Uncovering the Embryonic Origins of Duchenne Muscular Dystrophy

Abstract

Duchenne muscular dystrophy (DMD) is a severe degenerative muscle disease caused by mutations in the DMD gene, which encodes dystrophin. Despite its initial description in the late 19th century by French neurologist Guillaume Duchenne de Boulogne, and identification of causal DMD genetic mutations in the 1980s, therapeutics remain challenging. The current standard of care is corticosteroid treatment, which delays the progression of muscle dysfunction but is associated with significant adverse effects. Emerging therapeutic approaches, including AAV-mediated gene transfer, CRISPR gene editing, and small molecule interventions, are under development but face considerable obstacles. Although DMD is viewed as a progressive muscle disease, muscle damage and abnormal molecular signatures are already evident during fetal myogenesis. This early onset of pathology suggests that the limited success of current therapies may partly be due to their administration after aberrant embryonic myogenesis has occurred in the absence of dystrophin. Consequently, identifying optimal therapeutic strategies and intervention windows for DMD may depend on a better understanding of the earliest DMD disease mechanisms. As newer techniques are applied, the field is gaining increasingly detailed insights into the early muscle developmental abnormalities in DMD. A comprehensive understanding of the initial events in DMD pathogenesis and progression will facilitate the generation and testing of effective therapeutic interventions.

Keywords: DMD therapeutic window; Duchenne muscular dystrophy; muscle development; myogenesis; prenatal development.

FIGURE 1

Roles for Dystrophin in normal muscle and in disease. A. Cartoon of normal muscle cell showing Dystrophin as part of the DAPC complex at the sarcolemma. B. Cartoon illustrating many of the cellular events that occur in muscle cells upon loss of Dystrophin. Some of these events, such as sarcomere disorganization, have been shown to occur early in DMD disease. Created in BioRender.

FIGURE 2

Timeline of key historical studies of early-stage DMD muscle disease. References and their major findings are provided (blue dots) along a timeline representing the publication years. Also shown (orange dot) is the reference that identified dystrophin as the primary DMD gene product disrupted in DMD.

FIGURE 3

hiPSC myogenic differentiation facilitates investigation of the earliest aspects of DMD disease. A. The top row provides a cartoon representation of stages of human myogenesis, starting from the blastocyst, followed by the paraxial mesoderm, somites, myogenic progenitors, and fetal myofibers. B. The middle row presents representative images of stages of hiPSC myogenic differentiation, obtained using a specific hiPSC myogenic differentiation protocol (Chal et al., 2016). The series depicts morphological transitions of hiPSCs through paraxial mesoderm progenitors, somite-like cells, myoblasts, and myotubes. Overlaid are the expression profiles of dystrophin isoforms Dp412e and Dp427m, with Dp412e showing high expression in somites and Dp427m increasing in myoblasts and myotubes. C. The bottom row depicts the chronological representation of the earliest dysregulation mechanisms observed in DMD cells during myogenesis: somite stage (mitochondrial dysfunction, cell junction dysregulation), myoblast stage (calcium homeostasis disruption, fibrotic signaling, myomiR dysregulation), and myotube stage (DAPC dissociation, neuromuscular junction fragmentation, sarcomere destabilization). Created in BioRender.