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DUX4 promotes mitochondrial impairment in skeletal muscle

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE138768 | GEO | 2021/12/31

REPOSITORIES: GEO

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Project description:All types of facioscapulohumeral muscular dystrophy (FSHD) are caused by the aberrant myogenic activation of the somatically silent DUX4 gene, which initiates a cascade of cellular events ultimately leading to FSHD pathophysiology. Therefore, FSHD is a dominant gain-of-function disease that is amenable to modeling by DUX4 overexpression. However, there is large variability in the patient population. Typically, progressive skeletal muscle weakness becomes noticeable in the second or third decade of life, yet there are many genetically FSHD individuals who develop symptoms much later in life or remain relatively asymptomatic throughout their lives. Conversely, in rare cases, FSHD may present clinically prior to 5-10 yrs of age, ultimately manifesting as a very severe early onset form of the disease. Thus, there is a need to control the timing and severity of pathology in FSHD-like models. Methods: We have recently described a line of conditional DUX4 transgenic mice, FLExDUX4, that develop a myopathy upon induction of human DUX4-fl expression in skeletal muscle. Here, we use the FLExDUX4 mouse crossed with the skeletal muscle-specific and tamoxifen inducible line ACTA1-MerCreMer to generate a highly versatile bi-transgenic mouse model with chronic, low-level DUX4-fl expression and mild pathology, that can be induced to develop more severe FSHD-like pathology in a dose-dependent response to tamoxifen. We identified conditions to reproducibly generate models exhibiting mild, moderate, or severe DUX4-dependent pathophysiology, and characterized their progression. Results: We assayed DUX4-fl mRNA and protein levels, fitness, strength, global gene expression, histopathology, and immune response, all of which are consistent with an FSHD-like myopathic phenotype. Importantly, we identified sex-specific and muscle-specific differences that should be considered when using these models for preclinical studies. Conclusions: The ACTA1-MCM;FLExDUX4 bi-transgenic mouse model expresses a chronic low level of DUX4-fl and has mild pathology and detectable muscle weakness. The onset and progression of moderate to severe pathology can be controlled via tamoxifen injection to provide consistent and readily screenable phenotypes for assessing therapies targeting DUX4-fl mRNA and protein. Thus, these FSHD-like mouse models can be used to study a range of DUX4-fl expression and pathology dependent upon investigator need, through controlled mosaic expression of DUX4.

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DUX4 promotes mitochondrial impairment in skeletal muscle

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