A recent paper by Michael Rudnicki’s group at Ottawa Hospital Research Institute and the University of Ottawa has provided new insights into what we view as the critical targets for therapies in Duchenne (Dystrophin expression in muscle stem cells regulates their polarity and asymmetric division. Dumont et al., Nature Medicine 21 (12): 1455-63, 2015). A lay summary of the work is available by clicking here.
Dystrophin, of course, is the primary target for many therapeutic strategies under development (exon skipping, stop codon read-through, gene therapy) because it’s the primary genetic defect in Duchenne and the mechanisms by which loss of dystrophin leads to muscle fiber degeneration are now well established.
Muscle precursor cells that exist to provide for the normal growth and repair of skeletal muscles, also have been an important target for developing therapies for Duchenne. These precursor cells are the target of myostatin inhibition drugs, designed to increase muscle regeneration and thereby repair muscle fibers and delay the progression of muscle weakness. Once these precursor cells form new muscle fibers, we know that those fibers also suffer from the absence of dystrophin. Thus, the long-term view for drugs targeted to muscle regeneration is to combine them with drugs that address the primary dystrophin mutations and, collectively, this combination therapy strategy will work better than either therapy alone.
What we didn’t know before this new paper from Dr. Rudnicki is that dystrophin plays a key role in the muscle precursor cells themselves. Dystrophin mutations mean that the satellite cells have defects in cell division that reduce their ability to divide and reduce their numbers available to repair dystrophic muscle by as much as 10-fold. Their paper describes the muscle wasting in Duchenne as “not only caused by myofiber fragility, but also is exacerbated by impaired regeneration owing to intrinsic satellite cell dysfunction.” These findings show us that therapies to address the dystrophin mutations in Duchenne then will have to be directed at both the existing muscle fibers, to repair the membrane defect, and at the satellite cells as well, so they proliferate sufficiently to impact muscle repair.