DUX4 promotes mitochondrial impairment in skeletal muscle

Facioscapulohumeral muscular dystrophy (FSHD) is characterised by a progressive degeneration and weakness of skeletal muscle fibers attributed to inappropriate expression of the transcription factor double homeobox 4 (DUX4). However, the cellular events that precede pathology in DUX4 expressing muscle fibers remain incompletely understood. Using recombinant AAV vectors to activate species-specific DUX transcription factors in murine and human skeletal muscle fibers, we developed models for examining DUX4-induced pathology. RNA-sequencing prior to the onset of muscle pathology reveals that perturbation of metabolic and mitochondrial function is an early event following activation of DUX transcription factors across species. A reduction in mitochondrial membrane potential was confirmed following DUX4 activation in human muscle fibers prior to reductions in force generating capacity. These studies present new models that can be used to delineate the changes in biological processes following acute DUX4 activation in mouse and human skeletal muscle fibers, for greater insight into the pathogenesis of FSHD, and support further investigation of mitochondrial function as a therapeutic target in FSHD. RNA-seq was performed to understand gene expression changes of engineered human micromuscles (organoids) expressing DUX4.