Cell的Immediate Early Publications：Short Telomeres and Stem Cell

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Short Telomeres and Stem Cell Exhaustion Model Duchenne Muscular Dystrophy in mdx/mTR Mice
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SUMMARY5 t/ X& i2 m1 g: y: g
In Duchenne muscular dystrophy (DMD), dystrophin# U8 p, v0 I" ^+ n4 p1 I9 E
mutation leads to progressive lethal skeletal muscle9 [8 k1 J, ]/ r# n3 z$ e
degeneration. For unknown reasons, dystrophin deficiency
+ I" J$ e+ [  n4 Y& W' c5 N) Adoes not recapitulate DMD in mice (mdx),
# f9 D4 B6 l5 u2 xwhich have mild skeletal muscle defects and potent
  q) o+ N- P/ \2 @5 \% C% Xregenerative capacity. We postulated that human" m) _/ h* s9 n7 J/ l4 d
DMD progression is a consequence of loss of functional, X, R3 C- n9 {$ U7 _) q2 }
muscle stem cells (MuSC), and the mild mouse0 G# N2 C6 @; L0 R6 v
mdx phenotype results from greater MuSC reserve4 u" t$ m$ U+ J! S
fueled by longer telomeres. We report that mdx
- V+ Z- I; m$ B6 jmice lacking the RNA component of telomerase
2 o* |# M5 B' S- D; p/ y) Q(mdx/mTR) have shortened telomeres in muscle cells
* F) A7 ]2 L& b1 ?' n# Pand severe muscular dystrophy that progressively0 G7 @, b5 x# p1 o; E
worsens with age. Muscle wasting severity parallels" T1 h, i( g, e- @9 u# |
a decline in MuSC regenerative capacity and is9 |+ R. h- ^# H# @2 A7 B4 a& w
ameliorated histologically by transplantation of( s  G0 J/ z1 W/ D4 @3 ?& n
wild-type MuSC. These data show thatDMDprogression
3 m# e8 E4 L. Y, C5 o/ K' Jresults, in part, from a cell-autonomous failure8 p7 a! u8 g+ J) |8 g' f
of MuSC to maintain the damage-repair cycle initiated
5 n* [" f* Z- N* S- t* Z0 uby dystrophin deficiency. The essential role of
5 m) B1 C) @8 J# F% oMuSC function has therapeutic implications for DMD.

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