Littérature scientifique sur le sujet « Β-sarcoglycan »

The sarcoglycans are a complex of four transmembrane proteins (α, β, γ, and δ) which are primarily expressed in skeletal muscle and are closely associated with dystrophin and the dystroglycans in the muscle membrane. Mutations in the sarcoglycans are responsible for four autosomal recessive forms of muscular dystrophy. The function and the organization of the sarcoglycan complex are unknown. We have used coimmunoprecipitation and in vivo cross-linking techniques to analyze the sarcoglycan complex in cultured mouse myotubes. We demonstrate that the interaction between β- and δ-sarcoglycan is resistant to high concentrations of SDS and α-sarcoglycan is less tightly associated with other members of the complex. Cross-linking experiments show that β-, γ-, and δ-sarcoglycan are in close proximity to one another and that δ-sarcoglycan can be cross-linked to the dystroglycan complex. In addition, three of the sarcoglycans (β, γ, and δ) are shown to form intramolecular disulfide bonds. These studies further our knowledge of the structure of the sarcoglycan complex. Our proposed model of their interactions helps to explain some of the emerging data on the consequences of mutations in the individual sarcoglycans, their effect on the complex, and potentially the clinical course of muscular dystrophies.

The sarcoglycan complex (SGC) is a multimember transmembrane complex interacting with other members of the dystrophin–glycoprotein complex (DGC) to provide a mechanosignaling connection from the cytoskeleton to the extracellular matrix. The SGC consists of four proteins (α, β, γ, and δ). A fifth sarcoglycan subunit, ∊-sarcoglycan, shows a wider tissue distribution. Recently, a novel sarcoglycan, the ζ-sarcoglycan, has been identified. All reports about the structure of SGC showed a common assumption of a tetrameric arrangement of sarcoglycans. Addressing this issue, our immunofluorescence and molecular results showed, for the first time, that all sarcoglycans are always detectable in all observed samples. Therefore, one intriguing possibility is the existence of a pentameric or hexameric complex considering ζ-sarcoglycan of SGC, which could present a higher or lower expression of a single sarcoglycan in conformity with muscle type—skeletal, cardiac, or smooth—or also in conformity with the origin of smooth muscle. (J Histochem Cytochem 55:831–843, 2007)

γ-Sarcoglycan is a transmembrane, dystrophin-associated protein expressed in skeletal and cardiac muscle. The murine γ-sarcoglycan gene was disrupted using homologous recombination. Mice lacking γ-sarcoglycan showed pronounced dystrophic muscle changes in early life. By 20 wk of age, these mice developed cardiomyopathy and died prematurely. The loss of γ-sarcoglycan produced secondary reduction of β- and δ-sarcoglycan with partial retention of α- and ε-sarcoglycan, suggesting that β-, γ-, and δ-sarcoglycan function as a unit. Importantly, mice lacking γ-sarco- glycan showed normal dystrophin content and local- ization, demonstrating that myofiber degeneration occurred independently of dystrophin alteration. Furthermore, β-dystroglycan and laminin were left intact, implying that the dystrophin–dystroglycan–laminin mechanical link was unaffected by sarcoglycan deficiency. Apoptotic myonuclei were abundant in skeletal muscle lacking γ-sarcoglycan, suggesting that programmed cell death contributes to myofiber degeneration. Vital staining with Evans blue dye revealed that muscle lacking γ-sarcoglycan developed membrane disruptions like those seen in dystrophin-deficient muscle. Our data demonstrate that sarcoglycan loss was sufficient, and that dystrophin loss was not necessary to cause membrane defects and apoptosis. As a common molecular feature in a variety of muscular dystrophies, sarcoglycan loss is a likely mediator of pathology.

Case summaryA 5-month-old cat was evaluated for a 3 week history of cough, nasal discharge, decreased appetite and weight loss. Musculoskeletal examination was normal and serum creatine kinase (CK) activity was within the reference interval. The cat was treated during the next 10 months for chronic, persistent pneumonia. Weakness then became apparent, the cat developed dysphagia and was euthanized. Post-mortem evaluation revealed chronic aspiration pneumonia and muscular dystrophy associated with beta (β)-sarcoglycan deficiency.Relevance and novel informationThis is the first report of a cat with muscular dystrophy presenting for chronic pneumonia without obvious megaesophagus, dysphagia or prominent neuromuscular signs until late in the course of the disease. The absence of gait abnormalities, marked muscle atrophy or hypertrophy and normal serum CK activity delayed the diagnosis in this cat with β-sarcoglycan deficiency.

Muscular dystrophies are a clinically and genetically heterogeneous group of disorders that show myofiber degeneration and regeneration. Identification of animal models of muscular dystrophy has been instrumental in research on the pathogenesis, pathophysiology, and treatment of these disorders. We review our understanding of the functional status of dystrophic skeletal muscle from selected animal models with a focus on 1) the mdx mouse model of Duchenne muscular dystrophy, 2) the Bio 14.6 δ-sarcoglycan-deficient hamster model of limb-girdle muscular dystrophy, and 3) transgenic null mutant murine lines of sarcoglycan (α, β, δ, and γ) deficiencies. Although biochemical data from these models suggest that the dystrophin-sarcoglycan-dystroglycan-laminin network is critical for structural integrity of the myofiber plasma membrane, emerging studies of muscle physiology suggest a more complex picture, with specific functional deficits varying considerably from muscle to muscle and model to model. It is likely that changes in muscle structure and function, downstream of the specific, primary biochemical deficiency, may alter muscle contractile properties.

Effective therapy to reduce skeletal muscle injury associated with severe or eccentric exercise is needed. The purpose of this study was to determine whether adenosine receptor stimulation can mediate protection from eccentric exercise-induced muscle injury. Downhill treadmill exercise (−15°) was used to induce eccentric exercise-mediated skeletal muscle injury. Experiments were conducted in both normal wild-type (WT) mice and also in β-sarcoglycan knockout dystrophic mice, animals that show an exaggerated muscle damage with the stress of exercise. In the vehicle-treated WT animals, eccentric exercise increased serum creatine kinase (CK) greater than 3-fold to 358.9 ± 62.7 U/l (SE). This increase was totally abolished by stimulation of the A3 receptor. In the dystrophic β-sarcoglycan-null mice, eccentric exercise caused CK levels to reach 55,124 ± 5,558 U/l. A3 receptor stimulation in these animals reduced the CK response by nearly 50%. In the dystrophic mice at rest, 10% of the fibers were found to be damaged, as indicated by Evans blue dye staining. While this percentage was doubled after exercise, A3 receptor stimulation eliminated this increase. Neither the A1 receptor agonist 2-chloro- N6-cyclopentyladenosine (0.05 mg/kg) nor the A2A receptor agonist 2- p-(2-carboxyethyl)phenethylamino-5′- N-ethylcarboxamidoadenosine (0.07 mg/kg) protected skeletal muscle from eccentric exercise injury in WT or dystrophic mice. The protective effect of adenosine A3 receptor stimulation was absent in mice, in which genes for phospholipase C β2/β3 (PLCβ2/β3) and β-sarcoglycan were deleted. The present study elucidates a new protective role of the A3 receptor and PLCβ2/β3 and points to a potentially effective therapeutic strategy for eccentric exercise-induced skeletal muscle injury.

Muscle fibrosis, a hallmark of severe muscular dystrophies, is a mechanism not completely understood, characterized by marked deposition of collagens and other extracellular matrix (ECM) components, progressively replacing muscle fibres. Fibrosis also occurs in other human conditions affecting different organs/tissues including liver, heart, kidney and lung. In skeletal and cardiac muscle, dystrophin is associated with a large complex of sarcolemmal and cytoskeletal proteins, the dystrophin-glycoprotein complex (DGC), that confers a structural link between the laminin-α2 in the ECM and the cytoplasmic actin. Mutations in genes encoding several DGC components are associated with severe muscular dystrophies. In particular, Duchenne muscular dystrophy (DMD), due to lack of dystrophin protein, is the most frequent of such conditions in childhood. Moreover mutations in sarcoglycan genes cause autosomal recessive limb-girdle muscular dystrophies (LGMD2C-F), that have similar clinical and histopathological features to DMD, although severity is variable. The Sgcb-null mouse, with knocked-down β-sarcoglycan, develops severe muscular dystrophy as in human LGMD2E. This model exhibits disruption of DGC in skeletal, cardiac, and smooth muscle that causes severe muscular dystrophy, cardiomyopathy and vascular abnormalities. The mdx mouse, is the most-used model for DMD, however, differently from patients, the mdx mouse has mild clinical features and shows little endomysial fibrosis in limb muscles. In order to elucidate mechanisms leading to ECM protein deposition and characterize the progression of fibrosis, we have evaluated histopathological and molecular features in Sgcb-null mice at different ages, and compared them (at selected significant ages) with age-matched mdx mice. In particular, in Sgcb-null mouse quadriceps and diaphragms we determined extent of fibrosis, numbers of necrotic, regenerating and centronucleated fibres evaluating as well collagen (I, III and VI), decorin, and TGF-β1 transcript and protein levels. Then we compared Sgcb-null and mdx mice measuring the extent of fibrosis, protein levels of collagens, decorin and TGF-β1, and at the age of maximum tissue rearrangement (12 weeks), we assessed macrophage numbers and osteopontin and TGF-β1 transcript levels. The Sgcb-null mouse, which develops early fibrosis in limb muscles, appears a more promising model for probing pathogenetic mechanisms of muscle fibrosis and for developing anti-fibrotic treatments compared to mdx mice. MicroRNAs (miRNAs) are small non-coding RNA molecules, whose main function seems to be the downregulation of gene expression by various mechanisms. Recent evidences indicate that miRNAs play fundamental roles in pathological processes; aberrant expression of miRNAs has been related to fibrosis through regulation of anti- and pro-fibrotic genes. In particular, miR-21 is one of the most highly upregulated miRNAs during tissue injury, and its persistent overexpression disrupts tissue repair and contributes to fibrosis in various tissues. With in vitro study we assessed that miR-21 expression was significantly increased both in DMD muscle biopsies and DMD muscle-derived fibroblasts. To assess the therapeutic potential of miR-21 inhibition, we performed a pilot study in which we treated mdx mice with antagomiR-21. MiR-21 silencing in mdx mice reduced fibrosis in the diaphragm muscle and restored PTEN and SPRY-1 expression. These effects were evident only a month after treatment at lowest dose reported effective in the literature. These findings indicate that miR-21 could represent a therapeutic target to reduce fibrosis.