Cardiac dysfunction and pathology in the dystrophin and utrophin-deficient mouse during development of dilated cardiomyopathy.

Cardiac involvement in Duchenne muscular dystrophy is asymptomatic until function is severely affected. Little is known about its evolution, and few animal models are available to study potential treatments. We therefore examined cardiac function and pathology in mdx/utrn(-/-) dystrophin/utrophin-deficient mice. Decreased left ventricular fractional shortening and ejection fraction, as well as increased end-diastolic volume, left ventricle dilation, and thinning of the ventricular wall and septum develop by 15weeks. Fibrosis is also detected in the outer region of both ventricle walls and the septum and ultrastructure analysis revealed abnormalities in mitochondrial organization, size, and shape. The functional changes observed are comparable to the evolution of dilated cardiomyopathy in Duchenne muscular dystrophy, indicating that mdx/utrn(-/-) dystrophin/utrophin-deficient mice are a possible phenotypic model for cardiomyopathy in Duchenne muscular dystrophy.

Chun JL ，O'Brien R ，Berry SE 《-》

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

The genetic defect of mdx mice resembles that of Duchenne muscular dystrophy, although their functional performance and life expectancy is nearly normal. By contrast, mice lacking utrophin and dystrophin (mdx/utrn -/-) are severely affected and die prematurely. Mice with one utrophin allele (mdx/utrn +/-) are more severely affected than mdx mice, but outlive mdx/utrn -/- mice. We subjected mdx/utrn +/+, +/-, -/- and wild type males to a 12week functional test regime of four different functional tests. Mdx/utrn +/+ and +/- mice completed the regime, while mdx/utrn -/- mice died prematurely. Mdx/utrn +/- mice performed significantly worse compared to mdx/utrn +/+ mice in functional tests. Creatine kinase levels, percentage of fibrotic/necrotic tissue, morphology of neuromuscular synapses and expression of biomarker genes were comparable, whereas mdx/utrn +/- and -/- mice had increased levels of regenerating fibers. This makes mdx/utrn +/- mice valuable for testing the benefit of potential therapies on muscle function parameters.

van Putten M ，Kumar D ，Hulsker M ，Hoogaars WM ，Plomp JJ ，van Opstal A ，van Iterson M ，Admiraal P ，van Ommen GJ ，'t Hoen PA ，Aartsma-Rus A ... -  《-》

Injection of vessel-derived stem cells prevents dilated cardiomyopathy and promotes angiogenesis and endogenous cardiac stem cell proliferation in mdx/utrn-/- but not aged mdx mouse models for duchenne muscular dystrophy.

Chun JL ，O'Brien R ，Song MH ，Wondrasch BF ，Berry SE ... -  《-》

Increased constitutive nitric oxide production by whole body periodic acceleration ameliorates alterations in cardiomyocytes associated with utrophin/dystrophin deficiency.

Lopez JR ，Kolster J ，Zhang R ，Adams J ... -  《-》

Regulation of the cardiac sodium channel Nav1.5 by utrophin in dystrophin-deficient mice.

Albesa M ，Ogrodnik J ，Rougier JS ，Abriel H ... -  《-》