Dissociation of sarcoglycans and the dystrophin carboxyl terminus from the sarcolemma in enteroviral cardiomyopathy.

Abstract

Enteroviral infection can cause an acquired form of dilated cardiomyopathy. We recently reported that dystrophin is cleaved, functionally impaired, and morphologically disrupted in vitro as well as in vivo during infection with coxsackievirus B3. Genetic dystrophin truncations lead to a marked decrease in dystrophin-associated glycoproteins, whereas expression of only the naturally occurring dystrophin carboxyl terminus, Dp-71, restores the sarcolemmal association of the dystrophin-associated glycoproteins. We sought to determine whether acute cleavage of dystrophin leads to a dissociation of the carboxyl-terminal dystrophin fragment and of the sarcoglycans from the sarcolemma during coxsackievirus B3 infection. We found that in cultured cardiac myocytes and murine hearts infected with coxsackievirus B3, the sarcolemmal localization of the dystrophin carboxyl terminus is lost. The dystrophin-associated glycoproteins alpha-, beta-, gamma-, and delta-sarcoglycan and beta-dystroglycan were markedly decreased in the membrane fraction of infected cells in culture, and the typical sarcolemmal localization for each of these proteins was lost in coxsackievirus-B3-infected cardiomyocytes in vivo. Furthermore, sucrose gradient ultracentrifugation demonstrated that delta-sarcoglycan was physically dissociated from dystrophin within the membrane fraction. In vivo, the sarcolemmal integrity was functionally impaired with Evans blue dye uptake even though there was no generalized disruption of the sarcolemma of infected myocytes evidenced by intact wheat germ agglutinin staining. In analogy to hereditary sarcoglycanopathies, this disintegration of the sarcoglycan complex may, in addition to the dystrophin cleavage, play an important role in the pathogenesis of enterovirus-induced cardiomyopathy. These results imply a potential role for disruption of the sarcoglycans in an acquired form of heart failure.

• Authors: G H Lee, C Badorff, K U Knowlton
• Journal: Circulation research (Circ Res) Vol. 87 Issue 6 Pg. 489-95 (Sep 15 2000) ISSN: 1524-4571 [Electronic] United States
• PMID: 10988241 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Dystrophin
• Protein Isoforms
• Viral Proteins
• apo-dystrophin 1
• Cysteine Endopeptidases
• picornain 2A, Picornavirus

Topics

• Animals
• Blotting, Western
• Cardiomyopathy, Dilated (metabolism, pathology, virology)
• Cells, Cultured
• Coxsackievirus Infections (complications, metabolism, pathology)
• Cysteine Endopeptidases (metabolism)
• Dystrophin (analogs & derivatives, metabolism)
• Electrophoresis, Polyacrylamide Gel
• Enterovirus B, Human
• Fluorescent Antibody Technique
• Mice
• Mice, SCID
• Myocardium (metabolism, pathology, ultrastructure)
• Protein Isoforms (metabolism)
• Rats
• Sarcolemma (metabolism)
• Viral Proteins