Human Molecular Genetics Advance Access originally published online on February 2, 2005
Human Molecular Genetics 2005 14(6):775-783; doi:10.1093/hmg/ddi072
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Human Molecular Genetics, Vol. 14, No. 6 © Oxford University Press 2005; all rights reserved
-Sarcoglycan compensates for lack of 
-sarcoglycan in a mouse model of limb-girdle muscular dystrophy
1Department of Molecular Therapy, National Institute of Neuroscience, NCNP, 4-1-1 Ogawahigashi-cho, Kodaira, Tokyo 187-8502, Japan, 2Department of Plastic and Reconstructive Surgery, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan and 3The Burnham Institute, La Jolla, CA 92037, USA
* To whom correspondence should be addressed. Tel: +81 423461720; Fax: +81 423461750; Email: imamura{at}ncnp.go.jp
Received October 18, 2004; Accepted January 24, 2005
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ABSTRACT |
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Dystrophin and the dystrophin-associated protein (DAP) complex protect the sarcolemma against contraction-induced injury and serve as a mechanical link between the extracellular matrix and the actin cytoskeleton. Some of the functional properties of the DAP complex are mediated by its sarcoglycan (SG) subcomplex, which is composed of
-, ß-, 
- and 
-SGs. Autosomal recessive limb-girdle muscular dystrophy type-2D (LGMD 2D) results from reduction in SG subcomplex levels caused by specific mutations in the muscle-specific -SG gene. 
-SG is a widely expressed homolog of the muscle-specific -SG, and expression of -SG may compensate for the pathologic changes in -SG function. Thus, the goal of the present study was to investigate whether overexpression of -SG can compensate for dysfunction of -SG. Several transgenic mouse lines that overexpress -SG in skeletal muscle were established. Overexpression of -SG in normal mice resulted in substitution of -SG for -SG in the SG complex of skeletal muscle without any obvious abnormalities. To determine whether an increase in -SG expression may prevent muscular dystrophy in the context of -SG-deficiency, these -SG transgenic mice were crossed with -SG deficient mice. -SG-deficient mice overexpressing -SG exhibited no skeletal muscle cell membrane damage or abnormal contraction. These data suggest that the overexpression of -SG may represent a therapeutic strategy for treatment of LGMD 2D. |
INTRODUCTION |
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Sarcoglycans (SGs) are essential constituents of the dystrophin-associated protein (DAP) complex, which consists of several membrane-spanning and cytoplasmic proteins, including dystroglycans (
and ß), SGs (, ß, and ), sarcospan, syntrophins (1, ß1 and ß2) and dystrobrevins that directly or indirectly associate with dystrophin (1
–3). Dystrophin is an actin-binding cytoskeletal protein that mediates the association of cytoplasmic microfilaments to dystroglycan, which binds to laminin in the extracellular matrix (4). The dystrophin–DAP complex functions to protect the plasma membrane of striated muscle fibers from contraction-induced mechanical stress (3,5).
-, ß-, - and -SGs are membrane-spanning glycoproteins that associate with - and ß-dystroglycan and sarcospan (6,7). A defect in any one of the four SGs can disrupt the entire SG complex and lead to limb-girdle muscular dystrophy (LGMD types 2C–2F) (8–13). Analyses of striated muscle of SG-deficient animals have shown that the loss of the SG complex destabilizes interactions between - and ß-dystroglycans and between dystrophin and ß-dystroglycan (14–16). These findings indicate that SGs play an important role in stabilizing the molecular axis of the dystrophin–DAP complex, but are functional only when they exist as a complex.
-SG deficiency causes muscular dystrophy in human (LGMD 2D). -SG and -SG appear closely related to each other at the amino acid sequence level; however, their tissue and cell localization differs (17,18). Whereas -SG is only expressed in striated muscle, -SG is expressed in a variety of tissues including striated muscle, smooth muscle, lung, liver, kidney, spleen, testis, sciatic nerve and brain (17,19,20). Loss-of-function mutations in the -SG gene (SGCE) cause myoclonus–dystonia syndrome rather than muscular dystrophy (21). -SG deficiency causes a significant reduction in formation of the SG subcomplex in the dystrophin–DAP complex, but residual SG complexes may form in the absence of -SG and are composed of -, ß-, - and -SGs (22). In fact, an -SG complex represents a major SG complex in certain cells including smooth muscle cells (23,24). However, although -SG may be functionally similar to -SG, the low level of residual -SG complex in skeletal muscle cells does not prevent the development of muscular dystrophy in -SG-deficient mice (22,25). Therefore, the goal of the present study was to determine whether overexpression of -SG may compensate for -SG deficiency and prevent the muscular dystrophy phenotype in -SG-deficient mice.
To investigate whether an increase in levels of the minor SG complex in skeletal muscle prevents muscular dystrophy in -SG-deficiency, transgenic mice overexpressing mouse -SG were generated. In a wild-type background, overexpression of -SG reduced the amount of -SG at the sarcolemma and increased the incorporation of -SG into an SG complex without obvious side effects. In an -SG-deficient background, the increased -SG levels prevented the development of muscular dystrophy in mice up to at least 1 year of age. Biochemical and immunohistochemical analyses revealed that -SG overexpression resulted in the construction of a stable -SG-containing complex in the absence of -SG.
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RESULTS |
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Overexpression of
-SG increases -SG-deficient complex formationTwo types of SG complexes exist in normal skeletal muscle: a major complex, composed of
-, ß-, - and -SGs, and a minor complex, composed of -, ß-, - and -SGs (22). The minor complex exists even in -SG deficiency, but it does not prevent the development of muscular dystrophy. Analysis demonstrated that the minor -SG-containing complex (–ß––) was present at levels that were less than one-tenth those of the major -SG-containing complex in skeletal muscle (Fig. 1). To determine whether higher levels of the -SG complex can compensate for -SG deficiency, transgenic mouse lines expressing -SG under muscle-specific -SG gene promoter were generated (Fig. 2A). The transgene product was tagged at the C-terminal with a c-myc sequence to distinguish it from endogenous -SG. Four independent mouse lines, e3, e17, e27 and e29 showed varying levels of -SG mRNA in the skeletal muscle (Fig. 2B). The -SG mRNA levels were the highest in the e17 line (30-fold of normal endogenous levels) and were the lowest in the e27 line (6-fold). Transgene expression appeared to correlate with slightly reduced levels of -SG, but did not affect the levels of the other SGs (, ß and ). Interestingly, immunoblot analysis showed that the amount of -SG immunoreactivity, as a measure of protein level, did not correlate with -SG mRNA levels in the transgenic lines (Fig. 2C); all lines showed similar increases in -SG immunoreactivity levels in skeletal muscle, as compared to wild-type C57BL/6 (B6) mice. In contrast, the amount of -SG immunoreactivity was markedly lower in all transgenic lines when compared with wild-type mice. Levels of other interaction partners of -SG (e.g. ß- and -SGs and ß-dystroglycan) were similar in skeletal muscle from transgenic and wild-type mice.
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10% of that of
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The 5'-gsg (mouse
-SG) promoter/enhancer is less active in heart and testis than in skeletal muscle (26). Accordingly, c-myc-tagged -SG protein was only weakly detected in heart and absent in testis of e17 transgenic mice. Expression of the transgene had a minimal effect on -SG protein levels in the heart (Fig. 2D).
Immunostaining of sections of quadriceps muscles from e17 mice using anti-SG antibodies demonstrated a marked increase in -SG-staining and a marked decrease in -SG-staining of the sarcolemma (Fig. 3A), which is consistent with the immunoblotting results (Fig. 2C). However, the amounts and localizations of other SGs (ß, and ), sarcospan, dystrophin and utrophin remained unchanged. Similar results were obtained when using skeletal muscles from the three other transgenic lines, e3, e27 and e29 (data not shown). These finding suggest that overexpression of -SG replaced -SG at the sarcolemma, and that the amount of -SG at the sarcolemma is limited by levels of other SGs, even when -SG is overexpressed.
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Immunofluorescent staining of hearts from the e17 line revealed a mosaic pattern of transgene expression in a limited region of the ventricle (Fig. 3B). Relatively few cardiomyocytes showed high levels of c-myc-tagged
-SG with low levels of -SG expression. Most of the cardiomyocytes exhibited strong expression of -SG at the cell membrane, which is consistent with the immunoblotting results (Fig. 2D).
To determine whether -SG replaced -SG within the SG complex, interaction partners of -SG were immunoprecipitated from the leg muscle of transgenic mice (Fig. 3C). The anti-c-myc antibody co-immunoprecipitated -, ß,- - and -SG as well as sarcospan and ß-dystroglycan. The same pattern of co-precipitation was observed when an anti-ß-SG antibody was used for immunoprecipitation, demonstrating that the -SG transgene product was incorporated into the SG subcomplex of the DAP complex at the sarcolemma. Moreover, -SG was undetectable in this experiment suggesting that the normal adult -SG complex was replaced by an -SG complex composed of -, ß-, - and -SGs. No histopathological abnormalities, such as necrosis and regeneration of myocytes, interstitial fibrosis and fatty infiltration, were observed in the muscle of these mice up to 1 year of age. Furthermore, although the -SG gene is associated with myoclonus–dystonia syndrome (21), there were no abnormal behavior or muscle contractions in mice overexpressing -SG.
-SG overexpression prevents muscular dystrophy in -SG-deficient mice
To determine whether increased -SG levels could ameliorate the phenotype conferred by -SG deficiency, the transgenic mouse lines were crossed with -SG-deficient (Sgca–/–) mice, which represents the model for LGMD 2D. Two lines of Sgca–/–/tg (Sgca–/–/e17 and Sgca–/–/e27) were used for most analyses. Immunostaining analysis clearly showed normal expression and localization of ß-, - and -SGs and of sarcospan within the skeletal muscle of the Sgca–/–/tg mice (Fig. 4A). Furthermore, immunoprecipitation analysis with anti-c-myc and anti-ß-SG antibodies demonstrated normal assembly of the components of the DAP complex in the Sgca–/–/e17 muscle (Fig. 4B). These data indicate that -SG assembled with ß-, - and -SG in the absence of -SG and was correctly localized to the sarcolemma.
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To determine whether the
–ß–– complex was functional in muscle, muscle injury was assessed by measuring serum levels of muscle-specific creatine kinase (CK). Ten-week-old Sgca–/– mice had dramatically elevated serum levels of CK, whereas their Sgca–/–/tg littermates had CK levels that were similar to those of the wild-type B6 mice (Fig. 5A), indicating a lack of membrane leakage and necrosis in the Sgca–/–/tg mice. Muscle membrane integrity was also evaluated by the analysis of serum IgG uptake into muscle fibers (27) (Fig. 5B). Analysis of the tibialis anterior (TA) and rectus femoris muscles of Sgca–/– showed 6.2 ± 0.3% and 7.6 ± 0.8% IgG-positive fibers, respectively, whereas IgG-positive fibers were not observed in the muscles of Sgca–/–/tg littermates or of B6 mice. Histopathological examination of the TA, rectus femoris and diaphragm of 10-week-old Sgca–/– mice revealed -SG deficiency and evidence of muscular dystrophy including degeneration, regeneration, central nucleation and variable sizes of muscle fibers (Fig. 5C and D). In contrast, no such signs were detected in Sgca–/–/e17 mice up to 1 year of age.
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Contractile force generation of TA muscles from Sgca–/–, Sgca–/–/e17, e17 transgenic and normal B6 mice (Fig. 5E) was measured to evaluate functional recovery. Specific forces in Sgca–/–/e17 TA muscles were similar to those of B6 and e17 mice and were significantly stronger than those of Sgca–/– mice, suggesting that
–ß–– complexes are physiologically functional. Furthermore, these data suggest that -SG acts as a functional homolog of -SG in muscle and that -SG can act as a structural and functional replacement for -SG in the context of -SG deficiency. |
DISCUSSION |
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The present study demonstrated that
-SG can compensate for -SG deficiency and contribute to the formation of a stable dystrophin–DAP complex in skeletal muscle with amelioration of the dystrophic phenotype. Previous biochemical studies reported that the SG complex reinforces the dystrophin–dystroglycan molecular linkage between the extracellular matrix and cytoskeletal actin (14–16). Observations from the present study are consistent with this report and demonstrate that the -SG-containing SG complex (–ß––) has the same ability to stabilize the molecular linkage in skeletal muscle as the normal major SG complex (–ß––) in skeletal muscle.
In addition to a structural role, the SG complex may function as a scaffold and as an enzyme in various signal-transduction pathways (7,28,29). Indeed, -SG possesses a consensus sequence for nucleotide binding in its extracellular domain and was reported to act as an ecto-ATPase, suggesting that the loss of -SG in sarcoglycanopathies (LGMD 2C–2F) may elevate the extracellular ATP concentration around muscle fibers and result in prolonged stimulation of P2X receptors, calcium overload and muscle cell death (28). However, -SG does not possess this conserved sequence for nucleotide binding but can still compensate for -SG deficiency, suggesting that the loss of the -SG ecto-ATPase activity is not a major factor in the development of muscular dystrophy in sarcoglycanopathies.
We demonstrated that increased -SG expression in skeletal muscle of transgenic mice induces down-regulation of the -SG protein without changing the mRNA level. Analysis of cardiomyocytes showed that the amount of -SG protein in the cell membrane was indirectly correlated with that of -SG protein. These findings suggest that the amount of -SG in striated muscle is regulated by post-translational mechanisms. - and -SG proteins may compete in the process of SG complex formation in endoplasmic reticulum (30). Interestingly, a similar reciprocity between -SG and -SG protein expression is found during skeletal muscle development in wild-type mice (31). -SG protein is predominant at an early developmental stage, i.e. in myoblasts or myotubes in the formation of axial muscle, and declines after the increase in -SG protein. However, in the adult, the -SG protein is kept at low levels, even when -SG is completely absent from muscle cells (22,25), suggesting that the amount of -SG during skeletal muscle development is regulated at the transcriptional level as is the case of -SG expression (32).
In the present study, -SG levels in normal skeletal muscle tissue were approximately one-tenth those of -SG. Since -SG is highly expressed in vascular smooth muscle, endothelial cells and peripheral nerves, the amount of -SG-containing SG complex in skeletal muscle cells would be considerably less than 10%. It is not known whether this minor SG complex has a distinct function in normal skeletal muscle and to what degree it contributes to stabilization of the cell membrane. Loss-of-function mutations of the -SG gene cause myoclonus–dystonia syndrome but do not result in any obvious abnormalities in skeletal muscle and heart tissues (21). Therefore, the -SG-containing SG complex does not appear to be critical for the development and maintenance of the normal striated muscle cell. However, the presence of the minor -SG complex may reduce the severity of the phenotype associated with -SG deficiency.
Previous studies of experimental SG-deficiencies using viral vectors showed that increasing the levels of -SG, but not the levels of ß-, - or -SG, resulted in cytotoxity in skeletal muscle cells (33–35), possibly secondary to perturbations in SG complex assembly (33). In the present study, several transgenic mouse lines displayed equal levels of -SG immunoreactivity, despite the differing levels of -SG mRNA. Moreover, the transgene expression did not influence the immunoreactivity levels of other endogenous SGs (ß-, - and -SGs). This suggests that increased synthesis of -SG has no adverse effects on SG complex formation and that excess -SG may be degraded intracellularly without causing muscle pathology. This situation is similar to the lack of adverse effects observed when utrophin is overexpressed in normal or dystrophin-deficient muscle (36).
In conclusion, these findings show that -SG is an excellent replacement for -SG in mice and suggest that -SG expression may be a therapeutic target for the treatment of LGMD 2D in humans. Because -SG is encoded in a gene that is maternally imprinted (37,38), reactivation of the silenced maternal allele could potentially be achieved pharmacologically (39,40). It will be interesting to try to find and develop strategies for up-regulation of the endogenous -SG in striated muscle in the future.
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MATERIALS AND METHODS |
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-SG cDNA.Full-length mouse
-SG (nucleotides 10–1404 of GenBank accession no. AF031919) was cloned from a mouse skeletal muscle cDNA library (Clontech, Palo Alto, CA, USA) by polymerase chain reaction (PCR), as described previously (32). In order to add the c-myc-epitope sequence at the C-terminal of -SG, the cloned cDNA was subjected to repetitive PCR with reverse primers tagged with the c-myc-epitope sequence. The final cDNA product (1.3 kb) was cloned into pCR2.1 (Invitrogen Life Technologies, Carlsbad, CA, USA) and sequenced, as described previously (19).
Transgenic mice
A transgene vector was generated by replacement of the EGFP cDNA with the c-myc-tagged mouse -SG cDNA in the 5'-gsg (mouse -SG promoter/enhancer)-containing expression construct (26). The linear transgene construct (4.4 kb) was excised by digestion with SpeI and SalI prior to microinjection into pronuclei of fertilized eggs of C57BL/6 (B6) mice. Genomic DNA was extracted from tails and screened by PCR for integration of the transgene. The -SG transgenic (heterozygous) male mice were bred to -SG-deficient (Sgca–/–) female mice (22) supplied from the Burnham Institute (La Jolla, CA, USA). The resulting male mice (transgenic-Sgca+/–) were bred with Sgca–/– female mice and their offspring, transgenic-Sgca–/– and Sgca–/– mice, were used for analysis. The transgenic-Sgca–/– male mice were further bred with Sgca–/– female mice, and their offspring were used for analysis with an IgG-staining assay, quantification of centrally nucleated fibers and measurement of muscle contraction.
Tetanic force of TA muscles from 9-week-old Sgca–/– and Sgca–/–/e17 littermates and age-matched e17 transgenic and B6 normal mice was measured at a stimulus frequency of 126 Hz, as described previously (41). Serum CK levels of the mice were measured by the SRL Laboratory (Tokyo, Japan). All animal handling procedures were performed in accordance with a protocol approved by the National Institute of Neuroscience, NCNP, Japan.
Northern blot analysis
Two micrograms of total RNA were prepared from leg muscle of 5-week-old transgenic mice and wild-type (B6) mice and were separated by formaldehyde/agarose gel electrophoresis before transferring onto Nylon Membranes (Roche Diagnostics, Mannheim, Germany). Digoxigenin (DIG)-labeled SG RNA probes were generated by in vitro transcription using T7 RNA polymerase and were used for the detection of SG mRNAs according to the manufacturer's protocol.
Antibodies
Mouse monoclonal antibodies against -SG (NCL-a-SARC), ß-SG (NCL-b-SARC), -SG (NCL-g-SARC) and ß-dystroglycan (NCL-b-DG) were purchased from Novo Castra Laboratories (Newcastle-upon-Tyne, UK). A mouse monoclonal antibody against c-myc (9E10) and a 9E10-agarose-coupled antibody were purchased from Santa Cruz Biotechnology (Santa Cruz, CA, USA). A rat monoclonal antibody against the laminin-2 chain (4H8-2) was purchased from Alexis (Läufelfingen, Switzerland). Anti-c-myc rabbit antibodies were purchased from Upstate Biotechnology (Lake Placid, NY, USA) and MBL (Nagoya, Japan). A mouse monoclonal antibody against -SG (DSG-1) and affinity-purified rabbit antibodies against -SG, ß-SG, mouse sarcospan, ß-dystroglycan and utrophin (UT-2) were generated (16,19), and immunoprecipitation and immunoblotting were performed with these antibodies as previously described (19).
An anti-SG rabbit antibody, which recognizes homologous regions of - and -SG (/-SG antibody), was prepared by affinity-purification. The anti--SG cytoplasmic region (-SGcyt) antiserum was affinity-purified using recombinant glutathione S-transferase (GST) and GST--SGcyt fusion protein (19). This anti--SGcyt antibody was then further purified using a GST-fusion protein with the -SG cytoplasmic region (16). Quantification of /-SG immunoreactivity in immunoblot analysis (Fig. 1) was performed using an image analyzer (Lumi-Imager; Roche Diagnostics).
Histology
Muscles were immersed in Tragacanth Gum (Wako, Tokyo, Japan) and rapidly frozen in liquid nitrogen-cooled isopentane. Cryosections were subjected to hematoxylin and eosin (H&E) staining or to indirect immunofluorescent staining under conditions described previously (42).
Centrally nucleated fibers were counted in transverse H&E cryosections of TA and rectus femoris muscles from Sgca–/– and Sgca–/–/e17 littermates and from B6 normal mice.
Serum protein IgG that infiltrated into dystrophic muscle fibers was detected by immunofluorescent labeling (27). Labeling was performed on 3.5% formaldehyde-fixed 8 µm transverse cryosections using a Cy3-conjugated goat antibody against mouse IgG (Jackson ImmunoResearch, West Grove, PA, USA). To identify muscle fibers, these sections were double-stained with a rat monoclonal antibody against laminin-2 chain (4H8-2), as described previously (42). Fluorescent signal on the cryosections was observed under a confocal laser scanning microscope (Leica TCS SP; Leica, Heidelberg, Germany). IgG-positive and -negative fibers on the micrographs of the stained muscle sections were counted.
Double-staining of heart cryosections from e17 transgenic mice were performed using rabbit antibodies against the c-myc epitope tag and -SG. The heart cryosections were subsequently reacted with an anti-c-myc rabbit antibody (MBL) and a FITC-conjugated goat Fab (monovalent) antibody fragment against rabbit IgG. After washing with phosphate-buffered saline, these sections were reacted with Alexa568-conjugated affinity purified rabbit antibody against -SG.
Statistical analysis
The data shown in Fig. 5A, D and E and IgG-staining of muscle fibers are expressed as mean ± SEM. If a significant F ratio was detected after analysis of variance, comparisons among each group were performed using Fisher's PLSD. A P-value of <0.05 was considered to be statistically significant.
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ACKNOWLEDGEMENTS |
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We thank N. Noguchi for providing the 5'-gsg-promoter/enhancer cDNA and T. Sasaoka for advice on maintenance and care of mice. This study was supported by Grants-in-Aid for Center of Excellence (COE), Research on Nervous and Mental Disorders (13B-1), and Health Sciences Research Grants for Research on Psychiatric and Neurological Diseases and Mental Health (H12-kokoro-025), the Human Genome and Gene Therapy (H13-genome-001) from the Ministry of Health, Labor and Welfare of Japan, and a Grant-in-Aid for Scientific Research (B) from the Ministry of Education, Science, Sports and Culture of Japan (to M.I., Y.M. and S.T.) and from the National Institutes of Health and the Muscular Dystrophy Association, USA (to E.E.).
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