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IGF-II ameliorates the dystrophic phenotype and coordinately down-regulates programmed cell death
1School of Biosciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK. J.Smith.20@bham.ac.uk
Cell Death and Differentiation
|January 4, 2001
Summary
Duchenne muscular dystrophy (DMD) involves increased cell death in muscle stem cells. Over-expressing IGF-II in mdx mice reduced this programmed cell death (PCD) and ameliorated disease symptoms, suggesting IGF-II as a therapeutic target.
Area of Science:
- Biochemistry
- Genetics
- Cell Biology
Background:
- Duchenne muscular dystrophy (DMD) is a severe muscle-wasting disease.
- Muscle stem cells in DMD exhibit increased programmed cell death (PCD).
- IGF-II (Insulin-like Growth Factor II) has been shown to inhibit PCD.
Purpose of the Study:
- To investigate the role of PCD in the dystrophic phenotype of DMD.
- To determine if over-expressing IGF-II can ameliorate DMD pathology in a mouse model.
Main Methods:
- Utilized a transgenic mdx mouse model to over-express IGF-II.
- Assessed programmed cell death (PCD) levels in skeletal muscle stem cells.
- Evaluated histopathological changes in skeletal muscle.
Main Results:
- Ectopic expression of IGF-II significantly inhibited elevated PCD in mdx mouse skeletal muscle.
- Over-expression of IGF-II ameliorated early histopathological changes characteristic of DMD.
- Restoring dystrophin gene function dose-dependently abolished abnormal PCD.
Conclusions:
- Elevated stem cell PCD in dystrophic muscle is a direct result of functional dystrophin loss.
- Targeting PCD in dystrophic muscles reduces both cell death and pathology in mdx mice.
- IGF-II is a promising therapeutic candidate for treating dystrophinopathies.