Mammalian animal models for Duchenne muscular dystrophy

Willmann, Raffaella; Possekel, Stefanie; Dubach-Powell, Judith; Meier, Thomas; Rüegg, Markus A.

doi:10.1016/j.nmd.2008.11.015

Cited by 166 publications

(166 citation statements)

References 84 publications

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“…The tissue specificity of the identified lncRNAs was analyzed in different mouse body districts: skeletal muscles (gastrocnemius and tibialis) and heart and nonmuscle tissues (brain, cerebellum, and lung). Moreover, the corresponding tissues were also analyzed in the isogenic mdx mouse, the elective model system for muscular dystrophy (35,36). The use of wild-type and mdx tissues provides a powerful system for comparisons of the levels of expression in mature versus regenerating fibers, which are rich in activated myoblasts.…”

Section: Resultsmentioning

confidence: 99%

Novel Long Noncoding RNAs (lncRNAs) in Myogenesis: a miR-31 Overlapping lncRNA Transcript Controls Myoblast Differentiation

Ballarino

Cazzella

D’Andrea

et al. 2015

Molecular and Cellular Biology

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Transcriptome analysis allowed the identification of new long noncoding RNAs differentially expressed during murine myoblast differentiation. These transcripts were classified on the basis of their expression under proliferating versus differentiated conditions, muscle-restricted activation, and subcellular localization. Several species displayed preferential expression in dystrophic (mdx) versus wild-type muscles, indicating their possible link with regenerative processes. One of the identified transcripts, lnc-31, even if originating from the same nuclear precursor of miR-31, is produced by a pathway mutually exclusive. We show that lnc-31 and its human homologue hsa-lnc-31 are expressed in proliferating myoblasts, where they counteract differentiation. In line with this, both species are more abundant in mdx muscles and in human Duchenne muscular dystrophy (DMD) myoblasts, than in their normal counterparts. Altogether, these data suggest a crucial role for lnc-31 in controlling the differentiation commitment of precursor myoblasts and indicate that its function is maintained in evolution despite the poor sequence conservation with the human counterpart.

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Section: Resultsmentioning

confidence: 99%

Novel Long Noncoding RNAs (lncRNAs) in Myogenesis: a miR-31 Overlapping lncRNA Transcript Controls Myoblast Differentiation

Ballarino

Cazzella

D’Andrea

et al. 2015

Molecular and Cellular Biology

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“…DKO mice are considered to be a more appropriate model of human dystrophies than mdx mice as they display most of the clinical signs of DMD, including short stature, kyphosis, hindlimb weakness, laboured breathing, and premature death. 36 In addition, cardiac complications in DKO mice are similar to those seen in DMD patients. DKO mice exhibit abnormal ECG patterns with drastically decreased S-to-R wave ratios, a feature observed in 70 -80% of the DMD patients.…”

Section: Utrophin Up-regulation In Hearts Of Mdx5cv Micementioning

confidence: 93%

“…36 However, 'revertant' dystrophin-positive cells have been reported in these mice. 37 The mdx5cv mouse, generated by N-ethyl N-nitrosourea mutagenesis, also lacks full length dystrophin and does not display revertant cells.…”

Section: Utrophin Up-regulation In Hearts Of Mdx5cv Micementioning

confidence: 95%

Regulation of the Cardiac Sodium Channel Nav1.5 by Utrophin in Dystrophin Deficient Mice

et al. 2010

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AimsDuchenne muscular dystrophy (DMD) is a severe striated muscle disease due to the absence of dystrophin. Dystrophin deficiency results in dysfunctional sodium channels and conduction abnormalities in hearts of mdx mice. Disease progression in the mdx mouse only modestly reflects that of DMD patients, possibly due to utrophin up-regulation. Here, we investigated mice deficient in both dystrophin and utrophin [double knockout (DKO)] to assess the role of utrophin in the regulation of the cardiac sodium channel (Na v 1.5) in mdx mice. Methods and resultsCo-immunoprecipitation studies in HEK293 cells showed that utrophin interacts with Na v 1.5 via syntrophin proteins, an interaction abolished by deletion of the PDZ (PSD-95, Dlg, and Zona occludens) domain-binding motif of Na v 1.5. We also provide evidence for such interaction in mouse heart using Na v 1.5 C-terminus fusion proteins. In hearts of DKO mice, Na v 1.5 protein levels were decreased by 25 + 8%, together with a 42 + 12% reduction of syntrophins compared with mdx, where utrophin was up-regulated by 52 + 9% compared with C57BL/10 control mice. Sodium current was found to be reduced by 41 + 5% in DKO cardiomyocytes compared with mdx, representing a loss of 63 + 3% when compared with C57BL/10 wild-type control mice. Decreased Na v 1.5 protein and current in DKO were reflected in a significant slowing of 27 + 6% of maximal upstroke velocity of the cardiac action potential compared with mdx. ConclusionUtrophin plays a central role in the regulation of Na v 1.5 in mdx mice. These findings provide support for therapeutic strategies aimed at overexpressing utrophin in the hopes of reducing cardiac pathology in DMD patients.--

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“…It has been reported that limb muscle abnormality appear after 2 months of age and the dogs eventually die mainly due to cardiomyopathy . CXMD dog models show longer life span due to slower progression of muscle wasting compared to GRMD dogs (Willmann et al, 2009). Progress of cardiomyopathy in the CXMD dog is also milder than in GRMD (Yugeta et al, 2006).…”

Section: Canine Muscular Dystrophy Modelmentioning

confidence: 99%