Facioscapulohumeral dystrophy (FSHD) is the third most common form of inherited muscle disease, characterized by the development of progressive weakness in the face, proximal arm, and scapular stabilizer muscles. In more severe cases, the pelvic girdle may also be involved leading to confinement in a wheelchair. FSHD is inherited as an autosomal dominant trait. The mutation responsible for >95% of FSHD cases is known-a deletion of integral copies of a tandemly repeated 3.3kb element (D4Z4) on chromosome 4q35. However, the molecular and biochemical mechanisms of FSHD remain elusive. No gene has been identified within the D4Z4 repeats themselves, and the consensus is that the deletion likely affects the expression of genes proximal to the 3.3kb repeat array. Accordingly, multiple primary and secondary pathways are envisaged to be involved in the pathogenesis of FSHD. We have begun cell biology studies of FSHD myoblasts which display an aberrant phenotype in both the undifferentiated and differentiated states. As a result of these studies, we have determined that FSHD myoblasts are more susceptible to oxidative stress compared to myoblasts from control, and other muscle disease. FSHD myoblasts express p21, a cyclin kinase inhibitor and important intermediate in pathways related to intracellular stress, to a greater extent than controls. Their morphology and replicative capacity are reminiscent of senescence in control myoblasts. These are the first biochemical clues about cellular processes which are altered in FSHD. We now aim to: (1) Characterize the redox state of FSHD myoblasts and determine whether they respond to antioxidant agents. (2) Determine the relationship between p21 expression and two factors known to upregulate it-p53 and MyoD. (3) Establish whether FSHD myoblasts have undergone replicative senescence, by quantitation of telomere size and change of telomere size with replication. The overall aim of these experiments is a better understanding of the pathophysiology of FSHD. Moreover, the detailed characterization of the aberrant intracellular processes in FSHD myoblasts will be an important step for the development of intervention strategies based on muscle stem cell or myoblast transfer protocols, where maintenance of a healthy satellite cell population will be crucial to longterm therapeutic efficacy.
