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Animal Models |
-Sarcoglycan-Deficient Hamster
From the Howard Hughes Medical Institute, Department of Physiology and Biophysics and Department of Neurology, University of Iowa College of Medicine, Iowa City, Iowa
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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-sarcoglycan
gene was found to be the primary genetic defect in the hamster. In the
present investigation, we studied the effects of the
-sarcoglycan deletion on transcription, expression,
and function of the dystrophin-glycoprotein complex in skeletal and
cardiac muscle. We demonstrated that in striated muscle the genetic
defect leads to the complete deficiency of -sarcoglycan and a
concomitant loss of 
-, ß-, and 
-sarcoglycan. In
addition, absence of the sarcoglycan complex reduced the
expression of -dystroglycan in striated muscle fibers. These
findings indicated that the primary defect in the BIO14.6 hamster leads
to the dissociation of the dystroglycan complex from the sarcoglycan
complex and disrupted anchorage of -dystroglycan to the cell
surface. Using intravenous injection of Evans blue dye as an in
vivo tracer assay, we demonstrated that perturbation of
the dystrophin-glycoprotein complex caused extensive fiber damage in
skeletal and cardiac muscle of the BIO14.6 hamster. Based on our
results, we propose that loss of -sarcoglycan results in the
impairment of sarcolemmal integrity, finally leading to
muscular dystrophy and cardiomyopathy.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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- and
ß-subunits.5
The heterotrimeric basement membrane protein
laminin 2 serves as the major extracellular ligand of -dystroglycan
in striated muscle cells.5
Furthermore, the sarcoglycan
complex, composed of at least four single-pass transmembrane
proteins,6
the syntrophins,7
and the recently
characterized 25-kd protein sarcospan,8
are closely
associated with dystrophin and
dystroglycan.
Several components of the DGC have been implicated in various forms of
muscular dystrophy.9,10
Mutations in the genes for -,
ß-, -, and -sarcoglycan are responsible for four phenotypically
similar classes of autosomal recessive limb-girdle muscular dystrophy
(LGMD 2C-F).11-16
Recently, a mutation in the
-sarcoglycan gene of the BIO14.6 cardiomyopathic hamster had been
identified to cause the disease in this animal strain.17,18
The BIO14.6 hamster exhibits histological features of muscular
dystrophy characterized by central nucleation, wide variation in muscle
fiber diameter, and necrosis.19-21
In contrast to most of
the reported patients with sarcoglycan deficiency, the hamsters develop
cardiomyopathy leading to heart failure and death within one-half to
one-third of their normal life span.22
In the present study, we have investigated the pathological
manifestations of the -sarcoglycan gene mutation in the
cardiomyopathic hamster. We demonstrated by immunohistochemical and
biochemical analysis that -sarcoglycan was absent in skeletal and
cardiac muscle. As a consequence of the -sarcoglycan deficiency, we
observed a concomitant loss of the other sarcoglycans and reduced
expression levels of -dystroglycan in skeletal and cardiac muscle.
These findings indicate that the primary defect in the BIO14.6 hamster
leads to the dissociation of the dystroglycan complex from the
sarcoglycan complex. Using an in vivo tracer assay, we
demonstrated that in skeletal and cardiac muscle fibers the
-sarcoglycan mutation impairs sarcolemmal integrity in the
cardiomyopathic hamster.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Male F1B control and BIO14.6 cardiomyopathic hamsters were
obtained from BioBreeders (Fitchburg, MA). A colony of
-sarcoglycan-deficient hamsters was established at the University of
Iowa by breeding female Golden Syrian hamsters (Charles River
Laboratories, Wilmington, MA) with male BIO14.6 cardiomyopathic
hamsters. The F1 generation females were bred with male BIO14.6
cardiomyopathic hamsters to produce the F2 generation. The offspring
from the F2 generation were biopsied to identify -sarcoglycan
deficiency. Animals homozygous for the -sarcoglycan mutation were
used for further breeding. All animals were kept in the animal care
unit of the University of Iowa College of Medicine according to animal
care guidelines. We studied a total of 30 animals ranging from 2 to 56
weeks of age. For our studies, the F1B strain controls were age and sex
matched with the cardiomyopathic BIO14.6 strain animals.
Antibodies
Antibodies against the following components of the DGC were used:
dystrophin, -, ß-, -, and -sarcoglycan, - and
ß-dystroglycan, and the laminin 2 chain. Monoclonal antibodies
VIA42 against dystrophin,23
IIH6 against
-dystroglycan,24
8D5 against
ß-dystroglycan,12
and rabbit polyclonal antibodies
against -sarcoglycan25
and the laminin 2
chain26
were described previously. Monoclonal antibodies
20A6 against -sarcoglycan, 5B1 against ß-sarcoglycan, and 21B5
against -sarcoglycan were generated in collaboration with Louise
V. B. Anderson (Newcastle General Hospital, Newcastle on Tyne,
UK). An affinity-purified rabbit antibody (rabbit 208) was produced
against a carboxyl-terminal GST-fusion protein of -sarcoglycan.
Peptide antibodies were generated against an amino-terminal peptide
(MMPQEQYTHHRSTMPGAAC) of -sarcoglycan (rabbit 215). Polyclonal
antibodies against -dystroglycan fusion protein D were affinity
purified from goat 20.27
Immunofluorescence Analysis
The heart, femoral quadriceps, sural triceps, tongue, and diaphragm muscles were sampled in all animals. Additional skeletal muscle samples were taken from muscles that showed visible Evans blue staining. All tissues were embedded in Tissue-Tek OCT mounting media (Miles Laboratories, Elkhart, IN) and frozen in liquid nitrogen-cooled isopentane. Immunofluorescence microscopy of 7-µm cryosections was performed as described before.28,29 Briefly, sections were blocked with 5% bovine serum albumin (BSA) in PBS for 30 minutes and then incubated with the primary antibodies for 90 minutes in 1% BSA/PBS. After washing with 1% BSA/PBS, sections were incubated with biotinylated secondary antibodies (1:500) for 30 minutes, washed with 1% BSA/PBS, and then incubated with fluorescein-isothiocyanate-conjugated streptavidin (1:1000) for 30 minutes. After a rinse with PBS, sections were mounted with Vectashield mounting medium (Vector Laboratories, Burlingame, CA). Histochemical examination of tissues was performed using hematoxylin and eosin (H&E) staining. Sections were observed under a Zeiss Axioplan fluorescence microscope (Carl Zeiss, Thornwood, NY) or a MRC-600 laser scanning confocal microscope (Bio-Rad Laboratories, Hercules, CA).
Northern Blot Analysis
Total RNA from control F1B and BIO14.6 skeletal and cardiac muscle was extracted using RNAzol (Tel-Test, Friendswood, TX) according to manufacturer specifications, and 40 µg of total RNA was electrophoresed on a 1.25% agarose gel containing 5% formaldehyde and transferred to Hybond N membrane (Amersham Corp., Arlington Heights, IL). RNA was cross-linked to the membrane using an ultraviolet cross-linker (Stratagene, La Jolla, CA). Membranes were then prehybridized and hybridized in 20% formamide, 4X SSPE, 5X Denhardt's, 5% SDS, 10% dextran sulfate, 40 mmol/L HCl, 0.2 mg/ml yeast RNA, and 0.4 mg/ml single-stranded DNA at 65°C with polymerase chain reaction (PCR)-labeled or random-primed cDNA. Washes were carried out at 65°C in 1X SSC/1% SDS initially and then 0.2X SSC/1% SDS. As a control for loading, human actin cDNA (Clontech Laboratories, Palo Alto, CA) was used as a probe.
Sucrose Gradient Fractionation Analysis of Purified Dystrophin-Glycoprotein Complex
KCl-washed microsomes were prepared from age-matched control and BIO14.6 hamster skeletal muscle.30 KCl-washed microsomes (450 mg) were solubilized in 100 ml of 50 mmol/L Tris/HCl, pH 7.4, 500 mmol/L NaCl containing 1% digitonin (Sigma Chemical Co., St. Louis, MO). The solubilized proteins were circulated overnight on a 10-ml wheat germ agglutinin-agarose column (Vector Laboratories). The columns were washed with 100 ml of 50 mmol/L Tris/HCl, pH 7.4, 500 mmol/L NaCl containing 0.1% digitonin and eluted with 0.3 mol/L N-acetylglucosamine in 50 mmol/L Tris/HCl, pH 7.4, 500 mmol/L NaCl containing 0.1% digitonin. The eluted solution was diluted to 100 mmol/L NaCl with 50 mmol/L Tris/HCl, pH 7.4, containing 0.1% digitonin and applied to a DEAE-cellulose (3-ml) column and washed with 50 ml of 50 mmol/L Tris/HCl, pH 7.4, 100 mmol/L NaCl containing 0.1% digitonin. The column was eluted with a gradient of 100 mmol/L to 300 mmol/L NaCl buffer containing 50 mmol/L Tris/HCl, pH 7.4, 0.1% digitonin. The fractions containing DGC were pooled and concentrated to 800 µl. The samples were applied to a 5% to 30% sucrose gradient and centrifuged with a Beckman VTi65.1 vertical rotor at 200,000 x g for 90 minutes at 4°C. The gradients were fractionated into 1-ml fractions. KCl-washed microsomes from skeletal and cardiac muscle and gradient fractions were resolved by SDS-polyacrylamide gel electrophoresis (SDS-PAGE)31 on 3% to 15% linear gradient gels and transferred to nitrocellulose membranes.32 Immunoblot staining was performed as previously described.30
Evans Blue Dye Injection and Microscopic Evaluation
Evans blue (Sigma) was dissolved in PBS (10 mg/ml) and sterilized by passage through membrane filters with a pore size of 0.2 µm. Hamsters were anesthetized with pentobarbital (0.75 mg/10 g of body weight) via intraperitoneal injection, and 0.25 µl/10 g of body weight of the dye solution was injected intravenously through the front limb vein. Animals younger than 4 weeks were injected intraperitoneally. Animals were killed 48 hours after injection by asphyxiation with gaseous carbon dioxide. During the time period between injection and asphyxiation, animals were kept in standard laboratory cages. All hamsters were skinned and inspected for dye uptake in the skeletal muscles, indicated by blue coloration. Muscle sections for microscopic Evans blue dye (EBD) detection were incubated in ice-cold acetone at -20°C for 10 minutes and examined as described above.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To study the effect of the -sarcoglycan mutation on the
expression and localization of the sarcoglycans in skeletal and cardiac
muscle, we performed immunofluorescence analysis on cryosections of
normal and BIO14.6 hamsters. In control animals -, ß-, -, and
-sarcoglycan were homogeneously expressed at the muscle fiber plasma
membrane (Figure 1, A and B)
. In
contrast, the -sarcoglycan protein was completely deficient at the
sarcolemma of BIO14.6 skeletal muscle fibers and cardiomyocytes (Figure 1, A and B)
. In addition, there was a severe concomitant reduction of
-, ß-, and -sarcoglycan (Figure 1, A and B)
. We also asked
whether the -sarcoglycan mutation altered expression of other DGC
proteins. Immunofluorescence analysis revealed that dystrophin,
ß-dystroglycan, and the laminin 2 chain were expressed at
comparable levels in the BIO14.6 hamster and in control muscles (Figure 1, A and B)
. In contrast, expression of -dystroglycan was reduced at
the fiber surface in both skeletal and cardiac muscle tissues (Figure 1, A and B)
. However, the degree of reduction showed variation even
among littermates. In some cases, -dystroglycan was almost
completely deficient at the plasma membrane; in other cases, expression
levels were similar to those in control animals. We found no
correlation between the degree of -dystroglycan expression and the
age of the BIO14.6 hamsters.
|
-Sarcoglycan-Deficient Hamster
To confirm the reduction of all sarcoglycans at the sarcolemma in
BIO14.6 muscle, immunoblot analysis was performed on
sarcolemma-enriched preparations from control and BIO14.6 skeletal
muscle. All four sarcoglycans were greatly reduced or absent in
skeletal muscle membranes whereas dystrophin showed a slight reduction
in the BIO14.6 hamster compared with control animals (data not shown).
In all membrane preparations of the BIO14.6 hamster, -dystroglycan
was greatly reduced. Analysis of muscle extracts suggested that
-dystroglycan was synthesized and fully glycosylated, but it was not
associated with membranes (data not shown).
To examine the status of the dystroglycan complex in muscle lacking
-sarcoglycan, a glycoprotein preparation enriched in DGC components
was prepared from F1B and BIO14.6 skeletal muscle using chromatography
and sucrose gradient fractionation. Analysis of sucrose gradient
fractions was performed for the sarcoglycans and the dystroglycans
(Figure 2)
. The control hamster sucrose
gradient profile demonstrated that the sarcoglycans and - and
ß-dystroglycan co-sedimented with peak fractions 8 to 12 (Figure 2A)
.
In contrast, no sarcoglycan staining could be detected in BIO14.6
skeletal muscle fractions in agreement with immunofluorescence and
immunoblot analysis (Figure 2B)
. Interestingly, the dystroglycan
complex sedimented in two different peak fractions (4 to 6 and 8 to 12)
in control hamster, whereas the BIO14.6 dystroglycan complex sedimented
only in the earlier fractions 3 to 6 (Figure 2, A and B)
.
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To determine whether the loss of the entire sarcoglycan complex
and the reduction of -dystroglycan from the plasma membrane
reflected transcriptional regulation, we performed RNA analysis of
skeletal and cardiac tissues. For this, we used a full length reverse
transcription PCR product containing the entire coding sequence of the
-sarcoglycan gene. A major transcript of 9.5 kb, three transcripts
between 3 and 4 kb, and several transcripts around 1.35 kb were
detected in skeletal muscle (Figure 3A)
and cardiac tissue (Figure 3B)
of the control hamster. All of these
transcripts were dramatically reduced in the cardiomyopathic hamster
even after overexposure of the autoradiograms. In parallel, we analyzed
the expression of -, ß-, and -sarcoglycan in control and
cardiomyopathic skeletal and cardiac muscle and detected identical
message levels and sizes in each case (Figure 3, A and B)
. Because we
had demonstrated reduced expression of -dystroglycan in skeletal and
cardiac muscle of diseased hamsters by immunohistochemical and
biochemical analysis, we also investigated mRNA levels of dystroglycan.
The dystroglycan transcript in skeletal muscle of the BIO14.6 hamster
showed equal to higher levels compared with control animals (Figure 3A)
. In cardiac muscle, we detected identical message levels for
-dystroglycan in the control and BIO14.6 strains (Figure 3B)
. These
results confirm and extend those of previous reports.18,33
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-Sarcoglycan-Deficient Muscle
The DGC is believed to play an important role in linking the
cytoskeleton to the extracellular matrix, thereby maintaining the
structural integrity of the plasma membrane.34-36
Here, we
tested whether the mutation of the -sarcoglycan gene leads to plasma
membrane disruptions in skeletal muscle fibers of BIO14.6 hamsters.
Membrane permeability was assessed by intravenous injection of EBD, a
normally membrane-impermeant molecule. No obvious tracer uptake into
skeletal muscles of F1B control hamsters at any age was detected by
macroscopic inspection. Up to approximately 3 weeks of age, we also
found no dye uptake into skeletal muscles of BIO14.6 animals. In
contrast, intravenously administered EBD always stained skeletal
muscles in BIO14.6 hamsters of 6 weeks or older (Figure 4)
. The extent of EBD accumulation varied
among muscles. Areas of blue staining appeared mainly within the
proximal limb muscles and the muscles of the pelvic and the shoulder
girdle. Furthermore, the diaphragm and intercostal muscles always
showed partial incorporation of the dye into muscle fibers if diseased
animals were older than 4 weeks of age. The intercostals often showed
clusters of blue fibers that ran throughout the entire length of the
muscle (Figure 4)
. We found significant variation in the amount and
distribution of blue fibers between the BIO14.6 hamsters. The uptake of
the tracer into certain skeletal muscles could not be correlated with
the age of the animals and showed variability even between littermates.
|
. Intensity of the dye signal also
showed differences between fibers (Figure 5)
. An interesting finding
was the arrangement of EBD-positive fibers into groups (Figure 5)
.
Grouping of EBD-positive fibers was observed in all investigated muscle
types (Figure 5)
. On longitudinal sections we could demonstrate that
dye uptake was not confined to a small part of the fiber but appeared
over long segments of the entire muscle cell. In addition to the
muscles of the limbs and the trunk, we also looked at the muscle tissue
of the tongue for EBD uptake, as tongue lesions have been reported to
occur in 100% of the BIO14.6 hamsters.37
In the F1B
control strain, EBD-positive fibers in the tongue were not observed
(Figure 5)
. In contrast, all BIO14.6 animals older than 4 weeks of age
showed partial EBD-positive fibers (Figure 5)
. Furthermore, we looked
at EBD uptake into skeletal muscle fibers of the esophagus in
4-month-old F1B and BIO14.6 animals. Again, we found no dye uptake into
muscle fibers of control animals, whereas in diseased animals,
EBD-positive skeletal muscle cells were frequently detected (Figure 5)
.
Dye-positive fibers often showed characteristic features of
degeneration and necrosis in H&E staining.
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2 chain. EBD-positive fibers showed a
complete basal lamina, suggestive of normal regenerative potential
(data not shown).
After intravenous EBD injection, dye uptake was not readily visible in
cardiac muscle by macroscopic inspection, but microscopic analysis
revealed EBD in cardiomyocytes of BIO14.6 hamsters 4 weeks or older
(Figure 6)
. Dye uptake into cardiac
muscle cells did not occur in diseased animals younger than 4 weeks or
in control animals of any age (Figure 6)
. Most frequently, EBD-positive
fibers were detected in small clusters in the ventricular walls (Figure 6)
. Affected cells were homogeneously stained with the tracer and
showed signs of degeneration and necrosis by H&E staining.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-sarcoglycan mutation in cardiac and skeletal
muscle tissues of the BIO14.6 cardiomyopathic hamster. We demonstrated
that loss of -sarcoglycan from muscle fiber plasma membranes led to
reduced expression of several other components of the DGC, including
other sarcoglycans and -dystroglycan. Our findings confirmed the
tight association between sarcoglycans and suggest a close relationship
between the sarcoglycan and dystroglycan complexes. Although abnormal
expression of sarcoglycans and -dystroglycan in the BIO14.6 hamster
had been previously shown,18,33,40,41
this is the first
time that specific antibodies against all sarcoglycans and the
dystroglycans have been used for analysis in the animal. The
affinity-purified antibody against -dystroglycan allowed us for the
first time to demonstrate reduction of this peripheral glycoprotein by
immunohistochemical analysis in a subset of animals. Interestingly, the
reduction of -dystroglycan in BIO14.6 skeletal muscle tissue was not
a consistent immunohistochemical finding and even age- and sex-matched
animals revealed different expression levels, ranging from normal to
severely reduced. This observation may explain the results of a
previous report in which a reduction of -dystroglycan by
immunofluorescence analysis was not demonstrated.40
The
observation may also account for the considerable variation of disease
course in the cardiomyopathic animals, which can be slowly progressive
and, in other cases, rapidly leading to death within 80
days.42,43
Similar findings have been reported in families
with sarcoglycan-deficient LGMD, where patients with the same mutation
displayed both mild and severe forms of muscular dystrophy, implicating
other loci or environmental factors as mediators of the dystrophic
process.44
In the membrane preparations of the BIO14.6
hamster, on the other hand, we always found a reduction of
-dystroglycan. This may be explained by the fact that the anchorage
of -dystroglycan to the sarcolemma is impaired by sarcoglycan
deficiency and that during the microsome preparation -dystroglycan
may easily detach from the membrane. Our findings from Northern blot
analysis of skeletal and cardiac muscle samples indicated that effects
of the deletion in the -sarcoglycan gene on other DGC components are
post-transcriptional.
Functional Impairment of Plasma Membrane Integrity in Striated
Muscle Tissue of the -Sarcoglycan-Deficient BIO14.6 Hamster
It has recently been shown that loss of sarcolemmal integrity is a
characteristic feature of dystrophin-deficient muscular
dystrophies.35,45,46
Due to the phenotypic similarity
between Duchenne and Becker muscular dystrophy and the
sarcoglycan-deficient LGMDs, we investigated the status of sarcolemmal
damage in the BIO14.6 hamster by using intravenously injected EBD as an
in vivo tracer for membrane damage. The consistent finding
of EBD uptake into skeletal muscles of the cardiomyopathic hamster
emphasized the role membrane lesions play in the pathogenesis of this
disease model. This was further underlined by focal groups of
EBD-positive fibers in cardiac muscle of the BIO14.6 hamster. The
intravenous injection of EBD into BIO14.6 hamsters also revealed
membrane damage in the skeletal muscle layer of the esophagus. Although
only the proximal one-third of the esophagus is surrounded by skeletal
muscle fibers in humans, fiber damage in this region could cause the
swallowing problems reported for patients with muscular
dystrophy.47,48
Another interesting result we obtained by
EBD injection were membrane lesions in the tongue of the BIO14.6
hamster. There are several lines of evidence that sarcolemmal damage
leads to the release of growth factors into the surrounding
tissue.49,50
These growth factors may play an important
role in the pathogenic process of fibrosis and fiber hypertrophy in
dystrophic muscle tissue. They may not just be responsible for
hypertrophy of the calves, as reported in patients with
sarcoglycan-deficient LGMD,51
but could also explain
macroglossia in some of the patients with muscular
dystrophy.47
A common feature between the
dystrophin-deficient mdx mouse and the sarcoglycan-deficient
hamster were clusters of EBD-positive fibers in skeletal and cardiac
muscle.46
Moreover, both animal models reveal a reduction
of -dystroglycan at the sarcolemma. Structural and functional
alterations of this molecule may play an important role in the
pathogenesis of muscular dystrophies associated with the DGC. Our
biochemical findings gave additional evidence that the -sarcoglycan
mutation in the BIO14.6 hamster effects the stability of dystroglycan
at the muscle fiber plasma membrane. Although we are at present unable
to offer a precise description of the pathogenic pathway that accounts
for muscle fiber necrosis in muscular dystrophies, we have demonstrated
that loss of plasma membrane integrity in skeletal muscle fibers might
play a primary role in the course of these progressive muscle diseases.
Efforts to fully understand the functional role of the sarcoglycans
will involve the identification of their intracellular and
extracellular binding partners.
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Acknowledgements |
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Footnotes |
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Supported by a grant from the Deutsche Forschungsgemeinschaft (Str 498/1–1 to V. Straub) and by the Muscular Dystrophy Association (to K.P. Campbell) and the L'Association Française contre les Myopathies (to K.P. Campbell). K.P. Campbell is an Investigator of the Howard Hughes Medical Institute.
Accepted for publication August 5, 1998.
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References |
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-sarcoglycan in chromosome 13 muscular dystrophy. Science 1995, 270:819-8222-chain gene (LAMA2) cause merosin-deficient congenital muscular dystrophy. Nature Genet 1995, 11:216-218[Medline]
2-chain. Hum Mol Genet 1997, 6:747-752-sarcoglycans are normal in cardiomyopathic hamster heart. Biol Pharm Bull 1997, 20:134-137[Medline]
-sarcoglycan mutation. Am J Hum Genet 1996, 59:1040-1047[Medline]
-sarcoglycans in 20 -sarcoglycan (adhalin)-deficient patients: immunohistochemical analysis and clinical aspects. Acta Neuropathol (Berl) 1997, 94:28-35[Medline]
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H. Yamada, F. Saito, H. Fukuta-Ohi, D. Zhong, A. Hase, K. Arai, A. Okuyama, R. Maekawa, T. Shimizu, and K. Matsumura Processing of {beta}-dystroglycan by matrix metalloproteinase disrupts the link between the extracellular matrix and cell membrane via the dystroglycan complex Hum. Mol. Genet., July 1, 2001; 10(15): 1563 - 1569. [Abstract] [Full Text] [PDF]
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 H. Ueda, K. Ueda, T. Baba, and S. Ohno {{delta}}- and {{gamma}}-Sarcoglycan Localization in the Sarcoplasmic Reticulum of Skeletal Muscle J. Histochem. Cytochem., April 1, 2001; 49(4): 529 - 538. [Abstract] [Full Text]
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V. Allamand and K. P. Campbell Animal models for muscular dystrophy: valuable tools for the development of therapies Hum. Mol. Genet., October 1, 2000; 9(16): 2459 - 2467. [Abstract] [Full Text] [PDF]
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