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Role of telomere dysfunction in cardiac failure in Duchenne muscular dystrophy

Nature Cell Biology volume 15, pages 895904 (2013) | Download Citation


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/mTRKO) 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/mTRKO 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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We thank E. Ashley (Director, Stanford Center for Inherited Cardiovascular Disease), J. Cooke (Associate Director of Cardiovascular Institute, Stanford), M. V. McConnell (Cardiovascular Medicine, Stanford), A. Connolly (Pathology, Stanford), S. Artandi (Medicine-Hematology, Stanford) and J. Pomerantz (Center of Regeneration Medicine and Stem Cell Research, UCSF) for insightful discussions and critical comments. We greatly appreciate the input and thoughtful discussions from all Blau laboratory members and would like to especially thank S. Sampath for critical comments on the manuscript and A.T. Van Ho for help with the final formatting of the Supplementary Videos. We are grateful to D. Regula (Department of Pathology, Stanford) for providing the control cardiac samples, and M. Halushka (Department of Pathology, Johns Hopkins), A. H. Beggs (Harvard University) and H. Lidov (Department of Pathology, Boston Children’s Hospital) for providing us with DMD cardiac samples. Moreover, we are grateful to Muscular Dystrophy Center Core Laboratories at University of Minnesota, the Department of Pathology at Boston Children’s Hospital, and the DMD patients and their families who contribute to the tissue repository. We thank: E. Neri (Data Manager, Stanford) for computational algorithms for analysis of telomere lengths, A. Olson at the NMS (Stanford Neuroscience Microscopy Service, supported by NIH NS069375), K. Koleckar (Blau laboratory), and P. Chu (Comparative Medicine, Stanford), L. J. Pisani (MIPS MRI Physicist, Stanford Small Imaging Facility), J. Perrino (Electron Microscopy Facility, Stanford) as well as R. Zasio and E. Florendo (Stanford Mouse Facility) for excellent technical assistance. This work was supported by: the American Heart Association Scientist Development Grant 10SDG3510024 (F.M.); NIH/NIAMS P30 grants AR057220 (J.W.D.) and R01CA84628 (R.A.D.); NIH grants HL061535 (D.B.), P50CA058236 (W. Nelson) and NIHSPORE in ProstateCancer (A.K.M.); grants from the Robert A. and Renee E. Belfer Foundation (R.A.D., A.M. and A.P.); NIH grants HL096113, HL100397, AG020961 and AG009521 (H.M.B.); MDA grant 4320 (H.M.B.); and the Baxter Foundation (H.M.B.).

Author information


  1. 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

    • Foteini Mourkioti
    • , Jackie Kustan
    • , Peggy Kraft
    •  & Helen M. Blau
  2. Department of Neurology, Stanford School of Medicine, Stanford, California 94305, USA

    • John W. Day
  3. Department of Pediatrics (Cardiology), Stanford University, Stanford, California 94305, USA

    • Ming-Ming Zhao
    •  & Daniel Bernstein
  4. Institute for Applied Cancer Science, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, Texas 77030, USA

    • Maria Kost-Alimova
    •  & Alexei Protopopov
  5. Department of Cancer Biology, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, Texas 77030, USA

    • Ronald A. DePinho
  6. Department of Pathology, Department of Oncology, Johns Hopkins Medical Institution, Baltimore, Maryland 21231, USA

    • Alan K. Meeker


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F.M. designed the studies and performed the experiments, J.K. performed mouse work, histology, immunohistochemistry, mitochondrial quantification analysis and design of schematic diagrams, P.K. maintained the mouse colony and performed histological sections, F.M., A.K.M., M.K-A. and R.A.D. aided with telomere analyses in mouse samples, F.M. and A.K.M. performed the telomere analysis in human samples, F.M. and D.B. performed the ECG analyses, F.M. and M-M.Z. performed the osmotic minipump experiments, J.W.D. provided human cardiac samples, and F.M. and H.M.B. designed the experiments, discussed and interpreted the results, and wrote the paper with input from A.K.M., R.A.D. and D.B.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Helen M. Blau.

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  1. 1.

    Echocardiographic analysis indicates defect in G2 hearts.

    Representative movies from 32-week-old animals show increased LV size and impairment in ventricular function in G2 hearts.

  2. 2.

    Cardiac defect in G2 mice that received Angiotensin II.

    Representative movies 3 weeks after the mini-osmotic pump experiment from 12-week-old mdx/mTRHet (Het) and G2 hearts received either saline or Ang II. Note that the G2 hearts with Ang II show left ventricular dilation, thin myocardial wall and compromised contraction.

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