Cause of progression in Duchenne muscular dystrophy: Impaired differentiation more probable than replicative aging

Replicative aging of myogenic cells (satellite cells) owing to enhanced myo fiber turnover is a common explanation of the progression of Duchenne muscu lar dystrophy (DMD). This hypothesis has been reexamined recently by telome re length measurements in dystrophic tissue. We evaluate the controversial results of these studies. We also review a large body of in vitro, animal ( mdx), and patient data which indicate that impaired differentiation, but no t replicative aging, is the leading cause of progression in DMD. We recomme nd in vivo investigations of cell kinetics in DMD muscle, as well as telome re length and telomerase analyses of DMD satellite cells in vitro for a def inite judgement of the replicative aging hypothesis. Analogous investigatio ns were helpful in AIDS research where replicative aging was embraced as a simple explanation of the paradigmatic CD4 lymphocyte decline but had to be rejected in favour of more complex models of disturbed lymphocyte homeosta sis and regeneration. The question of replicative aging versus impaired dif ferentiation is relevant for the understanding of therapeutic failures and the design of new strategies. Impaired differentiation is compatible with t he failure of myoblast transfer in DMD and calls for further studies on the myofiber environment. Replicative aging, on the other hand, could possibly be treated by telomerase gene delivery.