during muscle differentiation and maintenance. In vitro studies suggest that members of the muscle-specific RING finger protein family (MURF-1, 2, and 3) act as cytoskeletal adaptors and signaling molecules by associating with myofibril components (including the giant protein, titin), microtubules and/or nuclear factors. We investigated the role of MURF-2, the least-characterized family member, in primary cultures of embryonic chick skeletal and cardiac myocytes. MURF-2 is detected as two species (∼55 kDa and ∼60 kDa) in embryonic muscle, which are down-regulated in adult muscle. Although predominantly located diffusely in the cytoplasm, MURF-2 also colocalizes with a sub-group of microtubules and the M-line region of titin. Reducing MURF-2 levels in cardiac myocytes using antisense oligonucleotides perturbed the structure of stable microtubule populations, the intermediate filament proteins desmin and vimentin, and the sarcomeric M-line region. In contrast, other sarcomeric regions and dynamic microtubules remained unaffected. MURF-2 knock-down studies in skeletal myoblasts also delayed myoblast fusion and myofibrillogenesis. Furthermore, contractile activity was also affected. We speculate that some of the roles of MURF-2 are modulated via titin-based mechanisms.

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The Absence of Desmin Leads to Cardiomyocyte Hypertrophy and Cardiac Dilation with Compromised Systolic Function

Cited by 158 publications

References 49 publications

Immunoadsorption and subsequent immunoglobulin substitution decreases myocardial gene expression of desmin in dilated cardiomyopathy

Immunoadsorption and subsequent immunoglobulin substitution decreases myocardial gene expression of desmin in dilated cardiomyopathy

Extensive Induction of Important Mediators of Fibrosis and Dystrophic Calcification in Desmin-Deficient Cardiomyopathy

Muscle-specific RING finger-2 (MURF-2) is important for microtubule, intermediate filament and sarcomeric M-line maintenance in striated muscle development

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