Facioscapulohumeral dystrophy (FSHD) is an incurable, hereditary disease primarily affecting skeletal
musculature. Clinically, FSHD is characterized by progressive muscle weakness and wasting. The
genetic cause of FSHD are mutations that lead to production of the protein DUX4, which is usually not
made in muscle. When DUX4 is erroneously present in muscle it triggers muscle degeneration. To date,
it is unclear precisely how DUX4 causes muscle disease. However, several studies suggest that FSHD
patients present with impaired muscle metabolism, suffering from a condition termed metabolic stress.
From the metabolic perspective, skeletal muscle is a highly active tissue and generating enough energy
to fulfill its many functions is of crucial importance for muscle health. Consequently, any chronic
perturbance of the complex bioenergetic mechanisms necessary for working muscles to meet their
metabolic demand causes functional muscle impairment over time. Mitochondria, small energy factories
inside cells, are essential to supply muscle with enough energy so it can perform work (for example
contraction). Any failure of mitochondria to function efficiently causes a state of energy crisis over time,
leading to subsequent muscle degeneration.
We have investigated the role of DUX4 in muscle cells from FSHD patients and found that DUX4
changes muscle cell metabolism so that large amounts of radicals, small but highly reactive and
potentially damaging molecules, are made. Radicals are an inevitable byproduct of metabolism, which
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. A complex interplay between
mitochondria, radicals and oxygen sensing enables muscle to adapt to metabolic and bioenergetic
fluctuations, and our preliminary analyses hint at a deregulation of mitochondrial function through
radical-induced impairment of oxygen sensing. Importantly, we found that antioxidants, substances
which can scavenge radicals and prevent them from causing damage in the cell, are effective in
restoring FSHD muscle function.
Antioxidant therapy has previously been tested in FSHD patients and a recent clinical trial found
moderate muscle functional improvement. However, therapeutic efficacy of antioxidants could likely be
improved if we better understand the mechanisms causing metabolic stress in FSHD. This project will
investigate the bioenergetic and metabolic differences between healthy and FSHD muscle models to
find novel therapeutic entry points. Specifically, we aim at deciphering the relationship between
mitochondria, radicals, oxygen sensing and muscle function. Many antioxidants are already available
as approved dietary supplements, so could be readily translated into clinics. 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.