Role of Telomere Dysfunction in Cardiac Failure in Duchenne Muscular Dystrophy

Baxter Laboratory for Stem Cell Biology, Department of Microbiology and Immunology, Institute for Stem Cell Biology and Regenerative Medicine, Clinical Sciences Research Center, Stanford University School of Medicine, Stanford, California 94305, USA.
Nature Cell Biology (Impact Factor: 19.68). 07/2013; 15(8). DOI: 10.1038/ncb2790
Source: PubMed


Duchenne muscular dystrophy (DMD), the most common inherited muscular dystrophy of childhood, leads to death due to cardiorespiratory failure. Paradoxically, mdx mice with the same genetic deficiency of dystrophin exhibit minimal cardiac dysfunction, impeding the development of therapies. We postulated that the difference between mdx and DMD might result from differences in telomere lengths in mice and humans. We show here that, like DMD patients, mice that lack dystrophin and have shortened telomeres (mdx/mTR(KO)) develop severe functional cardiac deficits including ventricular dilation, contractile and conductance dysfunction, and accelerated mortality. These cardiac defects are accompanied by telomere erosion, mitochondrial fragmentation and increased oxidative stress. Treatment with antioxidants significantly retards the onset of cardiac dysfunction and death of mdx/mTR(KO) mice. In corroboration, all four of the DMD patients analysed had 45% shorter telomeres in their cardiomyocytes relative to age- and sex-matched controls. We propose that the demands of contraction in the absence of dystrophin coupled with increased oxidative stress conspire to accelerate telomere erosion culminating in cardiac failure and death. These findings provide strong support for a link between telomere length and dystrophin deficiency in the etiology of dilated cardiomyopathy in DMD and suggest preventive interventions.

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    • "In terms of the underlying mouse substrate, increased life expectancy and comorbid obesity are particularly important variables that can be more easily incorporated than previously. While naturally aging mice might be impracticable due to cost, genetically aged mice (e.g., Terc-null mice) provide an alternative that has already been successfully used and found to model more closely the heart failure that occurs in muscular dystrophy patients (Mourkioti et al., 2013). Furthermore, many models of obese or diabetic mice currently exist that could also be utilized. "
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    ABSTRACT: Heart failure is one of the paramount global causes of morbidity and mortality. Despite this pandemic need, the available clinical counter-measures have not altered substantially in recent decades, most notably in the context of pharmacological interventions. Cell death plays a causal role in heart failure, and its inhibition poses a promising approach that has not been thoroughly explored. In previous approaches to target discovery, clinical failures have reflected a deficiency in mechanistic understanding, and in some instances, failure to systematically translate laboratory findings toward the clinic. Here, we review diverse mouse models of heart failure, with an emphasis on those that identify potential targets for pharmacological inhibition of cell death, and on how their translation into effective therapies might be improved in the future.
    Full-text · Article · Jun 2014 · Current Topics in Developmental Biology
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    • "An alternative strategy would have been to use one of the mdx cv models, as these are in a BL/6 background. However, these models are not widely used and information on the development of cardiomyopathy in these models has only very recently become available [40]. "
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    ABSTRACT: Duchenne muscular dystrophy is caused by mutations that prevent synthesis of functional dystrophin. All patients develop dilated cardiomyopathy. Promising therapeutic approaches are underway that successfully restore dystrophin expression in skeletal muscle. However, their efficiency in heart is limited. Improved quality and function of only skeletal muscle potentially accelerates the development of cardiomyopathy. Our study aimed to elucidate which dystrophin levels in heart are required to prevent or delay cardiomyopathy in mice. Heart function and pathology assessed with magnetic resonance imaging and histopathological analysis were compared between 2, 6 and 10-month-old female mdx-Xist(Δhs) mice, expressing low dystrophin levels (3-15%) in a mosaic manner based on skewed X-inactivation, dystrophin-negative mdx mice, and wild type mice of corresponding genetic backgrounds and gender. With age mdx mice developed dilated cardiomyopathy and hypertrophy, whereas the onset of heart pathology was delayed and function improved in mdx-Xist(Δhs) mice. The ejection fraction, the most severely affected parameter for both ventricles, correlated to dystrophin expression and the percentage of fibrosis. Fibrosis was partly reduced from 9.8% in mdx to 5.4% in 10 months old mdx-Xist(Δhs)mice. These data suggest that mosaic expression of 4-15% dystrophin in heart is sufficient to delay the onset and ameliorate cardiomyopathy in mice.
    Full-text · Article · Jan 2014 · Journal of Molecular and Cellular Cardiology
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    • "Despite the clear utility of this model, the pathology of the mdx model is somewhat different from human DMD, in part due to the increased telomere length and greater muscle stem cell reserve in mice compared with humans or dogs [97, 98]. Muscle degeneration is relatively milder in the mouse than in humans [93, 99]. "
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    ABSTRACT: Duchenne muscular dystrophy (DMD) is a devastating disease that dramatically decreases the lifespan and abilities of affected young people. The primary molecular cause of the disease is the absence of functional dystrophin protein, which is critical to proper muscle function. Those with DMD vary in disease presentation and dystrophin mutation; the same causal mutation may be associated with drastically different levels of disease severity. Also contributing to this variation are the influences of additional modifying genes and/or changes in functional elements governing such modifiers. This genetic heterogeneity complicates the efficacy of treatment methods and to date medical interventions are limited to treating symptoms. Animal models of DMD have been instrumental in teasing out the intricacies of DMD disease and hold great promise for advancing knowledge of its variable presentation and treatment. This review addresses the utility of comparative genomics in elucidating the complex background behind phenotypic variation in a canine model of DMD, Golden Retriever muscular dystrophy (GRMD). This knowledge can be exploited in the development of improved, more personalized treatments for DMD patients, such as therapies that can be tailor-matched to the disease course and genomic background of individual patients.
    Full-text · Article · Aug 2013 · Current Genomics
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