© 2000 American Heart Association, Inc.
Cellular Biology |
Dissociation of Sarcoglycans and the Dystrophin Carboxyl Terminus From the Sarcolemma in Enteroviral Cardiomyopathy
From the Department of Medicine, University of California, San Diego (La Jolla). Dr Lee’s present address is the Department of Internal Medicine, Catholic University of Korea, Seoul, Korea. Dr Badorff’s present address is the Department of Cardiology, Goethe-University, Frankfurt/Main, Germany.
Correspondence to Kirk U. Knowlton, MD, Department of Medicine, 0613K, University of California, San Diego, 9500 Gilman Dr, La Jolla, CA 92093-0613. E-mail kknowlton{at}ucsd.edu
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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
-, ß-, 
-, and 
-sarcoglycan and
ß-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 -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.
Key Words: heart failure • cardiomyopathy • sarcoglycans • myocarditis • coxsackievirus
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Introduction |
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In cardiac muscle, the dystrophin–glycoprotein complex includes dystrophin and the dystrophin-associated glycoproteins
-, ß-, -.
and -sarcoglycan; - and ß-dystroglycan1 ; and the
recently described sarcospan.2 This complex is part of the
extrasarcomeric cytoskeleton3 that collectively connects
the internal F-actin–based cytoskeleton to laminin-2 of the
extracellular space.1 Thereby, it is thought to play an
important role in the transmission of mechanical force to the
extracellular matrix.3
Genetic defects in -, ß-, -, or -sarcoglycan are the cause
of human limb-girdle muscular dystrophy type 2D, 2E, 2C, and 2F,
respectively,4 and can caused dilated
cardiomyopathy in humans.5 6 7 8 A defect
in -sarcoglycan causes cardiomyopathy in the
hamster,9 and genetic disruption of ß-, -, and
-sarcoglycans can cause cardiomyopathy in the
mouse.10 11 12 Mutations in dystrophin cause Duchenne and
Becker muscular dystrophy,13 both of which have a high
incidence of dilated cardiomyopathy.14
In addition, dystrophin mutations are a cause of X-linked dilated
cardiomyopathy.15 16 These studies and
others17 18 have led to the paradigm that familial dilated
cardiomyopathy can result from defective
transmission of mechanical force from the sarcomere to the
extracellular matrix19 and that disruption of the
dystrophin–glycoprotein complex may be a common mechanism
that causes cardiomyopathy.20 Although
the importance of genetic defects of the
dystrophin–glycoprotein complex in hereditary
cardiomyopathy is well established, little is known
about its role in acquired cardiomyopathy.
A subset of human acquired dilated cardiomyopathy is associated with an enteroviral infection of the heart, in particular, coxsackie B viruses.21 22 23 In mice, the transgenic expression of coxsackieviral proteins in the heart is sufficient to induce dilated cardiomyopathy.24 We recently proposed that cleavage of dystrophin has a role in the molecular pathogenesis of enterovirus-induced cardiomyopathy.25 Dystrophin is proteolytically cleaved by the coxsackieviral protease 2A in the hinge 3 region25 26 and is functionally impaired. Localization of the rod domain of dystrophin is disrupted in cultured cardiomyocytes as well as in the intact mouse heart infected with coxsackievirus B3 (CVB3). We proposed that the cleavage of dystrophin during CVB3 infection initiates a cascade of events that contributes to dilated cardiomyopathy.25
Genetic defects of individual components of the
dystrophin–glycoprotein complex can disrupt the assembly
and thus the molecular organization of the entire complex. For example,
dystrophin frameshift mutations lead to a marked decrease in the other
dystrophin-associated glycoproteins in Duchenne muscular
dystrophy.27 Interestingly, expression in the heart of a
naturally occurring carboxyl-terminal isoform of dystrophin, Dp-71,
that contains the ß-dystroglycan binding site, is sufficient to
restore the sarcolemmal localization of dystrophin–associated
glycoproteins in dystrophin-deficient mice but fails to
prevent the dystrophic phenotype observed in mdx
mice.28 29 This demonstrates that the
carboxyl-terminal region of dystrophin is sufficient for the
organization of the sarcoglycan complex and that the linkage between
actin and dystroglycan is not required for the assembly of the
dystrophin–glycoprotein complex. Disruption of
-sarcoglycan causes markedly decreased sarcolemmal staining for all
of the sarcoglycans, whereas disruption of -sarcoglycan has a
variable effect on individual sarcoglycan
components.10 12 30 This indicates that the mechanisms for
disruption of the dystrophin–glycoprotein complex
determine the pattern of disruption of the sarcoglycan complex. Little
is known about how acute cleavage of dystrophin will affect sarcoglycan
stability and the integrity of the dystrophin–glycoprotein
complex.
Because the viral protease 2A cleaves dystrophin in the hinge 3 region during coxsackievirus-B3 infection, an uncleaved carboxyl terminus of dystrophin may be sufficient to prevent complete dissociation of the sarcoglycans from the dystrophin–glycoprotein complex. For this reason, we sought to determine whether acute dystrophin cleavage by a viral protease has a phenotype that is similar to that observed with genetic dystrophin deficiency or whether it is more like the pattern observed with expression of the carboxyl-terminal dystrophin isoform, Dp71.
Our findings demonstrate that the sarcoglycan complex becomes physically, morphologically, and functionally disrupted with acute cleavage of dystrophin during CVB3 infection. In addition, cleavage of dystrophin results in a phenotype different from Dp71 expression, because the carboxyl-terminal cleavage fragment loses its sarcolemmal localization. Thus, acute cleavage of dystrophin by enteroviral protease 2A disrupts the sarcolemmal dystrophin-associated glycoproteins similar to that observed with genetic dystrophin mutations, which result in translation of a truncated protein. This disruption of the sarcoglycan complex, in addition to the cleavage of dystrophin, may play an important role in the induction of enteroviral cardiomyopathy.
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Materials and Methods |
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Viruses
CVB3 was derived from the infectious cDNA copy of the cardiotropic H3 strain of CVB3.31 Wild-type adenovirus 5 was a kind gift from S. Huang (Scripps Research Institute, La Jolla, Calif). Virus was titered with a plaque-forming assay on HeLa cells.31
Mice
Male SCID (C3HSmn.C-Prkdcscid/J)
mice32 were purchased from the Jackson Laboratories.
Agammaglobulinemia was verified in all SCID animals.33
Mice (5 to 6 weeks old) were infected with an
intraperitoneal injection of
103 plaque-forming units32 of CVB3
and killed at day 7 after infection. In some mice, Evans blue dye was
injected intraperitoneally at day 6 after
infection, and hearts were harvested 24 hours later.25
Myocyte Culture
Rat neonatal ventricular myocytes were isolated and
cultured as described previously. Myocytes were infected at a
multiplicity of infection of 100.
Antibodies
Rabbit polyclonal antibodies anti-CVB334 (generous
gift of Andreas Henke) and anti–-sarcoglycan9 (kindly
provided by Vincenzo Nigro) were previously described. Monoclonal
antibody MANDRA1 is specific for the carboxyl terminus of
dystrophin35 (kindly provided by G.E. Morris). Monoclonal
antibodies against -, ß-, and -sarcoglycans and
ß-dystroglycan were all from NovoCastra (Newcastle, UK).
Rhodamine-labeled wheat germ agglutinin (WGA), biotinylated horse
anti-mouse or anti-rabbit IgG, and streptavidin-alkaline phosphatase
were from Vector Laboratories. Alkaline phosphatase–labeled goat
anti-rabbit IgG and anti-mouse IgG (H+L) were obtained from Life
Technologies. FITC-, Rhodamine Red-X–, and Cy5-conjugated anti-rabbit
IgG were from Jackson ImmunoResearch Inc.
Myocyte Fractionation
Cytosolic and membrane fractions were prepared with the
pyrophosphate variant as reported previously.36 In some
experiments, the membrane fraction was layered onto a linear 5% to
20% sucrose density gradient and subjected to
ultracentrifugation as described36 (Sw41Ti
rotor, 200 000 rpm for 20 hours at 4°C). The gradient was then
fractionated; the fractions were collected and concentrated with
Centricon-10 devices (Millipore).
Western Blotting
Proteins were separated on a 6% or 12%
SDS–polyacrylamide gel and transferred to nitrocellulose.
Blots were then incubated with primary antibodies for 1 hour at room
temperature. Bound antibodies were detected with an alkaline
phosphatase–conjugated secondary antibody for 1 hour at room
temperature, followed by color development with
5-bromo-4-chloro-3-indolyl phosphate–nitro blue
tetrazolium25 (Promega).
Immunofluorescence
Heart tissue was embedded in Tissue-Tek O.C.T.
compound (Sakura) and snap-frozen in isopentane chilled in liquid
nitrogen. Unfixed 6-µm cryosections were
permeabilized with 0.3% Triton X-100 in TBS.
Coxsackievirus-infected cells were identified with a rabbit polyclonal
anti-CVB3 antibody at 1:200 dilution followed by Rhodamine Red-X– or
Cy5-conjugated anti-rabbit IgG antibody (1:100). Dystrophin and the
dystrophin-associated glycoproteins were visualized with
monoclonal antibodies followed by a biotinylated secondary antibody and
streptavidin-FITC (1:100). Cell membrane glycoproteins were
visualized with a rhodamine labeled WGA (1:100). Slides were imaged
with confocal laser scanning microscopy37
(Bio-Rad).
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Results |
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Dystrophin Cleavage in CVB3-Infected Myocytes Is Associated With Loss of Carboxyl-Terminal Dystrophin and Decreases in Transmembrane Components of the Dystrophin–Glycoprotein Complex
Separation of the amino-terminal dystrophin portion from the carboxyl-terminal region of dystrophin via cleavage in the hinge 3 region leads to loss of the sarcolemmal localization of the dystrophin rod domain and amino terminus during CVB3 infection. However, it is not known whether cleavage of dystrophin in the rod domain will also result in loss of sarcolemmal localization of the carboxyl terminus of dystrophin and a decrease in membrane concentration of other members of the dystrophin–glycoprotein complex.
As shown in Figure 1A
, the cleavage of
dystrophin with CVB3 infection led to loss of the dystrophin carboxyl
terminus in the membrane fraction. In addition, there was a marked
decrease in the amount of -, ß-, -, and -sarcoglycans in the
membrane fraction (Figure 1A). To determine whether each
component of dystrophin–glycoprotein complex is cleaved
during CVB3 infection, -, ß-, -, and -sarcoglycans and
ß-dystroglycan were examined with immunoblotting in
cultured rat ventricular cardiac myocytes infected with
CVB3. As shown in Figure 1B, cleavage of the 35-kDa
-sarcoglycan with CVB3 infection could not be detected in either the
membrane or cytosolic fractions despite a marked decrease in the amount
of intact protein in the membrane fraction. Similarly, cleavage for
-, ß-, and -sarcoglycans and ß-dystroglycan could not be
detected in the membrane or cytosolic fractions after CVB3 infection
(Figure 1A and data not shown). Adenovirus infection has been
implicated in the pathogenesis of human dilated
cardiomyopathy22 ; however, there was
no change in the level of the dystrophin-associated
glycoproteins after infection with wild-type adenovirus 5
at a time point that had a marked cytopathic effect (Figure 1A).
This indicates that the observed sarcoglycan reduction during infection
with CVB3 is not a nonspecific response to the virus-induced cytopathic
effect. Second, the overall membrane protein composition in
CVB3-infected cells was similar to that of uninfected cells as assessed
with Coomassie blue staining (Figure 1C). Because the
sarcoglycans and ß-dystroglycan are transmembrane proteins, they were
present only in the membrane and not in the cytosolic fraction.
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-Sarcoglycan Is Physically Dissociated From Dystrophin During
CVB3 Infection of Cultured Cardiomyocytes
Because the sarcoglycans were reduced in but not dissociated from
the membrane, we next investigated the physical integrity of the
dystrophin–glycoprotein complex within the membrane
fraction of virally infected cardiomyocytes. Normally, the
sarcoglycans are physically associated with dystrophin and
cofractionate together with dystrophin on sucrose density gradient
ultracentrifugation.36 Among the
sarcoglycans, only -sarcoglycan can be cross-linked to
ß-dystroglycan.38
We analyzed the fractions of a membrane preparation from
virally infected myocytes separated with sucrose density gradient
ultracentrifugation for the presence of dystrophin and
-sarcoglycan (Figure 2). In uninfected
cells, the intact dystrophin protein and -sarcoglycan were
physically associated and cofractionated in the lower fractions (5 to
7) of the gradient (Figure 2A). The weak signal seen in
fractions 11 and 12 represents an unknown immunoreactive band.
In the membrane fraction of infected myocytes, dystrophin was
reduced to nonmeasurable levels (Figure 2B). The presence
of the immunoreactive bands in fractions 11 and 12 and of
-sarcoglycan in fractions 3 to 8 indicates that the fractions of the
2 gradients were comparable and that there may be a small amount of
dystrophin in the membrane of infected cells. As observed previously
(Figure 1A
), the total amount of -sarcoglycan was reduced in
the membrane fraction from the virally infected myocytes. Most
important, however, -sarcoglycan was found in the upper fractions of
the gradient (fractions 9 to 15) dissociated from dystrophin.
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These results indicate not only that the level of -sarcoglycan is
decreased but also that the physical integrity of the
dystrophin–glycoprotein complex is impaired after CVB3
infection in cultured cardiomyocytes.
Sarcoglycan Complex Is Morphologically Disrupted in CVB3–Infected
Mouse Hearts
In addition to the biochemical analysis of the sarcoglycan
complex in cultured cells, we morphologically investigated dystrophin
and dystrophin-associated glycoproteins in the hearts of
SCID mice infected with CVB3 by immunostaining.
SCID mice (n=4) were chosen to demonstrate that any potential
alterations were a direct viral effect rather than an immune-mediated
event.32 As previously described,25 the
staining pattern for the dystrophin rod domain is disrupted in infected
cardiomyocytes in the intact mouse heart with a loss of the
typical sarcolemmal localization that is normally seen in uninfected
cells. Immunostaining for the carboxyl terminus of
dystrophin was performed to determine whether it retained its
physiological localization in the absence of a
functional rod domain. As shown in Figures 3A and 3B, the sarcolemmal localization
of the dystrophin carboxyl terminus was disrupted in infected cardiac
myocytes, similar to the result obtained for the dystrophin rod
domain.
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Triple-color staining with WGA, a plasma membrane marker;
ß-sarcoglycan; and CVB3 demonstrated that cleavage of dystrophin
during CVB3 infection was associated with a loss of ß-sarcoglycan
staining in infected cells. However, the loss of the
dystrophin-associated glycoproteins in the sarcolemma was
not due to a general disintegration of the plasma membrane, as
evidenced by preserved WGA stain in cells with a disrupted
ß-sarcoglycan (Figures 3E through 3H).
In the absence of the dystrophin carboxyl-terminus, the
dystrophin-associated glycoproteins are not localized to
the sarcolemma in Duchenne muscular dystrophy.27 Since the
Dystrophin carboxy-terminus was absent from the plasma membrane in
infected myocytes in vivo, we investigated whether a similar finding
would occur in CVB3-infected SCID mouse myocytes (n=4). The sarcolemmal
localization of -, ß-, - and -sarcoglycans and of
ß-dystroglycan was disrupted in infected cardiomyocytes
in the intact heart to varying degrees (Figure 4).
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These results demonstrate a morphological disruption of all components of the sarcoglycan complex tested and ß-dystroglycan in the mouse heart on infection with CVB3.
Functional Disruption of the
Dystrophin- Glycoprotein Complex In Vivo by
CVB3
Genetic sarcoglycan12 39 or dystrophin40
deficiency leads to increased sarcolemmal permeability with uptake of
the tracer dye Evans blue. Six days after infection, SCID mice were
injected with Evans blue to assess whether dye uptake would also occur
in virally infected cardiomyocytes and hearts were
harvested after 24 hours.
Immunostaining of Evans blue dye–injected mouse hearts
for carboxyl terminus of dystrophin or for -, ß-, -, and
-sarcoglycans showed that the dye uptake specifically occurred in
virally infected myocytes with a disrupted dystrophin staining pattern
(Figures 3C and 3D) or in virally infected myocytes with a
disrupted sarcoglycan staining patterns (Figure 4).
These data demonstrate a functional impairment of the dystrophin–glycoprotein complex in virally infected cardiomyocytes in vivo.
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Discussion |
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The main finding of the present study was that CVB3 infection leads to disruption of the association between dystrophin and the sarcoglycan complex. This was demonstrated by a marked reduction in membrane localization of the carboxyl terminus of dystrophin, each of the sarcoglycans, and ß-dystroglycan in infected cardiac myocytes. In addition, increased sarcolemmal permeability indicates functional impairment of the dystrophin–glycoprotein complex in virally infected cells. Because proteolytic cleavage of the sarcoglycans and ß-dystroglycan was not detected during viral infection, these effects appear to be indirect and secondary to dystrophin cleavage.
The sarcoglycans (, ß, , and ) form a complex of 4
single-pass transmembrane glycoproteins. Within the
multiprotein dystrophin–glycoprotein complex, they form a
distinct subcomplex.1 The
physiological role of this subcomplex is not well
understood,4 and the sarcoglycans may have functions
beyond stabilization of the sarcolemma.1 That the
sarcoglycans function as a complex is based on the finding that a
defect in any one sarcoglycan causes alterations in other components of
the sarcoglycan complex.4 The ß-dystroglycan component
of the dystroglycan complex binds to the carboxyl terminus of
dystrophin.41 The correct sarcolemmal localization of
ß-dystroglycan as well as the sarcoglycans depends on a functional
dystrophin carboxyl terminus. Consequently, in Duchenne muscular
dystrophy patients with dystrophin mutations that result in a truncated
protein, the dystrophin-associated proteins are in large part absent
from the sarcolemma.27
We previously reported that the viral protease 2A cleaves dystrophin during CVB3 infection in the hinge 3 region.26 Because dystrophin cleavage functionally impairs dystrophin with dissociation of the rod domain from the plasma membrane, we initially investigated the effects of protease 2A–mediated cleavage on the dystrophin carboxyl terminus and found that it lost its sarcolemmal localization in virally infected myocytes. In analogy to findings in Duchenne muscular dystrophy,27 the absence of an intact dystrophin carboxyl terminus led to a severe reduction in its binding partner, ß-dystroglycan, in the membrane fraction in cultured myocytes and to a loss of its sarcolemmal localization in the intact heart. In this regard, the carboxyl-terminal dystrophin cleavage fragment is different from the naturally occurring carboxyl-terminal isoform of dystrophin, Dp71. Dp71 has been shown to be able to restore the dystrophin–glycoprotein complex in dystrophin-deficient mice even though it does not prevent the muscular dystrophy observed in the mdx mice.28 29 It is notable that Dp71 has a 7-residue amino terminus that results from an alternative promoter site upstream of exon 63 and that it lacks the amino acids encoded by exons 50 to 62 that are present in the carboxyl-terminal fragment from cleavage by protease 2A.42 It is, therefore, possible that the protease 2A–generated carboxyl-terminal dystrophin fragment is susceptible to further degradation, whereas the Dp71 molecule is stable. Alternatively, it is possible that the conformational change in the carboxyl-terminal dystrophin cleavage fragment facilitates further degradation by other proteases, although such cleavage fragments were not detected.
Because ß-dystroglycan itself is not proteolytically cleaved
during CVB3 infection, its reduction in the membrane fraction appears
to be due to functional disruption of dystrophin and loss of membrane
localization of the dystrophin carboxyl terminus. Because
ß-dystroglycan is a component of the
dystrophin–glycoprotein complex and the dystroglycans can
be cross-linked to -sarcoglycan, a reduction in ß-dystroglycan was
predicted to also affect the sarcoglycan complex.1 4 43
Indeed, -, ß-, -, and -sarcoglycans were, similar to
ß-dystroglycan, reduced in the membrane of virally infected myocytes
in cell culture and in the intact mouse heart. Again, this effect on
the sarcoglycans appears to be indirect in the absence of any
detectable cleavage fragments. Not only were the members of the
sarcoglycan complex reduced in the membrane fraction, but also
-sarcoglycan was partially dissociated from dystrophin, indicating
physical disintegration of the dystrophin–glycoprotein
complex.
To test the functional relevance of these perturbations, we assessed the sarcolemmal integrity in vivo by injection of Evans blue dye. Only cells that have lost their membrane integrity take up this tracer dye.40 Genetic sarcoglycan deficiency causes Evans blue dye uptake,12 39 as do dystrophin defects.40 During CVB3 infection of the mouse heart, we found that Evans blue dye was specifically taken up by virally infected cardiomyocytes with a disrupted sarcoglycan staining pattern. This association suggests that the sarcoglycan complex deficiency may play an important role in the observed increase of sarcolemmal permeability.
Based on these results and the known role of sarcoglycan defects in
hereditary dilated cardiomyopathy, we conclude that
the disruption of the sarcoglycan complex during CVB3 infection may
participate in a cascade of events that ultimately lead to enteroviral
cardiomyopathy. Consequently, we significantly
extended our previous molecular model that exemplifies this
cascade.25 We propose that the initial cleavage of
dystrophin by the enteroviral protease 2A triggers loss of the
sarcolemmal dystrophin carboxyl terminus and ß-dystroglycan, as well
as a disruption of the sarcoglycan complex (Figure 5). It is notable, however, that the
sarcoglycan complex is disrupted before total loss of the sarcolemma,
as assessed with WGA staining. Because sarcoglycan defects cause human
dilated cardiomyopathy, this mechanism is
potentially relevant to human disease.
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In summary, the sarcoglycan complex is physically, morphologically, and functionally impaired during CVB3 infection. These perturbations appear to be secondary to the dystrophin cleavage and may play an important role in the induction of enteroviral cardiomyopathy.
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Acknowledgments |
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This work was supported in part by NIH grant 5-R01-HL-57365-02 to Dr Knowlton; an American Heart Association Established Investigator Award and support from Our Lady of Mercy Hospital, Catholic University of Korea, to Dr Lee; and a training grant from the Deutsche Forschungsgemeinschaft to Dr Badorff (Ba 1668/1-1). We thank Maryann E. Martone and Mark H. Ellisman (Department of Neuroscience, National Center for Microscopy and Imaging Research, University of California, San Diego) for providing the equipment and advice for obtaining confocal images. We also thank Robert Myers (Department of Anesthesiology, Peripheral Nerve Research, University of California, San Diego) for providing equipment and advice for immunostaining and obtaining cryosections.
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Footnotes |
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1 Both authors contributed equally to this study.
Received June 7, 2000; revision received July 20, 2000; accepted July 21, 2000.
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