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

Enteroviral infection can cause an acquired form of dilated cardiomyopathy. We recently reported that dystrophin is cleaved, functionally impaired, an d morphologically disrupted in vitro as well as in vivo during infection wi th coxsackievirus B3, Genetic dystrophin truncations lead to a marked decre ase in dystrophin-associated glycoproteins, whereas expression of only the naturally occurring dystrophin carboxyl terminus, Dp-71, restores the sarco lemmal 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 ca rdiac myocytes and murine hearts infected with coxsackievirus B3, the sarco lemmal localization of the dystrophin carboxyl terminus is lost. The dystro phin-associated glycoproteins alpha-, beta-, gamma-, and delta-sarcoglycan and beta-dystroglycan were markedly decreased in the membrane fraction of i nfected cells in culture, and the typical sarcolemmal localization for each of the se proteins was lost in coxsackievirus-B3-infected cardiomyocytes i n vivo. Furthermore, sucrose gradient ultracentrifugation demonstrated that delta-sarcoglycan was physically dissociated from dystrophin within the me mbrane fraction. In vivo, the sarcolemmal integrity was functionally impair ed with Evans blue dye uptake even though there was no generalized disrupti on of the sarcolemma of infected myocytes evidenced by intact wheat germ ag glutinin staining. In analogy to hereditary sarcoglycanopathies, this disin tegration of the sarcoglycan complex may, in addition to the dystrophin cle avage, play an important role in the pathogenesis of enterovirus-induced ca rdiomyopathy. These results imply a potential role for disruption of the sa rcoglycans in an acquired form of heart failure.