Comparison of skeletal muscle pathology and motor function of dystrophin and utrophin deficient mouse strains

Putten, Maaike van; Kumar, Darshan; Hulsker, Margriet; Hoogaars, Willem M.H.; Plomp, Jaap J.; Opstal, Annemarieke van; Iterson, Maarten van; Admiraal, P. J. J.; Ommen, Gert‐Jan B. van; Hoen, Peter A.C. ‘t; Aartsma‐Rus, Annemieke

doi:10.1016/j.nmd.2011.10.011

Cited by 68 publications

(63 citation statements)

References 33 publications

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“…For this study we used a dystrophin-deficient, utrophin haplo-insufficient ( utrn +/− ; mdx ) “het” mouse model, which has a more severe phenotype than mdx mice [9, 10]. C57BL/10 (Harwell) wild-type control mice were also used in this study.…”

Section: Methodsmentioning

confidence: 99%

The Angiotensin Converting Enzyme Inhibitor Lisinopril Improves Muscle Histopathology but not Contractile Function in a Mouse Model of Duchenne Muscular Dystrophy

Lowe

Wodarcyk

Floyd

et al. 2015

JND

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Background Angiotensin converting enzyme inhibitors (ACEi) are the current standard of care treatment for cardiac dysfunction in Duchenne muscular dystrophy patients. We previously showed treatment with an ACEi plus mineralocorticoid receptor (MR) antagonist improves limb and respiratory skeletal muscles, in addition to cardiac muscles, in a dystrophic mouse model at 20 weeks-of-age. Objective To determine whether previously observed preclinical benefits of an ACEi plus MR antagonist on dystrophic skeletal muscles can be reproduced by increasing ACEi dosage alone. We also compared functional and histological outcome measures at 10 and 20 weeks-of-age. Methods Dystrophin deficient utrophin haplo-insufficient (utrn+/−; mdx) “het” mice were treated with 10, 20, or 50 mg/kg × day of the ACEi lisinopril from 4 to 10 weeks-of-age via water bottles and compared with C57BL/10 wild-type control mice and untreated hets. Data from 10 week-old het mice were also compared to data collected from an untreated het group at 20 weeks-old. In vivo cardiac and grip strength measurements, in vitro diaphragm and extensor digitorum longus muscle force measurements, and histopathological analyses were performed. One-way ANOVA followed by Dunnett post hoc comparison was used to determine significance. Results ACEi treatment reduced skeletal muscle damage but had no significant effect on muscle force. Body weight, heart rate, grip strength and blood pressure were unaffected by treatment. Limb muscle histopathology was more informative at 10 than 20 weeks-of-age. Conclusions These results suggest increased ACEi dosage alone cannot improve all dystrophic parameters. Further optimization of MR antagonists in 20 week-old mice is warranted.

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Section: Methodsmentioning

confidence: 99%

The Angiotensin Converting Enzyme Inhibitor Lisinopril Improves Muscle Histopathology but not Contractile Function in a Mouse Model of Duchenne Muscular Dystrophy

Lowe

Wodarcyk

Floyd

et al. 2015

JND

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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

“…Considerando que este modelo pré-clínico atualmente, vem sendo utilizado em diversos experimentos que abordam a melhora da função respiratória (Huang et al 2011, Rafael-Fortney et al 2011, Van Putten et al 2012) o estudo da morfologia comparativa histológica e ultraestrutural dos pulmões de mdx por meio da microscopia de luz e eletrônica de varredura e a comparação com animais BALB/ C57 (Mus musculus) tem o objetivo de aprimorar a interpretação e comparação de dados publicados além de identificar possíveis diferenças entre estes dois modelos. Para a microscopia eletrônica de varredura (MEV), adaptou--se a metodologia descrita por Lessa et al 2012 para o processamento dos pulmões.…”

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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“…Images were taken with a Leica DC500 camera and Leica IM50 software (Leica Microsystems). The fibrotic/necrotic percentage of the entire cross section was determined with the freely available ImageJ software (NIH) (27, 28). Fiber size was measured with SMASH (Matlab based analysis; MatLab, Natick, MA, USA) (29).…”

Section: Methodsmentioning

confidence: 99%

New function of the myostatin/activin type I receptor (ALK4) as a mediator of muscle atrophy and muscle regeneration

et al. 2016

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Skeletal muscle fibrosis and impaired muscle regeneration are major contributors to muscle wasting in Duchenne muscular dystrophy (DMD). Muscle growth is negatively regulated by myostatin (MSTN) and activins. Blockage of these pathways may improve muscle quality and function in DMD. Antisense oligonucleotides (AONs) were designed specifically to block the function of ALK4, a key receptor for the MSTN/activin pathway in skeletal muscle. AON-induced exon skipping resulted in specific Alk4 down-regulation, inhibition of MSTN activity, and increased myoblast differentiation in vitro. Unexpectedly, a marked decrease in muscle mass (10%) was found after Alk4 AON treatment in mdx mice. In line with in vitro results, muscle regeneration was stimulated, and muscle fiber size decreased markedly. Notably, when Alk4 was down-regulated in adult wild-type mice, muscle mass decreased even more. RNAseq analysis revealed dysregulated metabolic functions and signs of muscle atrophy. We conclude that ALK4 inhibition increases myogenesis but also regulates the tight balance of protein synthesis and degradation. Therefore, caution must be used when developing therapies that interfere with MSTN/activin pathways.—Pasteuning-Vuhman, S., Boertje-van der Meulen, J. W., van Putten, M., Overzier, M., ten Dijke, P., Kiełbasa, S. M., Arindrarto, W., Wolterbeek, R., Lezhnina, K. V., Ozerov, I. V., Aliper, A. M., Hoogaars, W. M., Aartsma-Rus, A., Loomans, C. J. M. New function of the myostatin/activin type I receptor (ALK4) as a mediator of muscle atrophy and muscle regeneration.

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Comparison of skeletal muscle pathology and motor function of dystrophin and utrophin deficient mouse strains

Cited by 68 publications

References 33 publications

The Angiotensin Converting Enzyme Inhibitor Lisinopril Improves Muscle Histopathology but not Contractile Function in a Mouse Model of Duchenne Muscular Dystrophy

The Angiotensin Converting Enzyme Inhibitor Lisinopril Improves Muscle Histopathology but not Contractile Function in a Mouse Model of Duchenne Muscular Dystrophy

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

New function of the myostatin/activin type I receptor (ALK4) as a mediator of muscle atrophy and muscle regeneration

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