Influence of DUX4 Expression in Facioscapulohumeral Muscular Dystrophy and Possible Treatments

Abstract

Facioscapulohumeral muscular dystrophy (FSHD) represents the third most common form of muscular dystrophy and is characterized by muscle weakness and atrophy. FSHD is caused by the altered expression of the transcription factor double homeobox 4 (DUX4), which is involved in several significantly altered pathways required for myogenesis and muscle regeneration. While DUX4 is normally silenced in the majority of somatic tissues in healthy individuals, its epigenetic de-repression has been linked to FSHD, resulting in DUX4 aberrant expression and cytotoxicity in skeletal muscle cells. Understanding how DUX4 is regulated and functions could provide useful information not only to further understand FSHD pathogenesis, but also to develop therapeutic approaches for this disorder. Therefore, this review discusses the role of DUX4 in FSHD by examining the possible molecular mechanisms underlying the disease as well as novel pharmacological strategies targeting DUX4 aberrant expression.

Muscle Involvement in Amyotrophic Lateral Sclerosis: Understanding the Pathogenesis and Advancing Therapeutics

“…As previously stated, muscle regeneration primarily depends on the activation of SCs, which are highly resilient cells located beneath the basal membrane of differentiated muscle fibers and endowed with exceptional endurance [108] (Figure 3). In adults, these cells exist in a quiescent state, expressing the paired-box transcription factor Pax7, which is essential for the survival, maintenance, and myogenic potential of SCs [109,110]. Pax7-positive SCs are activated when muscle tissue is subjected to exercise-induced lesions or muscular pathologies, as shown in Figure 3.…”

“…Notably, a distinction betw SCs begin the process by proliferating and co-expressing the myogenic differentiation protein 1 (Myod1). These activated SCs then upregulate the expression of myogenin (Myog) and merge together to form myotubes, thereby regenerating the damaged muscle fiber within the muscle tissue [110][111][112]. The myogenic regulatory factors (MRFs) are capable of forming both homodimers and heterodimers.…”

“…The myogenic regulatory factors (MRFs) are capable of forming both homodimers and heterodimers. Through their basic helix-loop-helix (bHLH) domain, they bind to specific DNA sequences known as E-boxes (CANNTG), which are ubiquitously present in the promoter and enhancer regions of various genes, whether muscle-specific or non-muscle-specific [110]. In SOD1-G93A mice, mRNA levels of Pax7, Myf5, MyoD1, and Myog were all elevated during the advanced stages of the disease.…”

“…The fibronectin-integrin adhesion signal is required for myoblast differentiation to begin. Cell-to-cell recognition causes the cell cycle to be disrupted [110]. Myogenic stem cells expressing Pax7, referred to as SCs, are located in the region between the basal lamina and the sarcolemma of connected myofibers, playing a critical role in promoting adult muscle growth.…”

DNMT3B splicing dysregulation mediated by SMCHD1 loss contributes to DUX4 overexpression and FSHD pathogenesis

“…The suggested molecular basis of FSHD2 is hypomethylation of the D4Z4 macrosatellite array, caused by SMCHD1 loss of function. This results in overexpression of the DUX4 transcription factor in muscle cells leading to inhibition of myogenesis and induction of cell death ( 17 ). While FSHD2 is mediated by trans factors regulating D4Z4 methylation, loss of D4Z4 methylation in FSHD1 occurs in cis by genetic contraction of the D4Z4 macrosatellite repeats ( 18 ).…”