IGF-II ameliorates the dystrophic phenotype and coordinately down-regulates programmed cell death

Duchenne muscular dystrophy (DMD) is a fatal and crippling disease of skeletal muscle which displays increased fibre turnover and elevated levels of programmed cell death (PCD) in muscle stem cells. Previously we showed that this cell death is inhibited by the growth factor IGF-II. To determine the functional significance of PCD to the dystrophic phenotype, we used a transgene to over-express IGF-II in the mdx mouse. We found that ectopic expression of IGF-II inhibited the elevated PCD observed in skeletal muscles in the absence of functional dystrophin and significantly ameliorates the early gross histopathological changes in skeletal muscles characteristic of the dystrophic phenotype. Replacement of the dystrophin gene abolished abnormal skeletal muscle cell PCD levels in vivo in a dose-dependent manner and in dystrophic SMS cell lines cultured in vitro. Thus elevation of stem cell PCD in dystrophic skeletal muscle is a direct consequence of the loss of functional dystrophin, Together these data demonstrate that elevated skeletal muscle cell PCD is a critical component of dystrophic pathology and is inversely correlated with both dystrophin gene dosage and with muscle fibre pathology. Targeting PCD in dystrophic muscles reduces both PCD and the classical features of dystrophic pathology in the mdx mouse suggesting that IGF-II is a strong candidate for therapeutic intervention in the dystrophinopathies.