Short Telomeres and Stem Cell Exhaustion Model Duchenne Muscular Dystrophy in mdx/mTR Mice

被引：400

作者：

Sacco, Alessandra ^{[1
]}

Mourkioti, Foteini ^{[1
]}

Tran, Rose ^{[1
]}

Choi, Jinkuk ^{[2
]}

Llewellyn, Michael ^{[3
]}

Kraft, Peggy ^{[1
]}

Shkreli, Marina ^{[2
]}

Delp, Scott ^{[3
]}

Pomerantz, Jason H. ^{[1
]}

Artandi, Steven E. ^{[2
]}

Blau, Helen M. ^{[1
]}

机构：

[1] Stanford Univ, Dept Microbiol & Immunol, Baxter Lab Stem Cell Biol, Inst Stem Cell Biol & Regenerat Med,Sch Med, Stanford, CA 94305 USA

[2] Stanford Univ, Sch Med, Dept Med, Canc Biol Program, Stanford, CA 94305 USA

[3] Stanford Univ, James H Clark Ctr Biomed Engn & Sci, BioX Program, Stanford, CA 94305 USA

来源：

CELL | 2010年 / 143卷 / 07期

关键词：

MEDIATED GENE-THERAPY; SKELETAL-MUSCLE REGENERATION; REPLICATIVE LIFE-SPAN; SELF-RENEWAL; HUMAN LIVER; SPINAL DEFORMITY; SATELLITE CELLS; MITOTIC CLOCK; MOUSE; MDX;

D O I：

10.1016/j.cell.2010.11.039

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

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.

引用

页码：1059 / 1071

页数：13

共 58 条

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