Haploinsufficiency of utrophin gene worsens skeletal muscle inflammation and fibrosis in mdx mice

Zhou, Lan; Rafael‐Fortney, Jill A.; Huang, Ping; Zhao, Xinyu; Cheng, Georgina; Zhou, Xiaohua; Kaminski, Henry J.; Liu, Liping; Ransohoff, Richard M.

doi:10.1016/j.jns.2007.08.029

Cited by 70 publications

(106 citation statements)

References 16 publications

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“…Entretanto estes animais apresentam um fenótipo mais brando da DMD e após períodos de pico de inflamação, os músculos do mdx com exceção do músculo diafragma, voltam a apresentar sua função restaurada. Tal compensação funcional nestes animais tem sido atribuída a expressão de utrofina no sarcolema das células musculares de camundongos adultos, que atua restaurando proteínas do complexo distrofina, protegendo o fenótipo da distrofia muscular no camundongo mdx de forma dose-dependente (Zhou et al 2008, Huang et al 2011, Van Putten et al 2012.…”

Section: Introductionunclassified

Arquitetura comparativa dos pulmões de camundongos normais e afetados pela Distrofia Muscular de Duchenne

et al. 2015

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RESUMO.-A Distrofia Muscular de Duchenne (DMD) é uma doença genética de caráter recessivo que caracterizada por fraqueza muscular progressiva de cintura pélvica e escapular evoluindo para insuficiência respiratória e, ou cardíaca. O camundongo mdx é um modelo amplamente utilizado para estudos da DMD. Apesar do fenótipo destes animais serem mais suave, estes apresentam o principal músculo respiratório, o diafragma com morfologia e bioquímica semelhante à DMD humana, fato este que pode comprometer a função respirató-ria e consequentemente os pulmões. Foi realizado um estudo anatômico descritivo do parênquima pulmonar dos pulmões de 5 animais modelo mdx comparando estes com os pulmões de 5 camundongos BALB/C57 (Mus musculus). Os pulmões foram analisados macroscopicamente e através de microscopia de luz e eletrônica de varredura. Os achados sugerem que o modelo mdx apresenta morfologia pulmonar semelhante aos camundongos BALB/C57 e que seu uso deve ser cauteloso e criterioso em ensaios clínicos que aborde este órgão.TERMOS DE INDEXAÇÃO: Distrofia muscular, Duchenne, mdx, morfologia pulmonar, anatomia respiratória. INTRODUÇÃOA anatomia descritiva constitui parte dos princípios primordiais da pesquisa, uma vez que esta descreve tecidos biológicos fornecendo dados morfológicos importantes para análises de estudos de afecções que envolvem alterações teciduais e reparo.A Distrofia Muscular de Duchenne (DMD) é uma doença neuromuscular, de origem hereditária de caráter recessivo, incidindo em meninos em 1 a cada 3500 nascidos. Sua evolução é rápida e severa caracterizada por uma mutação do gene que codifica a proteína 427 kDA chamada distrofina. A distrofina corresponde por cerca de apenas 0,002% da massa proteica da célula muscular estriada, e está localizada na superfície intracelular do sarcolema e se associa a várias glicoproteínas integrais da membrana, formando The Duchenne Muscular Dystrophy (DMD) is a recessive genetic disease characterized by progressive muscle weakness of the pelvic and scapular girdle and progressing to respiratory or heart failure. The mdx mouse is a model widely used for studies. Although they possess a milder phenotype, the morphology and biochemistry of the diaphragm are similar to human DMD. We performed a descriptive anatomical study of the pulmonary parenchyma of five mdx animal models and compared these with the lungs of 5 mice BALB/ C57 (Mus musculus). The findings suggest that the mdx model has morphological features similar to BALB/C57 mice and it must be used with caution in clinical trials which involve the lung.

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Section: Introductionunclassified

Arquitetura comparativa dos pulmões de camundongos normais e afetados pela Distrofia Muscular de Duchenne

et al. 2015

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“…Inflammation and fibrosis in both skeletal muscle and diaphragm are more severe than in the mdx mouse, but less than in the mdx/utrn -/-mouse. Their life span is significantly longer than that of mdx/utrn -/-mice (Zhou et al, 2008).…”

Section: Mouse Models For Dmdmentioning

confidence: 91%

AON-Mediated Exon Skipping for Duchenne Muscular Dystrophy

Verhaart¹,

Aartsma‐Rus²

2012

Neuromuscular Disorders

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“…However the dramatically reduced lifespan of these mice can hamper their experimental use [40]. In an attempt to circumvent this problem it was reported that haploinsufficiency of utrophin in the mdx;utrn +/-mouse worsens SM pathology compared to the mdx, whilst extending life expectancy compared to the mdx;utrn -/- [42,43].). Some groups are using the golden retriever (GRMD) dog model, however a major limitation is the dramatic variation in phenotype which is often observed even between littermates [44].…”

Section: Preclinical Models Of Dmdmentioning

confidence: 99%

Pharmacologically Targeting the Primary Defect and Downstream Pathology in Duchenne Muscular Dystrophy

Fairclough

Perkins²,

Davies³

2012

CGT

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DMD is a devastatingly progressive muscle wasting disorder of childhood that significantly shortens life expectancy. Despite efforts to develop an effective therapy that dates back over a century, clinical interventions are still restricted to management of symptoms rather than a cure. The rationale to develop effective therapies changed in 1986 with the discovery of the dystrophin gene. Since then extensive research into both the molecular basis and pathophysiology of DMD has paved the way not only for development of strategies which aim to correct the primary defect, but also towards the identification of countless therapeutic targets with the potential to alleviate the downstream pathology. In addition to gene and cell-based therapies, which aim to deliver the missing gene and/or protein, an exciting spectrum of pharmacological approaches aimed at modulating therapeutic targets within DMD muscle cells through the use of small drugs are also being developed. This review presents promising pharmacological approaches aimed at targeting the primary defect, including suppression of nonsense mutations and functional compensation by upregulation of the dystrophin homologue, utrophin. Downstream of the primary membrane fragility, inflammation and fibrosis are reduced by blocking NF-κB, TGF-α and TGF-β, and free radical damage has been targeted using antioxidants and dietary/nutritional supplements. There are new hopes that ACE and PDE5 inhibitors can protect against skeletal as well as cardiac pathology, and modulating Ca2+ influx, NO, BMP, protein degradation and the mitochondrial permeability pore hold further promise in tackling the complex pathogenesis of this multifaceted disorder.

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Haploinsufficiency of utrophin gene worsens skeletal muscle inflammation and fibrosis in mdx mice

Cited by 70 publications

References 16 publications

Arquitetura comparativa dos pulmões de camundongos normais e afetados pela Distrofia Muscular de Duchenne

Arquitetura comparativa dos pulmões de camundongos normais e afetados pela Distrofia Muscular de Duchenne

AON-Mediated Exon Skipping for Duchenne Muscular Dystrophy

Pharmacologically Targeting the Primary Defect and Downstream Pathology in Duchenne Muscular Dystrophy

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