Research study Manuscript for J Cell Mol Med
Marietta Barro 1 , Gilles Carnac 1 , Sébastien Flavier 1 , Jacques Mercier 1 2 , Yegor Vassetzky 3 , Dalila Laoudj-Chenivesse 1 *
Several papers support a role for oxidative stress as a pathological cause in FSHD [38 ,39 ]. Free radicals may be part of a cascade, and may provide a biochemical tool by which the pathological process can be inhibited. More studies on the action of radical oxygen species (ROS) and their sources may lead to a better understanding of the basis of FSHD. Indeed, the demonstration that alterations in specific oxidant species or in their cognate antioxidant systems are a triggering event that leads to abnormalities in FSHD satellite cells would then have pathological value and represent molecular targets for therapeutic and diagnostic development.
In conclusion, this study shows that myoblasts derived from both clinically unaffected and affected muscles of patients with FSHD are more susceptible to oxidative stress than control myoblasts. Moreover, although myoblasts from patients affected with FSHD fully differentiated into multinucleated myotubes, they fused to form either thin and branched myotubes with aligned nuclei or large myotubes with random nuclei distribution. These two phenotypes might be the consequence of differences in oxidative stress sensitivity. Alternatively additional signaling pathways may contribute either independently or cooperatively with oxidative stress in FSHD. It has been shown that overexpression of FRG1 in transgenic mice induces skeletal muscle atrophy [9 ]. By comparing genome-wide gene expression data from muscle biopsies of patients with FSHD to those of 11 other neuromuscular disorders, paired-like homeodomain transcription factor 1 (PITX1) was found specifically upregulated in patients with FSHD [14 ]. Since DUX4 protein can activate PITX 1 promoter, both DUX4 and PITX1 in FSHD muscles may play critical roles in the molecular mechanisms of the disease [14 ].
Therefore, these abnormalities could be responsible for the muscle weakness observed in patients with FSHD and provide an important marker for FSHD myoblasts.