Immunohistochemical Characterization of FacioscapulohumeralMuscular Dystrophy Muscle Biopsies

Statland, Jeffrey; Odrzywolski, Karen; Shah, Bharati; Henderson, Don; Fricke, Alex F.; Maarel, S.M. van der; Tapscott, Stephen J.; Tawil, Rabi

doi:10.3233/jnd-150077

Cited by 29 publications

(30 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Notably, enrichment foci, within which many fibers were apparently devoid of any adjacent capillary. This result is intriguing, as histological analysis of FSHD muscle biopsies has similarly shown a reduction in capillary number (26).…”

Section: Resultsmentioning

confidence: 97%

Transcriptional and cytopathological hallmarks of FSHD in chronic DUX4-expressing mice

Bosnakovski

Shams

Yuan³

et al. 2020

Journal of Clinical Investigation

View full text Add to dashboard Cite

Section: Resultsmentioning

confidence: 97%

Transcriptional and cytopathological hallmarks of FSHD in chronic DUX4-expressing mice

Bosnakovski

Shams

Yuan³

et al. 2020

Journal of Clinical Investigation

View full text Add to dashboard Cite

“…The gene program that is transactivated by Dux4 is atypical of adult somatic cells (26) and has been shown to induce cell death when ectopically expressed in numerous cell lines (27,28). Furthermore, an increased percentage of apoptotic nuclei have been detected in FSHD muscle biopsies compared with healthy controls (29). Additional support for a causative role of Dux4 comes from the requirement of FSHD patients to have at least one copy of D4Z4 to develop the disease (30).…”

Section: Discussionmentioning

confidence: 99%

Protein kinase A activation inhibits DUX4 gene expression in myotubes from patients with facioscapulohumeral muscular dystrophy

Cruz¹,

Hupper²,

Wilson³

et al. 2018

Journal of Biological Chemistry

View full text Add to dashboard Cite

Facioscapulohumeral muscular dystrophy (FSHD) is among the most prevalent of the adult-onset muscular dystrophies. FSHD causes a loss of muscle mass and function, resulting in severe debilitation and reduction in quality of life. Currently, only the symptoms of FSHD can be treated, and such treatments have minimal benefit. The available options are not curative, and none of the treatments address the underlying cause of FSHD. The genetic, epigenetic, and molecular mechanisms triggering FSHD are now quite well-understood, and it has been shown that expression of the transcriptional regulator () is necessary for disease onset and is largely thought to be the causative factor in FSHD. Therefore, we sought to identify compounds suppressing expression in a phenotypic screen using FSHD patient-derived muscle cells, a zinc finger and SCAN domain-containing 4 (ZSCAN4)-based reporter gene assay for measuring DUX4 activity, and ∼3,000 small molecules. This effort identified molecules that reduce gene expression and hence DUX4 activity. Among those, β-adrenergic receptor agonists and phosphodiesterase inhibitors, both leading to increased cellular cAMP, effectively decreased expression by>75% in cells from individuals with FSHD. Of note, we found that cAMP production reduces expression through a protein kinase A-dependent mode of action in FSHD patient myotubes. These findings increase our understanding of how expression is regulated in FSHD and point to potential areas of therapeutic intervention.

show abstract

“…7, Table 2). As mentioned, DUX4-FL is a pro-apoptotic protein, its expression is highly toxic to muscle cells in culture [7,21,44,105], and an increased apoptosis rate compared is a feature of FSHD muscle [106]. To assess apoptosis in the three FSHD-like severity models, TUNEL assays were performed on TA muscles across the prior DUX4-FL induction time-courses in both the moderate and severe models as well as age-matched mild (No TMX) mice (Figs.…”

Section: Histological Analysis Of Fshd-like Model Micementioning

confidence: 95%

Transgenic mice expressing tunable levels of DUX4 develop characteristic facioscapulohumeral muscular dystrophy-like pathophysiology ranging in severity

et al. 2020

View full text Add to dashboard Cite

Background: All types of facioscapulohumeral muscular dystrophy (FSHD) are caused by the aberrant activation of the somatically silent DUX4 gene, the expression of which initiates a cascade of cellular events ultimately leading to FSHD pathophysiology. Typically, progressive skeletal muscle weakness becomes noticeable in the second or third decade of life, yet there are many individuals who are genetically FSHD but develop symptoms much later in life or remain relatively asymptomatic throughout their lives. Conversely, FSHD may clinically present prior to 5-10 years of age, ultimately manifesting as a severe early-onset form of the disease. These phenotypic differences are thought to be due to the timing and levels of DUX4 misexpression. Methods: FSHD is a dominant gain-of-function disease that is amenable to modeling by DUX4 overexpression. We have recently created 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 cumulative mild FSHD-like pathology that can be reproducibly induced to develop more severe pathology via tamoxifen induction of DUX4-fl in skeletal muscles. Results: We identified conditions to generate FSHD-like models exhibiting reproducibly mild, moderate, or severe DUX4-dependent pathophysiology and characterized progression of pathology. We assayed DUX4-fl mRNA and protein levels, fitness, strength, global gene expression, and histopathology, 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.

show abstract

Immunohistochemical Characterization of FacioscapulohumeralMuscular Dystrophy Muscle Biopsies

Cited by 29 publications

References 31 publications

Transcriptional and cytopathological hallmarks of FSHD in chronic DUX4-expressing mice

Transcriptional and cytopathological hallmarks of FSHD in chronic DUX4-expressing mice

Protein kinase A activation inhibits DUX4 gene expression in myotubes from patients with facioscapulohumeral muscular dystrophy

Transgenic mice expressing tunable levels of DUX4 develop characteristic facioscapulohumeral muscular dystrophy-like pathophysiology ranging in severity

Contact Info

Product

Resources

About