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Eijiro Ozawa - One of the best experts on this subject based on the ideXlab platform.
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Loss of the Sarcoglycan Complex and Sarcospan Leads to Muscular Dystrophy in β-Sarcoglycan-Deficient Mice
Human molecular genetics, 1999Co-Authors: Kenji Araishi, Satoru Noguchi, Toshikuni Sasaoka, Michihiro Imamura, Hiroshi Hama, Eriko Wakabayashi, Mikiharu Yoshida, Tetsuro Hori, Eijiro OzawaAbstract:beta-Sarcoglycan, one of the subunits of the sarcoglycan complex, is a transmembranous glycoprotein which associates with dystrophin and is the molecule responsible for beta-Sarcoglycanopathy, a Duchenne-like autosomal recessive muscular dystrophy. To develop an animal model of beta-Sarcoglycanopathy and to clarify the role of beta-sarcoglycan in the pathogenesis of the muscle degeneration in vivo, we developed beta-sarcoglycan-deficient mice using a gene targeting technique. beta-Sarcoglycan-deficient mice (BSG(-)(/-)mice) exhibited progressive muscular dystrophy with extensive degeneration and regeneration. The BSG(-)(/-)mice also exhibited muscular hypertrophy characteristic of beta-Sarcoglycanopathy. Immunohistochemical and immunoblot analyses of BSG(-)(/-)mice demonstrated that deficiency of beta-sarcoglycan also caused loss of all of the other sarcoglycans as well as of sarcospan in the sarcolemma. On the other hand, laminin-alpha2, alpha- and beta-dystroglycan and dystrophin were still present in the sarcolemma. However, the dystrophin-dystroglycan complex in BSG(-)(/-)mice was unstable compared with that in the wild-type mice. Our data suggest that loss of the sarcoglycan complex and sarcospan alone is sufficient to cause muscular dystrophy, that beta-sarcoglycan is an important protein for formation of the sarcoglycan complex associated with sarcospan and that the role of the sarcoglycan complex and sarcospan may be to strengthen the dystrophin axis connecting the basement membrane with the cytoskeleton.
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From dystrophinopathy to Sarcoglycanopathy: Evolution of a concept of muscular dystrophy
Muscle & nerve, 1998Co-Authors: Eijiro Ozawa, Satoru Noguchi, Yuji Mizuno, Yasuko Hagiwara, Mikiharu YoshidaAbstract:Duchenne and Becker muscular dystrophies are collectively termed dystrophinopathy. Dystrophinopathy and severe childhood autosomal recessive muscular dystrophy (SCARMD) are clinically very similar and had not been distinguished in the early 20th century. SCARMD was first classified separately from dystrophinopathy due to differences in the mode of inheritance. Studies performed several years ago clarified some immunohistochemical and genetic characteristics of SCARMD, but many remained to be clarified. In 1994, the sarcoglycan complex was discovered among dystrophin-associated proteins. Subsequently, on the basis of our immunohistochemical findings which indicated that all components of the sarcoglycan complex are absent in SCARMD muscles, and the previous genetic findings, we proposed that a mutation of any one of the sarcoglycan genes leads to SCARMD. This hypothesis explained and predicted various characteristics of SCARMD at the molecular level, most of which have been verified by subsequent discoveries in our own as well as various other laboratories. SCARMD is now called Sarcoglycanopathy, which is caused by a defect of any one of four different sarcoglycan genes, and thus far mutations in sarcoglycan genes have been documented in the SCARMD patients. In this review, the evolution of the concept of Sarcoglycanopathy separate from that of dystrophinopathy is explained by comparing studies on these diseases.
Toshikuni Sasaoka - One of the best experts on this subject based on the ideXlab platform.
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Cleavage of β-dystroglycan occurs in sarcoglycan-deficient skeletal muscle without MMP-2 and MMP-9.
Biochemical and biophysical research communications, 2017Co-Authors: Yuta Fukai, Toshikuni Sasaoka, Yutaka Ohsawa, Hideaki Ohtsubo, Shin Ichiro Nishimatsu, Hiroki Hagiwara, Makoto Noda, Tatsufumi Murakami, Yoshihide SunadaAbstract:Abstract Background The dystroglycan complex consists of two subunits: extracellular α-dystroglycan and membrane-spanning β-dystroglycan, which provide a tight link between the extracellular matrix and the intracellular cytoskeleton. Previous studies showed that 43 kDa β-dystroglycan is proteolytically cleaved into the 30 kDa fragment by matrix metalloproteinases (MMPs) in various non-muscle tissues, whereas it is protected from cleavage in muscles by the sarcoglycan complex which resides close to the dystroglycan complex. It is noteworthy that cleaved β-dystroglycan is detected in muscles from patients with Sarcoglycanopathy, sarcoglycan-deficient muscular dystrophy. In vitro assays using protease inhibitors suggest that both MMP-2 and MMP-9 contribute to the cleavage of β-dystroglycan. However, this has remained uninvestigated in vivo. Methods We generated triple-knockout (TKO) mice targeting MMP-2, MMP-9 and γ-sarcoglycan to examine the status of β-dystroglycan cleavage in the absence of the candidate matrix metalloproteinases in sarcoglycan-deficient muscles. Results Unexpectedly, β-dystroglycan was cleaved in muscles from TKO mice. Muscle pathology was not ameliorated but worsened in TKO mice compared with γ-sarcoglycan single-knockout mice. The gene expression of MMP-14 was up-regulated in TKO mice as well as in γ-sarcoglycan knockout mice. In vitro assay showed MMP-14 is capable to cleave β-dystroglycan. Conclusions Double-targeting of MMP-2 and MMP-9 cannot prevent cleavage of β-dystroglycan in Sarcoglycanopathy. Thus, matrix metalloproteinases contributing to β-dystroglycan cleavage are redundant, and MMP-14 could participate in the pathogenesis of Sarcoglycanopathy.
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Pathological analysis of muscle hypertrophy and degeneration in muscular dystrophy in γ-sarcoglycan-deficient mice
Neuromuscular disorders : NMD, 2003Co-Authors: Toshikuni Sasaoka, Satoru Noguchi, Kenji Araishi, Michihiro Imamura, Hiroshi Hama, Yuji Mizuno, Naomi Takagoshi, Eriko Wakabayashi-takai, Yukiko Yoshimoto-matsuda, Ikuya NonakaAbstract:Abstract While calf muscle hypertrophy is a striking diagnostic finding in Sarcoglycanopathy, as it is in Duchenne and Becker muscular dystrophies, its pathogenetic mechanism remains unknown. γ-Sarcoglycan, one of the subunits of the sarcoglycan complex, is the protein responsible for γ-Sarcoglycanopathy. To elucidate the pathogenetic mechanisms of muscle hypertrophy and degeneration in muscular dystrophy, we utilized a mutant mouse as a model animal. In this study, we generated γ-sarcoglycan-deficient ( gsg −/−) mice by gene targeting. The gsg −/− mice described here, similar to the gsg −/− mice reported previously (J Cell Biol 142 (1998) 1279), demonstrated skeletal and cardiac muscle degeneration. The limb, shoulder, and pelvic muscles of the gsg −/− mice exhibited progressive muscle hypertrophy and weakness with age, and the findings were similar to those seen in other mouse models for limb–girdle and Duchenne muscular dystrophy. We found that the number of muscle fibers increased with age, and most of the fibers in the hypertrophic muscle were centrally nucleated regenerating fibers. Therefore, muscle hypertrophy of the gsg −/− mice may result from an increase of the number of muscle fibers and probable fiber branching and may not be due to the pseudohypertrophy caused by fibrous and fat tissue replacement, as has been long supposed in muscular dystrophy. The muscle pathology became more ‘dystrophic’ in mice over 1 year of age when there was a marked variation in fiber size with interstitial fibrosis.
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Loss of the Sarcoglycan Complex and Sarcospan Leads to Muscular Dystrophy in β-Sarcoglycan-Deficient Mice
Human molecular genetics, 1999Co-Authors: Kenji Araishi, Satoru Noguchi, Toshikuni Sasaoka, Michihiro Imamura, Hiroshi Hama, Eriko Wakabayashi, Mikiharu Yoshida, Tetsuro Hori, Eijiro OzawaAbstract:beta-Sarcoglycan, one of the subunits of the sarcoglycan complex, is a transmembranous glycoprotein which associates with dystrophin and is the molecule responsible for beta-Sarcoglycanopathy, a Duchenne-like autosomal recessive muscular dystrophy. To develop an animal model of beta-Sarcoglycanopathy and to clarify the role of beta-sarcoglycan in the pathogenesis of the muscle degeneration in vivo, we developed beta-sarcoglycan-deficient mice using a gene targeting technique. beta-Sarcoglycan-deficient mice (BSG(-)(/-)mice) exhibited progressive muscular dystrophy with extensive degeneration and regeneration. The BSG(-)(/-)mice also exhibited muscular hypertrophy characteristic of beta-Sarcoglycanopathy. Immunohistochemical and immunoblot analyses of BSG(-)(/-)mice demonstrated that deficiency of beta-sarcoglycan also caused loss of all of the other sarcoglycans as well as of sarcospan in the sarcolemma. On the other hand, laminin-alpha2, alpha- and beta-dystroglycan and dystrophin were still present in the sarcolemma. However, the dystrophin-dystroglycan complex in BSG(-)(/-)mice was unstable compared with that in the wild-type mice. Our data suggest that loss of the sarcoglycan complex and sarcospan alone is sufficient to cause muscular dystrophy, that beta-sarcoglycan is an important protein for formation of the sarcoglycan complex associated with sarcospan and that the role of the sarcoglycan complex and sarcospan may be to strengthen the dystrophin axis connecting the basement membrane with the cytoskeleton.
Satoru Noguchi - One of the best experts on this subject based on the ideXlab platform.
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Pathological analysis of muscle hypertrophy and degeneration in muscular dystrophy in γ-sarcoglycan-deficient mice
Neuromuscular disorders : NMD, 2003Co-Authors: Toshikuni Sasaoka, Satoru Noguchi, Kenji Araishi, Michihiro Imamura, Hiroshi Hama, Yuji Mizuno, Naomi Takagoshi, Eriko Wakabayashi-takai, Yukiko Yoshimoto-matsuda, Ikuya NonakaAbstract:Abstract While calf muscle hypertrophy is a striking diagnostic finding in Sarcoglycanopathy, as it is in Duchenne and Becker muscular dystrophies, its pathogenetic mechanism remains unknown. γ-Sarcoglycan, one of the subunits of the sarcoglycan complex, is the protein responsible for γ-Sarcoglycanopathy. To elucidate the pathogenetic mechanisms of muscle hypertrophy and degeneration in muscular dystrophy, we utilized a mutant mouse as a model animal. In this study, we generated γ-sarcoglycan-deficient ( gsg −/−) mice by gene targeting. The gsg −/− mice described here, similar to the gsg −/− mice reported previously (J Cell Biol 142 (1998) 1279), demonstrated skeletal and cardiac muscle degeneration. The limb, shoulder, and pelvic muscles of the gsg −/− mice exhibited progressive muscle hypertrophy and weakness with age, and the findings were similar to those seen in other mouse models for limb–girdle and Duchenne muscular dystrophy. We found that the number of muscle fibers increased with age, and most of the fibers in the hypertrophic muscle were centrally nucleated regenerating fibers. Therefore, muscle hypertrophy of the gsg −/− mice may result from an increase of the number of muscle fibers and probable fiber branching and may not be due to the pseudohypertrophy caused by fibrous and fat tissue replacement, as has been long supposed in muscular dystrophy. The muscle pathology became more ‘dystrophic’ in mice over 1 year of age when there was a marked variation in fiber size with interstitial fibrosis.
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Loss of the Sarcoglycan Complex and Sarcospan Leads to Muscular Dystrophy in β-Sarcoglycan-Deficient Mice
Human molecular genetics, 1999Co-Authors: Kenji Araishi, Satoru Noguchi, Toshikuni Sasaoka, Michihiro Imamura, Hiroshi Hama, Eriko Wakabayashi, Mikiharu Yoshida, Tetsuro Hori, Eijiro OzawaAbstract:beta-Sarcoglycan, one of the subunits of the sarcoglycan complex, is a transmembranous glycoprotein which associates with dystrophin and is the molecule responsible for beta-Sarcoglycanopathy, a Duchenne-like autosomal recessive muscular dystrophy. To develop an animal model of beta-Sarcoglycanopathy and to clarify the role of beta-sarcoglycan in the pathogenesis of the muscle degeneration in vivo, we developed beta-sarcoglycan-deficient mice using a gene targeting technique. beta-Sarcoglycan-deficient mice (BSG(-)(/-)mice) exhibited progressive muscular dystrophy with extensive degeneration and regeneration. The BSG(-)(/-)mice also exhibited muscular hypertrophy characteristic of beta-Sarcoglycanopathy. Immunohistochemical and immunoblot analyses of BSG(-)(/-)mice demonstrated that deficiency of beta-sarcoglycan also caused loss of all of the other sarcoglycans as well as of sarcospan in the sarcolemma. On the other hand, laminin-alpha2, alpha- and beta-dystroglycan and dystrophin were still present in the sarcolemma. However, the dystrophin-dystroglycan complex in BSG(-)(/-)mice was unstable compared with that in the wild-type mice. Our data suggest that loss of the sarcoglycan complex and sarcospan alone is sufficient to cause muscular dystrophy, that beta-sarcoglycan is an important protein for formation of the sarcoglycan complex associated with sarcospan and that the role of the sarcoglycan complex and sarcospan may be to strengthen the dystrophin axis connecting the basement membrane with the cytoskeleton.
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From dystrophinopathy to Sarcoglycanopathy: Evolution of a concept of muscular dystrophy
Muscle & nerve, 1998Co-Authors: Eijiro Ozawa, Satoru Noguchi, Yuji Mizuno, Yasuko Hagiwara, Mikiharu YoshidaAbstract:Duchenne and Becker muscular dystrophies are collectively termed dystrophinopathy. Dystrophinopathy and severe childhood autosomal recessive muscular dystrophy (SCARMD) are clinically very similar and had not been distinguished in the early 20th century. SCARMD was first classified separately from dystrophinopathy due to differences in the mode of inheritance. Studies performed several years ago clarified some immunohistochemical and genetic characteristics of SCARMD, but many remained to be clarified. In 1994, the sarcoglycan complex was discovered among dystrophin-associated proteins. Subsequently, on the basis of our immunohistochemical findings which indicated that all components of the sarcoglycan complex are absent in SCARMD muscles, and the previous genetic findings, we proposed that a mutation of any one of the sarcoglycan genes leads to SCARMD. This hypothesis explained and predicted various characteristics of SCARMD at the molecular level, most of which have been verified by subsequent discoveries in our own as well as various other laboratories. SCARMD is now called Sarcoglycanopathy, which is caused by a defect of any one of four different sarcoglycan genes, and thus far mutations in sarcoglycan genes have been documented in the SCARMD patients. In this review, the evolution of the concept of Sarcoglycanopathy separate from that of dystrophinopathy is explained by comparing studies on these diseases.
Corrado Angelini - One of the best experts on this subject based on the ideXlab platform.
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Limb-Girdle Muscular Dystrophy Type 2F
Genetic Neuromuscular Disorders, 2014Co-Authors: Corrado AngeliniAbstract:LGMD2F is clinically characterized by limb-girdle weakness, cardiomyopathy, and respiratory impairment. Since it is caused by mutations in the SGCG gene, encoding the delta-sarcoglycan protein (Table 14.1), it belongs to the group of disorders named sarcoglycanopathies, in which a mutation in any one sarcoglycan gene results in the secondary deficiency of the entire sarcoglycan complex. In most populations, delta-Sarcoglycanopathy is the least common type of Sarcoglycanopathy. LGMD2F was first reported in four Brazilian families, where all the affected patients share the same homozygous mutation, resulting in the premature truncation of the protein. Two additional American patients were reported with nonsense mutations and clinical symptoms consistent with Duchenne muscular dystrophy: one 9-year-old girl had facial weakness, mild wasting of proximal muscles in upper and lower extremities, scapular winging, and slight decrease in proximal muscle strength and became wheelchair dependent at age 14; another girl had frequent falls, toe walking, large calves, and difficulty with stairs at age 22 months. Few other cases have been reported, but all the LGMD2F patients reported so far show a Duchenne-like phenotype, with complete absence of the whole sarcoglycan complex in muscle.
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Fatigue in muscular dystrophies.
Neuromuscular Disorders, 2012Co-Authors: Corrado Angelini, Elisabetta TascaAbstract:Fatigue is a frequent complaint in muscular dystrophies but it is yet not well defined or studied. We have examined the issue of muscle fatigue in a series of molecularly defined muscular dystrophies. A greater fatigability is seen in muscular dystrophy patients and can be an acute or chronic status. In Duchenne Muscular Dystrophy and beta-Sarcoglycanopathy besides the alteration of dystrophin and/or sarcoglycan complex, a neuronal nitric oxide synthase depletion is frequently found and might correlate with post-exercise fatigability as well as with cardiac involvement. Therefore, it might be an important modulating factor of the severity of myopathy. In myotonic dystrophy, fatigue is a common complaint: muscle is involved and type 1 atrophy is a frequent feature; brain involvement and depressed mood might likely explain the extent of fatigue and daytime sleepiness commonly observed in these patients. Furthermore, in our observation in a series of 24 cases, muscle and brain can be independently involved in DM1 patients. These observations have profound impact on the type of physical therapy to be prescribed in such patients.
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Sarcolemmal Neuronal Nitric Oxide Synthase Defect in Limb-Girdle Muscular Dystrophy: An Adverse Modulating Factor in the Disease Course?
Journal of neuropathology and experimental neurology, 2009Co-Authors: Marina Fanin, Elisabetta Tasca, Anna Chiara Nascimbeni, Corrado AngeliniAbstract:Reduction of neuronal nitric oxide synthase (nNOS) has been associated with the pathogenesis and clinical expression of inherited myopathies. To determine whether a defect in nNOS might be an adverse modulating factor in the course of limb-girdle muscular dystrophy, we investigated cytosolic and sarcolemmal nNOS expression in muscle biopsies from 32 patients with 7 forms of limb-girdle muscular dystrophy. Primary calpainopathy, dysferlinopathy, and caveolinopathy biopsies showed normal levels of cytosolic nNOS and preserved sarcolemmal nNOS immunoreactivity. By contrast, the cytosolic nNOS levels in Sarcoglycanopathy muscles were variably reduced. Sarcolemmal nNOS immunoreactivity varied from absent to reduced, depending on the integrity of the sarcoglycan complex. In muscles with loss of the entire sarcoglycan complex, sarcolemmal nNOS was absent; it otherwise depended on the specific sarcoglycan gene and type of mutation. The integrity of the entire sarcoglycan complex is, therefore, essential for the stabilization of nNOS to the sarcolemma. Absence of sarcolemmal nNOS in Sarcoglycanopathy muscle was always associated with severe muscular dystrophy and sometimes with dilated cardiomyopathy, supporting the hypothesis that nNOS defect might contribute to skeletal and cardiac muscle disease progression. These results emphasize the value of nNOS immunohistochemical analysis in limb-girdle muscular dystrophy and provide additional insights for future therapeutic interventions in these disorders.
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Cardiomyopathy in a patient with limb-girdle muscular dystrophy type 2D: Pathomorphological aspects
Forensic Science International Supplement Series, 2009Co-Authors: Marija Meznaric-petrusa, Corrado Angelini, Marina Fanin, Eduard Kralj, Darinka TrinkausAbstract:Abstract Sarcoglycanopathies are a group of autosomal recessive limb-girdle muscular dystrophies caused by mutations in the genes encoding for α-, β-, γ- and δ-sarcoglycan, which are expressed in skeletal and cardiac muscle. Cardiomyopathy has rarely been reported in patients with mutations in the α-sarcoglycan gene and descriptions of heart pathology are lacking. To our knowledge, this is the first report on characteristic pathomorphological changes in cardiac muscle detected at autopsy in a patient with a proven mutation (nucleotide substitution 229C>T (R77C) in exon 3) in the α-sarcoglycan gene. The patient had the phenotype of Duchenne-like muscular dystrophy. Due to severe weakness of the respiratory muscles, permanent nocturnal mechanical ventilation via a tracheostomy had been necessary since the age of 24 years. The patient also suffered from mild pulmonary and systemic hypertension. At the age of 36, he lost consciousness and was brought to the emergency room in asystolia and unsuccessfully reanimated for half an hour. Gross heart examination disclosed scattered unsharply demarcated grey and yellow areas, characteristically localised in the outer (subepicardial) part of the lateral and posterior left ventricular wall, while the interventricular septum was spared. Similar changes were present in the apical region of the posterior right ventricular wall. Histopathological changes in focal subepicardial myocardial lesions in the free left ventricular wall consisted of myocardial degeneration in the absence of inflammatory infiltrates, fibrosis and fatty replacement of the myocardium, strikingly similar to changes in skeletal muscle. Since autopsy did not reveal any significant coronary stenosis or valvular pathology, both chronic myocardial ischemia and valvular disease could be excluded as causes of the above-described changes, which were ascribed to α-Sarcoglycanopathy. Mild myocardial hypertrophy could be attributed to pulmonary and systemic hypertension. The progression of cardiomyopathy in α-Sarcoglycanopathy was considered slow, since it had not reached the stage of dilated cardiomyopathy at the time of death. Focal subepicardial myocardial lesions , most pronounced in the posterobasal segment of the left ventricle, were characteristic of cardiomyopathy in α-Sarcoglycanopathy. Since focal lesions may spread further, thorough cardiac monitoring is recommended in patients with α-Sarcoglycanopathy.
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LGMD2E patients risk developing dilated cardiomyopathy.
Neuromuscular disorders : NMD, 2003Co-Authors: Marina Fanin, Paola Melacini, C Boito, Elena Pegoraro, Corrado AngeliniAbstract:Abstract Sarcoglycan gene mutations cause various limb-girdle muscular dystrophies. The sarcoglycans are expressed both in skeletal and cardiac muscle but, surprisingly, so far only a few Sarcoglycanopathy patients have had documented cardiomyopathy. We studied six patients with β-Sarcoglycanopathy. Immunohistochemical and immunoblot analysis performed on skeletal muscle biopsies from five patients, showed the loss of all sarcoglycans in three cases and marked reduction in two patients. Non-invasive cardiac examinations revealed that three patients had cardiac involvement: one had a severe Duchenne-like dystrophy, lethal dilated cardiomyopathy, and shared the same mutation reported in another cardiomyopathic patient; the other two patients had limb-girdle dystrophy and moderate cardiac involvement (one of them has a novel gene mutation). Given the age profile of the patients studied, the 50% cardiac involvement found in our LGMD2E patients is likely to be a conservative estimate. Careful cardiac monitoring should be carried out in β-Sarcoglycanopathy patients who are at high risk of developing cardiomyopathy.
Kenji Araishi - One of the best experts on this subject based on the ideXlab platform.
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Pathological analysis of muscle hypertrophy and degeneration in muscular dystrophy in γ-sarcoglycan-deficient mice
Neuromuscular disorders : NMD, 2003Co-Authors: Toshikuni Sasaoka, Satoru Noguchi, Kenji Araishi, Michihiro Imamura, Hiroshi Hama, Yuji Mizuno, Naomi Takagoshi, Eriko Wakabayashi-takai, Yukiko Yoshimoto-matsuda, Ikuya NonakaAbstract:Abstract While calf muscle hypertrophy is a striking diagnostic finding in Sarcoglycanopathy, as it is in Duchenne and Becker muscular dystrophies, its pathogenetic mechanism remains unknown. γ-Sarcoglycan, one of the subunits of the sarcoglycan complex, is the protein responsible for γ-Sarcoglycanopathy. To elucidate the pathogenetic mechanisms of muscle hypertrophy and degeneration in muscular dystrophy, we utilized a mutant mouse as a model animal. In this study, we generated γ-sarcoglycan-deficient ( gsg −/−) mice by gene targeting. The gsg −/− mice described here, similar to the gsg −/− mice reported previously (J Cell Biol 142 (1998) 1279), demonstrated skeletal and cardiac muscle degeneration. The limb, shoulder, and pelvic muscles of the gsg −/− mice exhibited progressive muscle hypertrophy and weakness with age, and the findings were similar to those seen in other mouse models for limb–girdle and Duchenne muscular dystrophy. We found that the number of muscle fibers increased with age, and most of the fibers in the hypertrophic muscle were centrally nucleated regenerating fibers. Therefore, muscle hypertrophy of the gsg −/− mice may result from an increase of the number of muscle fibers and probable fiber branching and may not be due to the pseudohypertrophy caused by fibrous and fat tissue replacement, as has been long supposed in muscular dystrophy. The muscle pathology became more ‘dystrophic’ in mice over 1 year of age when there was a marked variation in fiber size with interstitial fibrosis.
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Loss of the Sarcoglycan Complex and Sarcospan Leads to Muscular Dystrophy in β-Sarcoglycan-Deficient Mice
Human molecular genetics, 1999Co-Authors: Kenji Araishi, Satoru Noguchi, Toshikuni Sasaoka, Michihiro Imamura, Hiroshi Hama, Eriko Wakabayashi, Mikiharu Yoshida, Tetsuro Hori, Eijiro OzawaAbstract:beta-Sarcoglycan, one of the subunits of the sarcoglycan complex, is a transmembranous glycoprotein which associates with dystrophin and is the molecule responsible for beta-Sarcoglycanopathy, a Duchenne-like autosomal recessive muscular dystrophy. To develop an animal model of beta-Sarcoglycanopathy and to clarify the role of beta-sarcoglycan in the pathogenesis of the muscle degeneration in vivo, we developed beta-sarcoglycan-deficient mice using a gene targeting technique. beta-Sarcoglycan-deficient mice (BSG(-)(/-)mice) exhibited progressive muscular dystrophy with extensive degeneration and regeneration. The BSG(-)(/-)mice also exhibited muscular hypertrophy characteristic of beta-Sarcoglycanopathy. Immunohistochemical and immunoblot analyses of BSG(-)(/-)mice demonstrated that deficiency of beta-sarcoglycan also caused loss of all of the other sarcoglycans as well as of sarcospan in the sarcolemma. On the other hand, laminin-alpha2, alpha- and beta-dystroglycan and dystrophin were still present in the sarcolemma. However, the dystrophin-dystroglycan complex in BSG(-)(/-)mice was unstable compared with that in the wild-type mice. Our data suggest that loss of the sarcoglycan complex and sarcospan alone is sufficient to cause muscular dystrophy, that beta-sarcoglycan is an important protein for formation of the sarcoglycan complex associated with sarcospan and that the role of the sarcoglycan complex and sarcospan may be to strengthen the dystrophin axis connecting the basement membrane with the cytoskeleton.
