Our research seeks to expand our understanding of the mechanisms that lead to the development of skeletal muscle degeneration in FSHD, and to test multiple interventions that we propose could be used to prevent and/or limit disease progression. Combining our expertise in skeletal muscle biology and gene therapies, we have developed new animal-based and human-cell-based models of FSHD. Here, we will use these models to demonstrate that skeletal muscle from individuals with FSHD uses fats and carbohydrates differently to healthy individuals and that this is critical for the progression of disease pathology. We believe the strategies outlined in our proposal to manipulate these vital pathways are viable approaches that could rapidly be deployed to improve outcomes for individuals with FSHD.

PROGRESS REPORTS

Update September 2019

Grant 43: Testing novel therapeutic strategies to combat the metabolic disturbances underlying the muscle pathology of FSHD

In the initial months of the project, we have developed and validated 2 new human muscle models of DUX4 driven muscle degeneration. Using these model systems, we have identified that DUX4 activation leads to disturbed metabolic function that precedes cell death and functional impairment. We have since found that DUX4 alters the expression of a set of genes that influence metabolic function in both human muscle, and mouse limb muscles expressing the mouse Dux protein. These findings validate our recently developed mouse model system of Dux-induced pathology and show that impaired metabolism is an early event following activation of the DUX/DUX4 proteins across species.

More recently, we have determined that activation of DUX4 in human muscle impairs the health of mitochondria. We are assessing the impact of DUX4 activation on the capacity of human muscle fibres to use fats and carbohydrates to make energy. Our hope is that identification of the metabolic processes that are disturbed due to DUX4 mis-expression will reveal targets for intervention strategies, to test if protecting metabolic function can prevent DUX4-induced cell death and degeneration.