Characteristics of Skeletal Muscle in Mdx Mutant Mice

Porte, Sabine de la; Morin, S.; Koenig, Jeanine

doi:10.1016/s0074-7696(08)60158-8

Cited by 89 publications

(70 citation statements)

References 300 publications

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“…The percentage of myofibers with central nuclei is used as a measure of cycles of muscle degeneration and regeneration, because dystrophic mouse muscles maintain nuclei within the center of the muscle at much higher incidence once regeneration has occurred after muscle injury or loss. 58 Likewise, dystrophic processes lead to both hypertrophy and the presence of smaller regenerating muscles, which lowers the average measure of myofiber diameter and increases its variance. 58 In addition, skeletal myofibers can take up serum IgG on membrane rupture, and the percentage of nonmuscle area in the muscle is increased as muscle fibers are lost and replaced with extracellular matrix or fat.…”

Section: Raavrh74mckgalgt2 Treatment Of Fkrp P448lneo à Mice Reducementioning

confidence: 99%

“…58 Likewise, dystrophic processes lead to both hypertrophy and the presence of smaller regenerating muscles, which lowers the average measure of myofiber diameter and increases its variance. 58 In addition, skeletal myofibers can take up serum IgG on membrane rupture, and the percentage of nonmuscle area in the muscle is increased as muscle fibers are lost and replaced with extracellular matrix or fat. Age-matched WT (C57Bl/6) muscles were used for comparison in some instances.…”

Section: Raavrh74mckgalgt2 Treatment Of Fkrp P448lneo à Mice Reducementioning

confidence: 99%

“…Multiple published studies have shown that this level is not elevated beyond 5% and is often well below that in WT muscles. 36,58 At 1 month after treatment (between 6 and 8 weeks of age), most FKRP P448Lneo À muscles have not yet undergone a significant extent of myofiber damage, but in treated muscles, only nonexpressing myofibers had central nuclei. By 3 months after treatment, all contralateral (untreated) FKRP P448Lneo À muscles had significant elevations in percentages of myofibers with central nuclei relative to 1 month after treatment (P < 0.001 for all; not shown), and myofibers expressing the GALGT2 transgene had significantly reduced percentages relative to both contralateral untreated myofibers and ipsilateral The gastroc, quad, and TA muscles of FKRP P448Lneo À mice were injected with rAAVrh74.MCK.GALGT2 (treated) and analyzed at 1, 3, and 6 months after injection compared with contralateral PBS-injected controls (untreated).…”

Section: Raavrh74mckgalgt2 Treatment Of Fkrp P448lneo à Mice Reducementioning

confidence: 99%

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B4GALNT2 (GALGT2) Gene Therapy Reduces Skeletal Muscle Pathology in the FKRP P448L Mouse Model of Limb Girdle Muscular Dystrophy 2I

Thomas

Martin

2016

The American Journal of Pathology

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Overexpression of B4GALNT2 (previously GALGT2) inhibits the development of muscle pathology in mouse models of Duchenne muscular dystrophy, congenital muscular dystrophy 1A, and limb girdle muscular dystrophy 2D. In these models, muscle GALGT2 overexpression induces the glycosylation of a dystroglycan with the cytotoxic T cell glycan and increases the overexpression of dystrophin and laminin a2 surrogates known to inhibit disease. Here, we show that GALGT2 gene therapy significantly reduces muscle pathology in FKRP P448Lneo À mice, a model for limb girdle muscular dystrophy 2I. rAAVrh74.MCK.GALGT2-treated FKRP P448Lneo À muscles showed reduced levels of centrally nucleated myofibers, reduced variance, increased size of myofiber diameters, reduced myofiber immunoglobulin G uptake, and reduced muscle wasting at 3 and 6 months after treatment. GALGT2 overexpression in FKRP P448Lneo À muscles did not cause substantial glycosylation of a dystroglycan with the cytotoxic T cell glycan or increased expression of dystrophin and laminin a2 surrogates in mature skeletal myofibers, but it increased the number of embryonic myosin-positive regenerating myofibers. These data demonstrate that GALGT2 overexpression can reduce the extent of muscle pathology in FKRP mutant muscles, but that it may do so via a mechanism that differs from its ability to induce surrogate gene expression. (Am J Pathol 2016 http://dx

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Section: Raavrh74mckgalgt2 Treatment Of Fkrp P448lneo à Mice Reducementioning

confidence: 99%

Section: Raavrh74mckgalgt2 Treatment Of Fkrp P448lneo à Mice Reducementioning

confidence: 99%

Section: Raavrh74mckgalgt2 Treatment Of Fkrp P448lneo à Mice Reducementioning

confidence: 99%

See 1 more Smart Citation

B4GALNT2 (GALGT2) Gene Therapy Reduces Skeletal Muscle Pathology in the FKRP P448L Mouse Model of Limb Girdle Muscular Dystrophy 2I

Thomas

Martin

2016

The American Journal of Pathology

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“…Similarly, neuromuscular development is largely complete by 2 weeks of age [24]. In mdx mice, by contrast, muscular dystrophy is not present for the first three weeks of life [4]. There is a window, therefore, in 2-3 week old mdx animals when the contribution of satellite cells to myofiber growth has largely occurred but when muscular dystrophy is not yet present.…”

Section: Inhibition Of Muscular Dystrophy By Aav-galgt2mentioning

confidence: 99%

“…mdx mice are a commonly used model for testing therapeutic approaches to DMD; mdx animals do not express dystrophin protein in most of their skeletal myofibers, and mdx myofibers exhibit several important pathological hallmarks of DMD [3,4]. In addition, loss of dystrophin protein expression, both in DMD and mdx muscles, correlates with loss of membrane expression of proteins in the dystrophin-glycoprotein complex, including dystroglycans and sarcoglycans, along the myofiber membrane [5].…”

Section: Introductionmentioning

confidence: 99%

Postnatal overexpression of the CT GalNAc transferase inhibits muscular dystrophy in mdx mice without altering muscle growth or neuromuscular development: Evidence for a utrophin-independent mechanism

Camboni

Martin

2007

Neuromuscular Disorders

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Overexpression of the cytotoxic T cell (CT) GalNAc transferase (Galgt2) in the skeletal muscles of transgenic mdx mice inhibits the development of muscular dystrophy. The profound effect of Galgt2 on muscular dystrophy in transgenic mice, where overexpression is begins from embryonic stages, is complicated by its additional effects on muscle growth and neuromuscular structure. Here, we use Adeno-associated virus (AAV) to show that overexpression of Galgt2 in skeletal myofibers in the early postnatal period is equally effective in inhibiting muscular dystrophy, but that it does so without altering muscle growth or neuromuscular structure. Unlike embryonic overexpression, postnatal overexpression of Galgt2 did not reproducibly increase the expression of utrophin, synaptic laminins, or dystrophin-associated glycoproteins along infected myofibers. Moreover, Galgt2 overexpression inhibited muscular dystrophy to the same extent in utrophin-deficient mdx muscles as it did in utrophin-expressing mdx muscles. Thus, Galgt2 is a molecular target for therapy in DMD that can be utilized in a manner that separates its clinical benefit from its effects on development, and its clinical benefit is distinct from that achieved by utrophin.

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Identification of the increased expression of monocyte chemoattractant protein-1, cathepsin S, UPIX-1, and other genes in dystrophin-deficient mouse muscles by suppression subtractive hybridization

2000

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The lack of dystrophin results in muscular dystrophy characterized by degeneration, inflammation, and partial regeneration of skeletal muscles. The fate of these muscles may be determined by the extent of adaptation to the defect and the efficiency of regeneration that is affected by inflammatory cells. We have used suppression subtractive hybridization and quantitative Northern blot analysis to identify differentially expressed genes. Increased expression of murine monocyte chemoattractant protein-1 (JE/MCP-1), cathepsin S, UPIX-1, nmb, cathepsin B, and lysozyme M mRNAs were identified in 2-month-old mdx mouse leg muscles. UPIX-1 is a novel gene. Although it was not expressed in control muscles, it was expressed in control brain, heart, and spleen. JE/MCP-1 and cathepsin S proteins in mdx muscles, as well as JE/MCP-1 protein in the serum of mdx mice were also detected. JE/MCP-1 may be responsible for attraction of inflammatory cells, and cathepsin S, a potent elastolytic protease, may contribute to the remodeling of the extracellular matrix that is required for the migration of these cells to the injured muscles.

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Characteristics of Skeletal Muscle in Mdx Mutant Mice

Cited by 89 publications

References 300 publications

B4GALNT2 (GALGT2) Gene Therapy Reduces Skeletal Muscle Pathology in the FKRP P448L Mouse Model of Limb Girdle Muscular Dystrophy 2I

B4GALNT2 (GALGT2) Gene Therapy Reduces Skeletal Muscle Pathology in the FKRP P448L Mouse Model of Limb Girdle Muscular Dystrophy 2I

Postnatal overexpression of the CT GalNAc transferase inhibits muscular dystrophy in mdx mice without altering muscle growth or neuromuscular development: Evidence for a utrophin-independent mechanism

Identification of the increased expression of monocyte chemoattractant protein-1, cathepsin S, UPIX-1, and other genes in dystrophin-deficient mouse muscles by suppression subtractive hybridization

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