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Duchenne muscular dystrophy (DMD) is an incurable X-linked genetic disease that is caused by a mutation in the dystrophin gene and affects one in every 3,600 boys. We previously showed that long telomeres protect mice from the lethal cardiac disease seen in humans with the same genetic defect, dystrophin deficiency. By generating the mdx4cv/mTRG2 mouse model with "humanized" telomere lengths, the devastating dilated cardiomyopathy phenotype seen in patients with DMD was recapitulated. Here, we analyze the degenerative sequelae that culminate in heart failure and death in this mouse model. We report progressive telomere shortening in developing mouse cardiomyocytes after postnatal week 1, a time when the cells are no longer dividing. This proliferation-independent telomere shortening is accompanied by an induction of a DNA damage response, evident by p53 activation and increased expression of its target gene p21 in isolated cardiomyocytes. The consequent repression of Pgc1α/β leads to impaired mitochondrial biogenesis, which, in conjunction with the high demands of contraction, leads to increased oxidative stress and decreased mitochondrial membrane potential. As a result, cardiomyocyte respiration and ATP output are severely compromised. Importantly, treatment with a mitochondrial-specific antioxidant before the onset of cardiac dysfunction rescues the metabolic defects. These findings provide evidence for a link between short telomere length and metabolic compromise in the etiology of dilated cardiomyopathy in DMD and identify a window of opportunity for preventive interventions.

Original publication

DOI

10.1073/pnas.1615340113

Type

Journal article

Journal

Proc Natl Acad Sci U S A

Publication Date

15/11/2016

Volume

113

Pages

13120 - 13125

Keywords

Duchenne muscular dystrophy, dilated cardiomyopathy, metabolic compromise, mitochondrial dysfunction, telomere, Animals, Cardiomyopathy, Dilated, Cell Cycle, Cell Proliferation, DNA Damage, Male, Membrane Potential, Mitochondrial, Mice, Inbred C57BL, Mice, Knockout, Mitochondria, Heart, Mitosis, Muscular Dystrophy, Animal, Muscular Dystrophy, Duchenne, Myocytes, Cardiac, Reactive Oxygen Species, Telomere Shortening