title: Short telomeres and stem cell exhaustion model Duchenne muscular dystrophy in mdx/mTR mice.
abstract: In Duchenne muscular dystrophy (DMD), dystrophin mutation leads to progressive lethal skeletal muscle degeneration. For unknown reasons, dystrophin deficiency does not recapitulate DMD in mice (mdx), which have mild skeletal muscle defects and potent regenerative capacity. We postulated that human DMD progression is a consequence of loss of functional muscle stem cells (MuSC), and the mild mouse mdx phenotype results from greater MuSC reserve fueled by longer telomeres. We report that mdx mice lacking the RNA component of telomerase (mdx/mTR) have shortened telomeres in muscle cells and severe muscular dystrophy that progressively worsens with age. Muscle wasting severity parallels a decline in MuSC regenerative capacity and is ameliorated histologically by transplantation of wild-type MuSC. These data show that DMD progression results, in part, from a cell-autonomous failure of MuSC to maintain the damage-repair cycle initiated by dystrophin deficiency. The essential role of MuSC function has therapeutic implications for DMD.
authors.affiliation: Baxter Laboratory for Stem Cell Biology, Department of Microbiology and Immunology, Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Sacco
authors.forename: Foteini
authors.initials: F
authors.lastname: Mourkioti
authors.forename: Rose
authors.initials: R
authors.lastname: Tran
authors.forename: Jinkuk
authors.initials: J
authors.lastname: Choi
authors.forename: Michael
authors.initials: M
authors.lastname: Llewellyn
authors.forename: Peggy
authors.initials: P
authors.lastname: Kraft
authors.forename: Marina
authors.initials: M
authors.lastname: Shkreli
authors.forename: Scott
authors.initials: S
authors.lastname: Delp
authors.forename: Jason H
authors.initials: JH
authors.lastname: Pomerantz
authors.forename: Steven E
authors.initials: SE
authors.lastname: Artandi
authors.forename: Helen M
authors.initials: HM
authors.lastname: Blau
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D004195:Disease Models, Animal; D016189:Dystrophin / Q000378:metabolism; D006801:Humans; D051379:Mice; D018101:Mice, Inbred mdx; D009137:Muscular Dystrophy, Animal / Q000235:genetics; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics*; D011287:Prejudice; D013234:Stem Cells / Q000378:metabolism*; D016615:Telomere / Q000378:metabolism*
chemical_list: D016189:Dystrophin