Complement 3 deficiency and oral prednisolone improve strength and prolong survival of laminin α2-deficient mice

Connolly, Anne M.; Keeling, Richard M.; Streif, Elizabeth M.; Pestronk, Alan; Mehta, Shobhna

doi:10.1016/s0165-5728(02)00104-2

Cited by 27 publications

(20 citation statements)

References 28 publications

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“…In order to validate these results we measured the RNA levels of C3 , a central component of the complement system, confirming its up-regulation in UCMD muscles. Complement system activation is not an exclusive feature of UCMD because it has been described in other muscular dystrophies [70] such as DMD [71], dysferlinopathy (LGMD2B) [72] and merosin deficiency (MDC1A) [73][74] where it is thought to contribute to membrane damage and macrophage recruitment amplifying in turn the immune response and muscle damage. In a mouse model of LGMD2B, other authors confirmed the active role of complement activation in the progression of muscular dystrophy and the attenuation of muscle pathology following the disruption of C3 providing a new therapeutic target for muscular dystrophies [75].…”

Section: Resultsmentioning

confidence: 99%

Gene Expression Profiling Identifies Molecular Pathways Associated with Collagen VI Deficiency and Provides Novel Therapeutic Targets

et al. 2013

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Ullrich congenital muscular dystrophy (UCMD), caused by collagen VI deficiency, is a common congenital muscular dystrophy. At present, the role of collagen VI in muscle and the mechanism of disease are not fully understood. To address this we have applied microarrays to analyse the transcriptome of UCMD muscle and compare it to healthy muscle and other muscular dystrophies. We identified 389 genes which are differentially regulated in UCMD relative to controls. In addition, there were 718 genes differentially expressed between UCMD and dystrophin deficient muscle. In contrast, only 29 genes were altered relative to other congenital muscular dystrophies. Changes in gene expression were confirmed by real-time PCR. The set of regulated genes was analysed by Gene Ontology, KEGG pathways and Ingenuity Pathway analysis to reveal the molecular functions and gene networks associated with collagen VI defects. The most significantly regulated pathways were those involved in muscle regeneration, extracellular matrix remodelling and inflammation. We characterised the immune response in UCMD biopsies as being mainly mediated via M2 macrophages and the complement pathway indicating that anti-inflammatory treatment may be beneficial to UCMD as for other dystrophies. We studied the immunolocalisation of ECM components and found that biglycan, a collagen VI interacting proteoglycan, was reduced in the basal lamina of UCMD patients. We propose that biglycan reduction is secondary to collagen VI loss and that it may be contributing towards UCMD pathophysiology. Consequently, strategies aimed at over-expressing biglycan and restore the link between the muscle cell surface and the extracellular matrix should be considered.

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Section: Resultsmentioning

confidence: 99%

Gene Expression Profiling Identifies Molecular Pathways Associated with Collagen VI Deficiency and Provides Novel Therapeutic Targets

et al. 2013

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“…It too, therefore, may have some beneficial effect in concert with increased CT glycosylation, perhaps analogous to the posited role for laminin ␣5 in miniagrin experiments. 8 Several other approaches have proved effective in dy mouse models, including corticosteroids such as prednisolone, 88 apoptosis inhibitors such as BCL2, 89 and muscle growth mediators such as IGF1. 10 At the moment, we have no evidence as to whether these mechanisms are involved in the Galgt2's therapeutic effect.…”

Section: Discussionmentioning

confidence: 99%

Overexpression of the Cytotoxic T Cell (CT) Carbohydrate Inhibits Muscular Dystrophy in the dyW Mouse Model of Congenital Muscular Dystrophy 1A

Chandrasekharan²,

Yoon³

et al. 2007

The American Journal of Pathology

108

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A number of recent studies have demonstrated therapeutic effects of transgenes on the development of muscle pathology in the mdx mouse model for Duchenne muscular dystrophy, but none have been shown also to be effective in mouse models for laminin ␣2-deficient congenital muscular dystrophy (MDC1A). Here, we show that overexpression of the cytotoxic T cell (CT) GalNAc transferase (Galgt2) is effective in inhibiting the development of muscle pathology in the dy W mouse model of MDC1A, much as we had previously shown in mdx animals. Embryonic overexpression of Galgt2 in skeletal muscles using transgenic mice or postnatal overexpression using adenoassociated virus both reduced the extent of muscle pathology in dy W /dy W skeletal muscle. As with mdx mice, embryonic overexpression of the Galgt2 transgene in dy W /dy W myofibers inhibited muscle growth, whereas postnatal overexpression did not. Both embryonic and postnatal overexpression of Galgt2 in dy W /dy W muscle increased the expression of agrin, a protein that, in recombinant form, has been shown to ameliorate disease, whereas laminin ␣1, another disease modifier, was not expressed. Galgt2 overexpression also stimulated the glycosylation of a glycolipid with the CT carbohydrate, and glycolipids accounted for most of the CT-reactive material in postnatal overexpression experiments. These experiments demonstrate that Galgt2 overexpression is effective in altering disease progression in skeletal muscles of dy W mice and should be considered as a therapeutic target in

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“…In those studies, restoration of laminin function likely both restored muscle function and eliminated apoptosis in muscle cells. Partial amelioration of 1 or more aspects of laminin-α2 deficiency in mice can also be produced by feeding a 50% protein diet, inactivating the complement system, or by administering IGF-1, clenbuterol, or prednisolone (18)(19)(20)(21). Whether these treatments reduce pathology through inhibition of apoptosis remains to be determined.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of apoptosis improves outcome in a model of congenital muscular dystrophy

Girgenrath¹,

Dominov²,

Kostek³

et al. 2004

J. Clin. Invest.

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The most common form of human congenital muscular dystrophy (CMD) is caused by mutations in the laminin-α2 gene. Loss of laminin-α2 function in this autosomal recessive type 1A form of CMD results in neuromuscular dysfunction and, often, early death. Laminin-α2-deficient skeletal muscles in both humans and mice show signs of muscle cell death by apoptosis. To examine the significance of apoptosis in CMD1A pathogenesis, we determined whether pathogenesis in laminin-α2-deficient (Lama2 -/-) mice could be ameliorated by inhibiting apoptosis through either (a) inactivation of the proapoptosis protein Bax or (b) overexpression of the antiapoptosis protein Bcl-2 from a muscle-specific transgene. We found that both of these genetic interventions produced a several-fold increase in the lifespan of Lama2 -/-mice. Bax inactivation also improved postnatal growth rate and myofiber histology and decreased fixed contractures of Lama2 -/-mice. Thus, Bcl-2 family-mediated apoptosis contributes significantly to pathogenesis in the mouse model of CMD1A, and antiapoptosis therapy may be a possible route to amelioration of neuromuscular dysfunction due to laminin-α2 deficiency in humans.

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Complement 3 deficiency and oral prednisolone improve strength and prolong survival of laminin α2-deficient mice

Cited by 27 publications

References 28 publications

Gene Expression Profiling Identifies Molecular Pathways Associated with Collagen VI Deficiency and Provides Novel Therapeutic Targets

Gene Expression Profiling Identifies Molecular Pathways Associated with Collagen VI Deficiency and Provides Novel Therapeutic Targets

Overexpression of the Cytotoxic T Cell (CT) Carbohydrate Inhibits Muscular Dystrophy in the dyW Mouse Model of Congenital Muscular Dystrophy 1A

Inhibition of apoptosis improves outcome in a model of congenital muscular dystrophy

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