Role of telomere dysfunction in cardiac failure in Duchenne muscular dystrophy

Foteini Mourkioti, Jackie Kustan, Peggy Kraft, John W. Day, Ming Ming Zhao, Maria Kost-Alimova, Alexei Protopopov, Ronald A. Depinho, Daniel Bernstein, Alan K. Meeker, Helen M. Blau

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)895-904
Number of pages10
JournalNature cell biology
Volume15
Issue number8
DOIs
StatePublished - Aug 1 2013

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ASJC Scopus subject areas

  • Cell Biology

Cite this

Mourkioti, F., Kustan, J., Kraft, P., Day, J. W., Zhao, M. M., Kost-Alimova, M., Protopopov, A., Depinho, R. A., Bernstein, D., Meeker, A. K., & Blau, H. M. (2013). Role of telomere dysfunction in cardiac failure in Duchenne muscular dystrophy. Nature cell biology, 15(8), 895-904. https://doi.org/10.1038/ncb2790