muscle weakness and wasting. FSHD is caused by mis-expression of the transcription factor DUX4,
which is linked to oxidative stress, a condition especially detrimental to skeletal muscle with its high
metabolic activity and energy demands. Oxidative damage characterises FSHD and recent work
suggests metabolic dysfunction and perturbed hypoxia signalling as novel pathomechanisms.
However, redox biology of FSHD remains poorly understood, and integrating the complex dynamics
of DUX4-induced metabolic changes is lacking.
Here we pinpoint the kinetic involvement of altered mitochondrial ROS metabolism and
impaired mitochondrial function in aetiology of oxidative stress in FSHD. Transcriptomic analysis in
FSHD muscle biopsies reveals strong enrichment for pathways involved in mitochondrial complex I
assembly, nitrogen metabolism, oxidative stress response and hypoxia signalling. We found
elevated mitochondrial ROS (mitoROS) levels correlate with increases in steady-state mitochondrial
membrane potential in FSHD myogenic cells. DUX4 triggers mitochondrial membrane polarisation
prior to oxidative stress generation and apoptosis through mitoROS, and affects mitochondrial health
through lipid peroxidation. We identify complex I as the primary target for DUX4-induced
mitochondrial dysfunction, with strong correlation between complex I-linked respiration and cellular
oxygenation/hypoxia signalling activity in environmental hypoxia. Thus, FSHD myogenesis is
uniquely susceptible to hypoxia-induced oxidative stress as a consequence of metabolic misadaptation.
Importantly, mitochondria-targeted antioxidants rescue FSHD pathology more effectively
than conventional antioxidants, highlighting the central involvement of disturbed mitochondrial ROS
metabolism. This work provides a pathomechanistic model by which DUX4-induced changes in
oxidative metabolism impair muscle function in FSHD, amplified when metabolic adaptation to
varying O2 tension is required.
- Facioscapulohumeral muscular dystrophy, DUX4, reactive oxygen species, mitochondrial dysfunction, hypoxia, antioxidants