@article{41402e31415946a7b0200f7dabf08aba,
title = "Role of telomere dysfunction in cardiac failure in Duchenne muscular dystrophy",
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.",
author = "Foteini Mourkioti and Jackie Kustan and Peggy Kraft and Day, {John W.} and Zhao, {Ming Ming} and Maria Kost-Alimova and Alexei Protopopov and Depinho, {Ronald A.} and Daniel Bernstein and Meeker, {Alan K.} and Blau, {Helen M.}",
note = "Funding Information: 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{\textquoteright}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{\textquoteright}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.).",
year = "2013",
month = aug,
doi = "10.1038/ncb2790",
language = "English (US)",
volume = "15",
pages = "895--904",
journal = "Nature cell biology",
issn = "1465-7392",
publisher = "Nature Publishing Group",
number = "8",
}