Overexpression of γ-Sarcoglycan Induces Severe Muscular Dystrophy

Zhu, Xiaolei; Hadhazy, Michele; Groh, Margaret E.; Wheeler, Matthew T.; Wollmann, Robert L.; McNally, Elizabeth M.

doi:10.1074/jbc.m101877200

Cited by 51 publications

(13 citation statements)

References 28 publications

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“…The level of ␥-SG expression must be well controlled because both loss of production and increased expression can lead to muscle pathology (14,30). The truncated desmin promoter provided the tissue specificity needed for this study (15), and the levels of transgene expression were sufficient to stabilize muscle fibers as shown by the reduction of centrally nucleated fibers.…”

Section: Discussionmentioning

confidence: 99%

Restoration of γ-Sarcoglycan Localization and Mechanical Signal Transduction Are Independent in Murine Skeletal Muscle

Barton

2010

Journal of Biological Chemistry

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Limb girdle muscular dystrophy 2C is caused by mutations in the ␥-sarcoglycan gene (gsg) that results in loss of this protein, and disruption of the sarcoglycan (SG) complex. Signal transduction after mechanical perturbation is mediated, in part, through the SG complex and leads to phosphorylation of tyrosines on the intracellular portions of the sarcoglycans. This study tested if the Tyr 6 in the intracellular region of ␥-sarcoglycan protein (␥-SG) was necessary for proper localization of the protein in skeletal muscle membranes or for the normal pattern of ERK1/2 phosphorylation after eccentric contractions. Viral mediated gene transfer of wild type gsg (WTgsg) and mutant gsg lacking Tyr 6 (Y6Agsg) was performed into the muscles of gsg ؊/؊ mice. Muscles were examined for production and stability of the ␥-SG, as well as the level of ERK1/2 phosphorylation before and after eccentric contraction. Sarcolemmal localization of ␥-SG was achieved regardless of which construct was expressed. However, only expression of WTgsg corrected the aberrant ERK1/2 phosphorylation associated with the absence of ␥-SG, whereas Y6Agsg failed to have any effect. This study shows that localization of ␥-SG does not require Tyr 6, but localization alone is insufficient for restoration of normal signal transduction patterns after mechanical perturbation.More than 30 genetic disorders of muscle have been identified and arise from mutations in a wide range of genes including those that encode proteins of the dystrophin glycoprotein complex (DGC), 2 the nuclear membrane, and extracellular matrix (1). Although each disease manifests in a unique pattern, there is a common set of pathologies associated with the muscular dystrophies. Disease hallmarks include muscle weakness, fragility, and degeneration.Many of the limb girdle muscular dystrophies are caused by mutations in the sarcoglycans. The sarcoglycan (SG) complex is a subcomplex of the DGC, comprised of ␣-, ␤-, ␥-, and ␦-SG in skeletal muscle (2, 3). These proteins form an integral membrane complex with a short intracellular domain, a single transmembrane focal domain, and a large extracellular domain. The intracellular regions of ␣-, ␤-, and ␥-SG have potential tyrosine phosphorylation sites. In cell culture studies, adhesion gives rise to phosphorylation of each of these SGs, indicating that the SGs can be modified in response to cell attachment (4). Furthermore, we have been able to identify the SG complex as a player in the mechanical signal transduction process, where ␥-SG tyrosine phosphorylation occurs after a series of eccentric contractions, and disruption of the SG complex in mice lacking ␥-SG, which is a genetic model for limb girdle muscular dystrophies 2C, leads to an aberrant ERK1/2 response that is distinct from that observed in mdx mice in which the entire DGC is absent (5). Based on these findings, the SG complex has been proposed to be a mechanosensor, which can convert changes in load at the sarcolemma to distinct changes in gene expression and maintenance of muscle su...

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Section: Discussionmentioning

confidence: 99%

Restoration of γ-Sarcoglycan Localization and Mechanical Signal Transduction Are Independent in Murine Skeletal Muscle

Barton

2010

Journal of Biological Chemistry

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“…In these patients, the other three sarcoglycans are still present at the sarcolemma though at a reduced level, suggesting α-sarcoglycan association may not be required for the membrane trafficking of the SG complex. Overexpression of α-sarcoglycan or γ-sarcoglycan have been associated with cytotoxicity and pathology in mice muscle, presumably due to the disruption of the SG assembly process in the ER presumably leading to ER stress (51, 166). …”

Section: Dystrophinmentioning

confidence: 99%

The Dystrophin Complex: Structure, Function, and Implications for Therapy

Gao

McNally

2015

Comprehensive Physiology

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309

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The dystrophin complex stabilizes the plasma membrane of striated muscle cells. Loss of function mutations in the genes encoding dystrophin, or the associated proteins, triggers instability of the plasma membrane and myofiber loss. Mutations in dystrophin have been extensively cataloged providing remarkable structure-function correlation between predicted protein structure and clinical outcomes. These data have highlighted dystrophin regions necessary for in vivo function and fueled the design of viral vectors and now, exon skipping approaches for use in dystrophin restoration therapies. However, dystrophin restoration is likely more complex, owing to the role of the dystrophin complex as a broad cytoskeletal integrator. This review will focus on dystrophin restoration, with emphasis on the regions of dystrophin essential for interacting with its associated proteins and discuss the structural implications of these approaches.

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“…The PCR product was subcloned into pCR2.1-TOPO (Invitrogen) and the sequence of the insert confirmed. The insert was excised by digestion with EcoRI and cloned into the EcoRI site of the mouse muscle-specific creatine kinase (mMCK) promoter-bovine growth hormone (bGH) polyadenylation signal vector (15). The 4.28-kb mMCK-hCAST-bGH was excised from the vector by digestion with HhaI and purified by sucrose gradient centrifugation (Fig.…”

Section: Generation Of Mck-hcast Transgenic Mice-full-length Human Camentioning

confidence: 99%

Calpain System Regulates Muscle Mass and Glucose Transporter GLUT4 Turnover

Otani

Han

Ford

et al. 2004

Journal of Biological Chemistry

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The experiments in this study were undertaken to determine whether inhibition of calpain activity in skeletal muscle is associated with alterations in muscle metabolism. Transgenic mice that overexpress human calpastatin, an endogenous calpain inhibitor, in skeletal muscle were produced. Compared with wild type controls, muscle calpastatin mice demonstrated normal glucose tolerance. Levels of the glucose transporter GLUT4 were increased more than 3-fold in the transgenic mice by Western blotting while mRNA levels for GLUT4 and myocyte enhancer factors, MEF 2A and MEF 2D, protein levels were decreased. We found that GLUT4 can be degraded by calpain-2, suggesting that diminished degradation is responsible for the increase in muscle GLUT4 in the calpastatin transgenic mice. Despite the increase in GLUT4, glucose transport into isolated muscles from transgenic mice was not increased in response to insulin. The expression of protein kinase B was decreased by ϳ60% in calpastatin transgenic muscle. This decrease could play a role in accounting for the insulin resistance relative to GLUT4 content of calpastatin transgenic muscle. The muscle weights of transgenic animals were substantially increased compared with controls. These results are consistent with the conclusion that calpain-mediated pathways play an important role in the regulation of GLUT4 degradation in muscle and in the regulation of muscle mass. Inhibition of calpain activity in muscle by overexpression of calpastatin is associated with an increase in GLUT4 protein without a proportional increase in insulin-stimulated glucose transport. These findings provide evidence for a physiological role for calpains in the regulation of muscle glucose metabolism and muscle mass.

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Overexpression of γ-Sarcoglycan Induces Severe Muscular Dystrophy

Cited by 51 publications

References 28 publications

Restoration of γ-Sarcoglycan Localization and Mechanical Signal Transduction Are Independent in Murine Skeletal Muscle

Restoration of γ-Sarcoglycan Localization and Mechanical Signal Transduction Are Independent in Murine Skeletal Muscle

The Dystrophin Complex: Structure, Function, and Implications for Therapy

Calpain System Regulates Muscle Mass and Glucose Transporter GLUT4 Turnover

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