IGF-II ameliorates the dystrophic phenotype and coordinately down-regulates programmed cell death

Smith, Janet; Goldsmith, Corinne M.; Ward, Andrew; LeDieu, R

doi:10.1038/sj.cdd.4400738

Cited by 28 publications

(19 citation statements)

References 47 publications

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“…The persistent increased expression of both genes in mdx muscles (and of IGF-II in human dystrophic hindlimb muscles) underlines the importance of massive muscle cell proliferation and dedifferentiation in each mdx muscle type along the mouse life span. In parallel, it was recently documented that expression of IGF-II ameliorates the mdx phenotype by downregulating programmed cell death, as shown by a reduction of degenerative regions and of the number of centrally located nuclei (42,43). In addition, a link between IGF-II expression and collagen accumulation was proposed recently, suggesting a role of this protein in the mechanism of fibrosis in dystrophic cells (22,31).…”

Section: Conclusion 1: Dystrophin Deficiency Initiates Globally Identmentioning

confidence: 89%

Global/temporal gene expression in diaphragm and hindlimb muscles of dystrophin-deficient (mdx) mice

Rouger

Cunff

Steenman

et al. 2002

American Journal of Physiology-Cell Physiology

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The mdx mouse is a model for human Duchenne muscular dystrophy (DMD), an X-linked degenerative disease of skeletal muscle tissue characterized by the absence of the dystrophin protein. The mdx mice display a much milder phenotype than DMD patients. After the first week of life when all mdx muscles evolve like muscles of young DMD patients, mdx hindlimb muscles substantially compensate for the lack of dystrophin, whereas mdx diaphragm muscle becomes progressively affected by the disease. We used cDNA microarrays to compare the expression profile of 1,082 genes, previously selected by a subtractive method, in control and mdx hindlimb and diaphragm muscles at 12 time points over the first year of the mouse life. We determined that 1) the dystrophin gene defect induced marked expression remodeling of 112 genes encoding proteins implicated in diverse muscle cell functions and 2) two-thirds of the observed transcriptomal anomalies differed between adult mdx hindlimb and diaphragm muscles. Our results showed that neither mdx diaphram muscle nor mdx hindlimb muscles evolve entirely like the human DMD muscles. This finding should be taken under consideration for the interpretation of future experiments using mdx mice as a model for therapeutic assays.

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Section: Conclusion 1: Dystrophin Deficiency Initiates Globally Identmentioning

confidence: 89%

Global/temporal gene expression in diaphragm and hindlimb muscles of dystrophin-deficient (mdx) mice

Rouger

Cunff

Steenman

et al. 2002

American Journal of Physiology-Cell Physiology

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“…Hyperproliferation and elevated muscle cell apoptosis are wellestablished, widespread features of postnatal MD muscle pathology, which characterise both mouse and human forms of mdx/DMD and cav-3 -/-/LGMD-1c, as well as most other MD types (Baghdiguian et al, 1999;Smith et al, 1995;Smith et al, 2000;Smythe et al, 2003). Dystrophin, dystroglycan and caveolin-3 have roles in survival signalling (Glass, 2005;Smythe et al, 2003).…”

Section: Loss Of Pax7 Myoblastsmentioning

confidence: 99%

“…previously to generate dystrophin-deficient mutants that are heterozygous for an Igf2 transgene (mdxIgf-2 +/-) (Smith et al, 2000). Genotyping was achieved by PCR for neomycin (to detect the Cav3 knockout transgene) and caveolin-3 (expressed by WT, mdx and cav-3 +/-mice, but not by cav-3 -/-mice) (Fig.…”

Section: Research Articlementioning

confidence: 99%

Muscular dystrophy begins early in embryonic development deriving from stem cell loss and disrupted skeletal muscle formation

Merrick

Stadler

Larner

et al. 2009

Disease Models &Amp; Mechanisms

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SUMMARYExamination of embryonic myogenesis of two distinct, but functionally related, skeletal muscle dystrophy mutants (mdx and cav-3 -/-) establishes for the first time that key elements of the pathology of Duchenne muscular dystrophy (DMD) and limb-girdle muscular dystrophy type 1C (LGMD1c) originate in the disruption of the embryonic cardiac and skeletal muscle patterning processes. Disruption of myogenesis occurs earlier in mdx mutants, which lack a functional form of dystrophin, than in cav-3 -/-mutants, which lack the Cav3 gene that encodes the protein caveolin-3; this finding is consistent with the milder phenotype of LGMD-1c, a condition caused by mutations in Cav3, and the earlier [embryonic day (E)9.5] expression of dystrophin. Myogenesis is severely disrupted in mdx embryos, which display developmental delays; myotube morphology and displacement defects; and aberrant stem cell behaviour. In addition, the caveolin-3 protein is elevated in mdx embryos. Both cav-3 -/-and mdx mutants (from E15.5 and E11.5, respectively) exhibit hyperproliferation and apoptosis of Myf5-positive embryonic myoblasts; attrition of Pax7-positive myoblasts in situ; and depletion of total Pax7 protein in late gestation. Furthermore, both cav-3 -/-and mdx mutants have cardiac defects. In cav-3 -/-mutants, there is a more restricted phenotype comprising hypaxial muscle defects, an excess of malformed hypertrophic myotubes, a twofold increase in myonuclei, and reduced fast myosin heavy chain (FMyHC) content. Several mdx mutant embryo pathologies, including myotube hypotrophy, reduced myotube numbers and increased FMyHC, have reciprocity with cav-3 -/-mutants. In double mutant (mdxcav-3) embryos that are deficient in dystrophin (mdx) and heterozygous for caveolin-3 (cav-3), whereby caveolin-3 is reduced to 50% of wild-type (WT) levels, these phenotypes are severely exacerbated: intercostal muscle fibre density is reduced by 71%, and Pax7-positive cells are depleted entirely from the lower limbs and severely attenuated elsewhere; these data suggest a compensatory rather than a contributory role for the elevated caveolin-3 levels that are found in mdx embryos. These data establish a key role for dystrophin in early muscle formation and demonstrate that caveolin-3 and dystrophin are essential for correct fibre-type specification and emergent stem cell function. These data plug a significant gap in the natural history of muscular dystrophy and will be invaluable in establishing an earlier diagnosis for DMD/LGMD and in designing earlier treatment protocols, leading to better clinical outcome for these patients.

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“…It is already known that IGF2 is ectopically expressed throughout the gut epithelium of the K:Igf2 mouse, and that the colon becomes larger than normal (Smith et al, 2000). It has a higher DNA content, indicating that the difference is based on the presence of more cells rather than just water or extracellular material (Ward et al, 1994).…”

Section: Colonmentioning

confidence: 99%

“…The K:Igf2 mouse has the IGF2 gene driven by a bovine keratin 10 promoter that is active in the suprabasal layers of keratinocytes (Smith et al, 2000). Although the excess IGF2 is not expressed in the basal layer itself, the protein evidently reaches the basal layer as in all three strains of mice this is the only layer containing dividing cells.…”

Section: Skinmentioning

confidence: 99%

Structural-proliferative units and organ growth: effects of insulin-like growth factor 2 on the growth of colon and skin

et al. 2003

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Many epithelial renewal tissues in vertebrates are organised into structural-proliferative units. We have examined the effect of IGF2 dose on the structure of structural-proliferative units in skin and colon. The mouse strains used were the Igf2 knockout, wild type and K:Igf2, a transgenic in which Igf2 is overexpressed under control of a keratin promoter. For both skin and colon, the histological organisation of structural-proliferative units was unaltered with increasing IGF2 dose,although there was a higher fraction of dividing cells in the proliferative compartment. In the colon an increase in IGF2 dose increases the overall area of the epithelium. This is due to an increase in the number of crypts with no change of cell size or of crypt area. Growth stimulation appears to be due to a reduction in the duration of crypt fission. The conclusion is that the IGF2 pathway can stimulate the multiplication of colonic crypts independently of stimulating increased cell proliferation. The results for the skin are consistent with this. An increase of IGF2 dose increases the proportion of dividing cells in the basal layer, the thickness of the epidermis and the total area of the epidermis. By comparison with Drosophila, these results show no effects on cell size, but do show the possibility of inducing disproportionate growth. These differences may represent properties of the SPU organisation that is characteristic of vertebrate tissues.

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IGF-II ameliorates the dystrophic phenotype and coordinately down-regulates programmed cell death

Cited by 28 publications

References 47 publications

Global/temporal gene expression in diaphragm and hindlimb muscles of dystrophin-deficient (mdx) mice

Global/temporal gene expression in diaphragm and hindlimb muscles of dystrophin-deficient (mdx) mice

Muscular dystrophy begins early in embryonic development deriving from stem cell loss and disrupted skeletal muscle formation

Structural-proliferative units and organ growth: effects of insulin-like growth factor 2 on the growth of colon and skin

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