Rapid depletion of muscle progenitor cells in dystrophic mdx/utrophin-/- mice.
Duchenne muscular dystrophy (DMD) patients lack dystrophin from birth; however, muscle weakness becomes apparent only at 3-5 years of age, which happens to coincide with the depletion of the muscle progenitor cell (MPC) pools. Indeed, MPCs isolated from older DMD patients demonstrate impairments in myogenic potential. To determine whether the progression of muscular dystrophy is a consequence of the decline in functional MPCs, we investigated two animal models of DMD: (i) dystrophin-deficient mdx mice, the most commonly utilized model of DMD, which has a relatively mild dystrophic phenotype and (ii) dystrophin/utrophin double knock-out (dKO) mice, which display a similar histopathologic phenotype to DMD patients. In contrast to age-matched mdx mice, we observed that both the number and regeneration potential of dKO MPCs rapidly declines during disease progression. This occurred in MPCs at both early and late stages of myogenic commitment. In fact, early MPCs isolated from 6-week-old dKO mice have reductions in proliferation, resistance to oxidative stress and multilineage differentiation capacities compared with age-matched mdx MPCs. This effect may potentially be mediated by fibroblast growth factor overexpression and/or a reduction in telomerase activity. Our results demonstrate that the rapid disease progression in the dKO model is associated, at least in part, with MPC depletion. Therefore, alleviating MPC depletion could represent an approach to delay the onset of the histopathologies associated with DMD patients.
Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, PA 15219, USA.
Aiping
A
Lu
Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, PA 15219, USA.
Minakshi
M
Poddar
Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, PA 15219, USA.
Ying
Y
Tang
Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, PA 15219, USA.
Jonathan D
JD
Proto
Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, PA 15219, USA.
Jihee
J
Sohn
Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, PA 15219, USA.
Xiaodong
X
Mu
Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, PA 15219, USA.
Nicholas
N
Oyster
Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, PA 15219, USA.
Bing
B
Wang
Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, PA 15219, USA jhuard@pitt.edu.
Johnny
J
Huard
D000818:Animals; D004195:Disease Models, Animal; D018450:Disease Progression; D016189:Dystrophin / Q000235:genetics*; D006801:Humans; D051379:Mice; D018101:Mice, Inbred mdx; D018345:Mice, Knockout; D009136:Muscular Dystrophies / Q000235:genetics / Q000473:pathology*; D032448:Myoblasts, Skeletal / Q000473:pathology* / Q000502:physiology; D012038:Regeneration; D049411:Utrophin / Q000235:genetics*
D016189:Dystrophin; D049411:Utrophin