Novel Therapeutics for FSHD: Mitochondria-targeted Antioxidants

Investigators: Philipp Heher PhD, Professor Peter Zammit

Category: Research - Translational

Facioscapulohumeral dystrophy (FSHD) is a disease characterized by progressive muscle weakness and wasting. The genetic cause of FSHD are mutations that lead to production of the toxic protein DUX4, which is usually not made in muscle, but when it is, DUX4 triggers muscle degeneration. To date, it is unclear precisely how DUX4 causes muscle disease. However, several studies suggest that FSHD patients have impaired metabolism, a condition termed metabolic stress. Since muscle is a highly metabolically active tissue, generating enough energy to fulfill its many functions is of crucial importance for muscle health. Thus, any chronic perturbance of the complex bioenergetic mechanisms necessary for working muscles to meet their metabolic demand, will lead to functional muscle impairment over time. Mitochondria, small energy factories inside cells, are essential to supply enough energy for muscle to work. Any failure of mitochondria to function efficiently causes a state of energy crisis, leading to subsequent muscle degeneration.

We have investigated the role of DUX4 in muscle cells from FSHD patients and found that DUX4 changes the way mitochondria work, so that they start to produce large amounts of radicals, small but highly reactive and potentially damaging molecules. Radicals are an inevitable by-product of metabolism, but have to be properly controlled and detoxified by the muscle cells to avoid damage to the cells. Increased radical levels in FSHD interfere with muscle metabolism and lead to muscle impairment, especially when they disturb how muscle utilizes Oxygen. Oxygen is an important metabolite in muscle, and local Oxygen availability can fluctuate greatly, for example when we exercise. In our preliminary experiments, we found that radicals change the way FSHD muscle cells sense and react to low Oxygen availability, thus interfering with the ability of muscle to adapt its metabolism accordingly. Antioxidants are substances that can decrease the levels of radicals in cells. Our preliminary studies show that antioxidants that specifically target radicals produced by mitochondria are very effective in improving FSHD muscle cell function. In this project, we will explore how mitochondria-targeted antioxidants act on specific radical-controlled cellular systems to find new therapies that can alleviate the symptoms of FSHD. Thus, our investigation of FSHD muscle metabolism will both broaden our understanding of how DUX4 causes FSHD, and identify new refined antioxidant-based therapeutics to complement and support more experimental therapies directed at reducing DUX4 levels.

Original grant extended to the optional second year, with an added $28,577.05 funds.

Related Material

Progress Update 1

Progress Update 2

See publication Interplay between mitochondrial reactive oxygen species, oxidative stress and hypoxic adaptation in facioscapulohumeral muscular dystrophy: Metabolic stress as potential therapeutic target