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.
    Current Topics in Developmental Biology 06/2014; 109:171-247. DOI:10.1016/B978-0-12-397920-9.00002-0 · 4.68 Impact Factor
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    • "It lacks dystrophin expression, and, though with a milder phenotype, exhibits extensive limb muscle degeneration and inflammation, as well as myocardial lesions [13] [14] [15]. Available data sets, although limited and not comprehensive, suggest that early immune cell infiltration in DMD patients and mdx mice represent an important, but underappreciated, aspect of dystrophic muscle pathology. "
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    ABSTRACT: Skeletal muscle is able to restore contractile functionality after injury thanks to its ability to regenerate. Following muscle necrosis, debris is removed by macrophages, and muscle satellite cells (MuSCs), the muscle stem cells, are activated and subsequently proliferate, migrate, and form muscle fibers restoring muscle functionality. In most muscle dystrophies (MDs), MuSCs fail to properly proliferate, differentiate, or replenish the stem cell compartment, leading to fibrotic deposition. However, besides MuSCs, interstitial nonmyogenic cells and inflammatory cells also play a key role in orchestrating muscle repair. A complete understanding of the complexity of these mechanisms should allow the design of interventions to attenuate MDs pathology without disrupting regenerative processes. In this review we will focus on the contribution of immune cells in the onset and progression of MDs, with particular emphasis on Duchenne muscular dystrophy (DMD). We will briefly summarize the current knowledge and recent advances made in our understanding of the involvement of different innate immune cells in MDs and will move on to critically evaluate the possible role of cell populations within the acquired immune response. Revisiting previous observations in the light of recent evidence will likely change our current view of the onset and progression of the disease.
    BioMed Research International 06/2014; 2014(5):438675. DOI:10.1155/2014/438675 · 3.17 Impact Factor
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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.
    Journal of Molecular and Cellular Cardiology 01/2014; 69. DOI:10.1016/j.yjmcc.2014.01.009 · 4.66 Impact Factor
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