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.
authors.affiliation: 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.
authors.forename: Foteini
authors.initials: F
authors.lastname: Mourkioti
authors.forename: Jackie
authors.initials: J
authors.lastname: Kustan
authors.forename: Peggy
authors.initials: P
authors.lastname: Kraft
authors.forename: John W
authors.initials: JW
authors.lastname: Day
authors.forename: Ming-Ming
authors.initials: MM
authors.lastname: Zhao
authors.forename: Maria
authors.initials: M
authors.lastname: Kost-Alimova
authors.forename: Alexei
authors.initials: A
authors.lastname: Protopopov
authors.forename: Ronald A
authors.initials: RA
authors.lastname: DePinho
authors.forename: Daniel
authors.initials: D
authors.lastname: Bernstein
authors.forename: Alan K
authors.initials: AK
authors.lastname: Meeker
authors.forename: Helen M
authors.initials: HM
authors.lastname: Blau
mesh_terms: D000818:Animals; D048429:Cell Size; D004195:Disease Models, Animal; D016189:Dystrophin / Q000235:genetics; D006333:Heart Failure / Q000209:etiology*; D006801:Humans; D051379:Mice; D018101:Mice, Inbred mdx; D020388:Muscular Dystrophy, Duchenne / Q000150:complications* / Q000235:genetics*; D032383:Myocytes, Cardiac / Q000473:pathology; D016615:Telomere / Q000473:pathology*
chemical_list: D016189:Dystrophin